COMBINATION AND THE USE THEREOF

FIELD

[0001] Provided herein are methods of treating cancer in a mammal and combinations useful in such treatment. In particular, the method relates to a novel combination comprising a B-Raf inhibitor, particularly 5-(((lR,laS,6bR)-l-(6-(trifluoromethyl)-lH-benzo(d)imidazol- 2-yl)-la,6b- dihydro-lH-cyclopropa(b)benzofuran-5-yl)oxy)-3,4-dihydro-l,8 -naphthyridin-2(lH)-one or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, and a MEK inhibitor N-((R)-2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro- 4-iodo-phenylamino)-benzamide, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, pharmaceutical compositions comprising the same and compositions in the treatment of conditions in which the inhibition of B-Raf and/or MEK is beneficial, e.g., cancer.

BACKGROUND

[0002] Effective treatment of hyperproliferative disorders including cancer is a continuing goal in the oncology field. Generally, cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death and is characterized by the proliferation of malignant cells which have the potential for unlimited growth, local expansion and systemic metastasis. Deregulation of normal processes include abnormalities in signal transduction pathways and response to factors which differ from those found in normal cells.

[0003] An important large family of enzymes is the protein kinase enzyme family.

[0004] Currently, there are about 500 different known protein kinases. Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the y-phosphate of the ATP-Mg2+ complex to said amino acid side chain. These enzymes control the majority of the signaling processes inside cells, thereby governing cell function, growth, differentiation and destruction (apoptosis) through reversible phosphorylation of the hydroxyl groups of serine, threonine and tyrosine residues in proteins. Studies have shown that protein kinases are key regulators of many cell functions, including signal transduction, transcriptional regulation, cell motility, and cell division. Several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in oncogenesis. These processes are highly regulated, often by complex intermeshed pathways where each kinase is regulated by one or more kinases. Consequently, aberrant or inappropriate protein kinase activity can contribute to the rise of disease states associated with such aberrant kinase activity including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems. Due to their physiological relevance, variety and ubiquitousness, protein kinases have become one of the most important and widely studied family of enzymes in biochemical and medical research.

[0005] The protein kinase family of enzymes is typically classified into two main subfamilies: Protein Tyrosine Kinases and Protein Serine/Threonine Kinases, based on the amino acid residue they phosphorylate. The protein serine/threonine kinases (PSTK), includes cyclic AMP- and cyclic GMP-dependent protein kinases, calcium and phospholipid dependent protein kinase, calcium- and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins. Aberrant protein serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases.

[0006] Accordingly, serine/threonine kinases and the signal transduction pathways which they are part of are important targets for drug design. The tyrosine kinases phosphorylate tyrosine residues. Tyrosine kinases play an equally important role in cell regulation. These kinases include several receptors for molecules such as growth factors and hormones, including epidermal growth factor receptor, insulin receptor, platelet derived growth factor receptor and others. Studies have indicated that many tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Much work is also in progress to identify modulators of tyrosine kinases as well.

[0007] Receptor tyrosine kinases (RTKs) catalyze phosphorylation of certain tyrosyl amino acid residues in various proteins, including themselves, which govern cell growth, proliferation and differentiation.

[0008] Downstream of the several RTKs lie several signaling pathways, among them is the Ras-Raf-MEK-ERK kinase pathway. It is currently understood that activation of Ras GTPase proteins in response to growth factors, hormones, cytokines, etc. stimulates phosphorylation and activation of Raf kinases. These kinases then phosphorylate and activate the intracellular protein kinases MEK1 and MEK2, which in turn phosphorylate and activate other protein kinases, ERK1 and 2. This signaling pathway, also known as the mitogen-activated protein kinase (MAPK) pathway or cytoplasmic cascade, mediates cellular responses to growth signals. The ultimate function of this is to link receptor activity at the cell membrane with modification of cytoplasmic or nuclear targets that govern cell proliferation, differentiation, and survival.

[0009] The constitutive activation of this pathway is sufficient to induce cellular transformation. Disregulated activation of the MAP kinase pathway due to aberrant receptor tyrosine kinase activation, Ras mutations or Raf mutations has frequently been found in human cancers, and represents a major factor determining abnormal growth control. In human malignances, Ras mutations are common, having been identified in about 30% of cancers. The Ras family of GTPase proteins (proteins which convert guanosine triphosphate to guanosine diphosphate) relay signals from activated growth factor receptors to downstream intracellular partners. Prominent among the targets recruited by active membrane-bound Ras are the Raf family of serine/threonine protein kinases. The Raf family is composed of three related kinases (A-, B- and C-Raf) that act as downstream effectors of Ras. Ras-medicated Raf activation in turn triggers activation of MEK1 and MEK2 (MAP / ERK kinases 1 and 2) which in turn phosphorylate ERK1 and ERK2 (extracellular signal-regulated kinases 1 and 2) on th tyrosine- 185 and threonine- 183. Activated ERK1 and ERK2 translocate and accumulate in the nucleus, where they can phosphorylate a variety of substrates, including transcription factors that control cellular growth and survival. Given the importance of the Ras /Raf / MEK / ERK pathway in the development of human cancers, the kinase components of the signaling cascade are merging as potentially important targets for the modulation of disease progression in cancer and other proliferative diseases.

[0010] MEK1 and MEK2 are members of a larger family of dual-specificity kinases (MEK1 -7) that phosphorylate threonine and tyrosine residues of various MAP kinases. MEK1 and MEK2 are encoded by distinct genes, but they share high homology (80%) both within the C- terminal catalytic kinase domains and the most of the /V -terminal regulatory region. Oncogenesis forms of MEK1 and MEK2 have not been found in human cancers, but constitutive activation of MEK has been shown to result in cellular transformation. In addition to Raf, MEK can also be activated by other oncogene as well. So far, the only known substrates of MEK1 and MEK2 are ERK1 and ERK2. This unusual substrate specificity in addition to the unique ability to phosphorylate both tyrosine and threonine residues places MEK1 and MEK2 at a critical point in the signal transduction cascade which allows it to integrate many extracellular signals into the MAPK pathway.

[0011] Accordingly, it has been recognized that an inhibitor of a protein of the MAPK kinase pathway (e.g., MEK) should be of value both as an anti -proliferative, pro-apoptotic and anti- invasive agent for use in the containment and/or treatment of proliferative or invasive disease. [0012] Moreover, it is also known that a compound having MEK inhibitory activity effectively induces inhibition of ERK1/2 activity and suppression of cell proliferation (The Journal of Biological Chemistry, vol. 276, No. 4 pp. 2686-2692, 2001), and the compound is expected to show effects on diseases caused by undesirable cell proliferation, such as tumor genesis and/or cancer.

[0013] Mutations in various Ras GTPases and the B-Raf kinase have been identified that can lead to sustained and constitutive activation of the MAPK pathway, ultimately resulting in increased cell division and survival. As a consequence of this, these mutations have been strongly linked with the establishment, development, and progression of a wide range of human cancers. The biological role of the Raf kinases, and specifically that of B-Raf, in signal transduction is described in Davies, H ., et al., Nature (2002) 9: 1 -6; Garnett, MJ. & Marais, R., Cancer Cell (2004) 6:313-319; Zebisch, A. & Troppmair, J., Cell. Mol. Life Sei. (2006) 63:1314- 1330; Midgley, R.S. & Kerr, D.J., Crit. Rev. Onc/Hematol. (2002) 44: 109-120; Smith, R.A., et al., Curr. Top. Med. Chem. (2006) 6:1071 -1089; and Downward, J., Nat. Rev. Cancer (2003) 3: 1 1-22.

[0014] Naturally occurring mutations of the B-Raf kinase that activate MAPK pathway signaling have been found in a large percentage of human melanomas (Davies (2002) supra) and thyroid cancers (Cohen et al J. Nat. Cancer Inst. (2003) 95(8) 625-627 and Kimura et al Cancer Res. (2003) 63(7) 1454-1457), as well as at lower, but still significant, frequencies in the following: Barret's adenocarcinoma (Garnett et al., Cancer Cell (2004) 6 313-319 and Sommerer et al Oncogene (2004) 23(2) 554-558), billiary tract carcinomas (Zebisch et al., Cell. Mol. Life Sci. (2006) 63 1314-1330), breast cancer (Davies (2002) supra), cervical cancer (Moreno-Bueno et al Clin. Cancer Res. (2006) 12(12) 3865-3866), cholangiocarcinoma (Tannapfel et al Gut (2003) 52(5) 706-712), central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas and ependymomas (Knobbe et al Acta Neuropathol. (Bed.) (2004) 108(6) 467-470, Davies (2002) supra, and Garnett et al., Cancer Cell (2004) supra) and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system), colorectal cancer, including large intestinal colon carcinoma (Yuen et al Cancer Res. (2002) 62(22) 6451 -6455, Davies (2002) supra and Zebisch et al., Cell. Mol. Life Sci. (2006), gastric cancer (Lee et al Oncogene (2003) 22(44) 6942- 6945), carcinoma of the head and neck including squamous cell carcinoma of the head and neck (Cohen et al J. Nat. Cancer Inst. (2003) 95(8) 625-627 and Weber et al Oncogene (2003) 22(30) 4757- 4759), hematologic cancers including leukemias (Garnett et al., Cancer Cell (2004) supra, particularly acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004) supra and Gustafsson et al Leukemia (2005) 19(2) 310-312), acute myelogenous leukemia (AML) (Lee et al Leukemia (2004) 18(1) 170- 172, and Christiansen et al Leukemia (2005) 19(12) 2232-2240), myelodysplasia syndromes (Christiansen et al Leukemia (2005) supra) and chronic myelogenous leukemia (Mizuchi et al Biochem. Biophys. Res. Commun. (2005) 326(3) 645-651); Hodgkin's lymphoma (Figi et al Arch. Dermatol. (2007) 143(4) 495-499), non-Hodgkin's lymphoma (Lee et al Br. J. Cancer (2003) 89(10) 1958-1960), megakaryoblastic leukemia (Eychene et al Oncogene (1995) 10(6) 1 159-1 165) and multiple myeloma (Ng et al Br. J. Haematol. (2003) 123(4) 637- 645), hepatocellular carcinoma (Garnett et al., Cancer Cell (2004), lung cancer (Brose et al Cancer Res. (2002) 62(23) 6997-7000, Cohen et al J. Nat. Cancer Inst. (2003) supra and Davies (2002) supra), including small cell lung cancer (Pardo et al EMBO J. (2006) 25(13) 3078-3088) and non-small cell lung cancer (Davies (2002) supra), ovarian cancer (Russell & McCluggage J. Pathol. (2004) 203(2) 617-619 and Davies (2002) supr), endometrial cancer (Garnett et al., Cancer Cell (2004) supra, and Moreno-Bueno et al Clin. Cancer Res. (2006) supra), pancreatic cancer (Ishimura et al Cancer Lett. (2003) 199(2) 169-173), pituitary adenoma (De Martino et al J. Endocrinol. Invest. (2007) 30(1) RC1 -3), prostate cancer (Cho et al Int. J. Cancer (2006) 1 19(8) 1858-1862), renal cancer (Nagy et al Int. J. Cancer (2003) 106(6) 980- 981), sarcoma (Davies (2002) supra), and skin cancers (Rodriguez-Viciana et al., Science (2006) 31 1 (5765) 1287-1290 and Davies (2002) supra). Overexpression of c- Raf has been linked to AML (Zebisch et al., Cancer Res. (2006) 66(7) 3401 -3408, and Zebisch (Cell. Mol. Life Sci. (2006)) and erythroleukemia (Zebisch et la., Cell. Mol. Life Sci. (2006).

[0015] By virtue of the role played by the Raf family kinases in these cancers and exploratory studies with a range of preclinical and therapeutic agents, including one selectively targeted to inhibition of B-Raf kinase activity (King A. I , et al ., (2006) Cancer Res 66: 1 1 100- 1 1 105), it is generally accepted that inhibitors of one or more Raf family kinases is useful for the treatment of such cancers or other condition associated with Raf kinase.

[0016] Mutation of B-Raf has also been implicated in other conditions, including cardio- facio cutaneous syndrome (Rodriguez-Viciana et al Science (2006) 31 1 (5765) 1287- 1290) and polycystic kidney disease (Nagao et al Kidney Int. (2003) 63(2) 427-437).

[0017] Though there have been many recent advances in the treatment of cancer with compounds such as the MEK and B-Raf inhibitors, there remains a need for more effective and/or enhanced treatment of an individual suffering the effects of cancer, in particular, in cancers with MAPK pathway aberrations.

[0018] Citation or identification of any reference in this section is not to be construed as an admission that the reference is prior art to the present application.

SUMMARY

[0019] Provided here is a method of treating a cancer in a subject in need thereof, comprising administering to said subject a combination or a combination product comprising:

(i) Compound A having the name of 5-(((lR,laS,6bR)-l-(6-(trifluoromethyl)-lH- benzo(d)imidazol-2-yl)-la,6b-dihydro-lH-cyclopropa(b)benzofu ran-5-yl)oxy)-3,4-dihydro-l,8- naphthyridin-2(lH)-one, or the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof; and

(ii) Compound B having the name of N-((R)-2,3-dihydroxy-propoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, or the structure of formula (II): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.

[0020] In one embodiment, the method comprises administering a lead-in dose of Compound A in a lead-in dosing period and administering a maintenance dose of Compound A in a maintenance dosing regimen, wherein the lead-in dose of Compound A during the lead-in dosing period is lower than the maintenance dose of Compound A administered during the maintenance dosing regimen. Tn one embodiment the method comprises administering Compound A in an intermittent dosing regimen; the intermittent dosing regimen comprises at least one treatment cycle; each treatment cycle comprises at least one break day; and Compound A is not administered on the break day.

[0021] In one embodiment, the method of treating begins with administering Compound A and Compound B with a lead-in dosing period or an intermittent dosing regimen.

[0022] In one embodiment, the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, thyroid tumor, and their complications; preferably melanoma, ovarian cancer, and non-small cell lung cancer. In one embodiment, the cancer is melanoma. In one embodiment, the melanoma is cutaneous melanoma. In one embodiment, the melanoma is metastatic melanoma. In one embodiment, cancer is ovarian cancer. In one embodiment, the cancer is non-small cell lung cancer.

[0023] In one embodiment, the cancer is characterized by a mutation in a gene selected from the group consisting of RAS, NRAS, KRAS, RAF, BRAF, CRAF, A RAF, and their combination thereof; preferably RAS, NRAS, KRAS, RAF, BRAF, and their combination thereof; more preferably NRAS, KRAS, BRAF, and their combination thereof. In one embodiment, the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS G13R, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof; preferably NRAS Q61R, NRAS their combination thereof; more preferably NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and their combination thereof. In one embodiment, the cancer is characterized by other MAPK pathway genomic aberration. In one embodiment, the other MAPK pathway genomic aberration is RASA1 splice isoform. In one embodiment, the other MAPK pathway genomic aberration is RASA 1 chr5:86,587,807.

[0024] In one embodiment, the treating begins with a lead-in dosing period; the lead-in dosing period comprises 2 to 48 days; and the dose of Compound A in the lead-in dosing period is lower than the dose of Compound A administered after the lead-in dosing period.

[0025] In one embodiment, the method comprises administering a lead-in dose of Compound A in a lead-in dosing period; or the method comprises administering a lead-in dose of Compound A in a lead-in dosing period and administering a maintenance dose of Compound A in a maintenance dosing regimen; and the lead-in dose of Compound A during the lead-in dosing period is lower than the maintenance dose of Compound A administered during the maintenance dosing regimen.

|0026[ In one embodiment, the lead-in dosing period further comprises 1 to 14 break day(s); Compound A is not administered in the break day(s); and the break days are consecutive days or non-consecutive days.

[0027] In one embodiment, the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the lead-in dose of Compound A is administered in the first 5 days of each cycle; and Compound A or Compound B is not administered in the last 2 days of each cycle. In one embodiment, the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A is administered in the first 10 days of each cycle; and Compound A or Compound B is not administered in the last 2 days of each cycle.

[0028] In one embodiment, Compound A is administered at about 5 mg per day or about 10 mg per day during the lead-in dosing period. In one embodiment, Compound A and Compound B is administered, together or separately, once per day during the lead-in dosing period. In one embodiment, Compound A is administered once per day and Compound B is administered twice per day during the lead-in dosing period. [0029] In one embodiment, the treating comprises an intermittent dosing regimen; the intermittent dosing regimen comprises 2 to 28 days; the intermittent dosing regimen further comprises 1 to 14 break days; Compound A is not administered in the break day(s); the break day(s) are consecutive days or non-consecutive days.

[0030] In one embodiment, the intermittent dosing regimen comprises 1 to 4 cycles, wherein every cycle consists of 7 days; Compound A is administered in the first 5 days of each cycle; and Compound A or Compound B is not administered in the last 2 days of each cycle.

[0031] In one embodiment, Compound A is administered at about 15 mg per day or about 20 mg per day during the intermittent dosing regimen. In one embodiment, Compound A and Compound B is administered, together or separately, once per day during the intermittent dosing regimen. In one embodiment, Compound A is administered once per day and Compound B is administered twice per day during the intermittent dosing regimen.

[0032] In one embodiment, Compound A is administered at about 10 mg QD during the lead-in dosing period; and (i) Compound B is administered at about 3 mg QD during the lead-in dosing period; or (ii) Compound B is administered at about 2 mg BID, 3 mg BID, or about 4 mg BID during the lead-in dosing period. In one embodiment, Compound A is administered at about 15 mg QD or about 20 mg QD during the intermittent dosing regimen; and (i) Compound B is administered at about 3 mg QD or 4 mg QD during the intermittent dosing regimen; or (ii) Compound B is administered at about 2 mg BID, 3 mg BID, or about 4 mg BID during the intermittent dosing regimen. In one embodiment, Compound A is administered at about 15 mg QD or about 20 mg QD during the maintenance dosing regimen; and (i) Compound B is administered at about 2 mg QD, about 3 mg QD or 4 mg QD during the maintenance dosing regimen; or (ii) Compound B is administered at about 2 mg BID or 3 mg BID during the maintenance dosing regimen.

[ 0033 [ In one embodiment, Compound A and Compound B, each independently, is administered one to three times a day. In one embodiment, Compound A is administered once a day. In one embodiment, Compound A is administered at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg per day. In one embodiment, Compound B is administered once a day. In one embodiment, Compound B is administered twice a day. Tn one embodiment, Compound B is administered at about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 6 mg, or about 8 mg per day.

[0034] In one embodiment, Compound A is administered at about 15 mg per day or about 20 mg per day after the lead-in dosing period or the intermittent dosing regimen. In one embodiment, Compound A and Compound B is administered, together or separately, once per day. In one embodiment, Compound A is administered once per day and Compound B is administered twice per day.

[0035] In one embodiment, the method as described herein provides a plasma Compound A AUC24h between about 16,686 ng*h/ml and about 25,030 ng*h/ml in the subject. In one embodiment, the method as described herein provides a plasma Compound A AUC2411 between about 22,052 ng*h/ml and about 33,078 ng*h/ml in the subject. In one embodiment, the method as described herein provides a plasma Compound A AUC2411 between about 38,358 ng*h/ml and about 57,536 ng*h/ml in the subject. In one embodiment, the method as described herein provides a plasma Compound A AUC2411 between about 41,534 ng*h/ml and about 62,302 ng*h/ml in the subject.

[0036] In one embodiment, the subject achieves a stable disease, a partial response, or a complete response. In one embodiment, the subject does not experience a progressive disease. [0037] Also provided here is a combination or a combination product comprising: (i) Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof; and (ii) Compound B or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof. In one embodiment, the combination comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg of Compound A. In one embodiment, the combination comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 6 mg, or about 8 mg of Compound B.

[0038] Also provided here is a kit comprising the combination as disclosed herein. In one embodiment, the kit further comprises a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF DRAWINGS

[0039] Fig. 1 describes the best change (%) from baseline in sum of diameters per RECIST 1.1 (efficacy in total 37 evaluable patients). [0040] Fig. 2 describes the study schema of dose-escalation and dose-finding component to establish the MTD and/or RP2D and to evaluate the PK of Compound A in combination with Compound B.

[0041] Fig. 3 describes the best change (%) from baseline in sum of diameters per RECIST

1.1 LGSOC patients.

[0042] Fig. 4 describes the mean plasma concentrations over time by doselevel and cycle presented graphically on a logarithmic scale.

[0043] Fig. 5 describes the Dose Escalation/Dose Finding Study Design/Schema.

Lead-in periods of 7 or 21 days are considered based on emergent data; DLT period adjusted as appropriate to include lead-in days. BID, twice a day; MTD, maximum tolerated dose; PK, pharmacokinetic(s); QD, once a day; RP2D, recommended phase 2 dose.

DETAILED DESCRIPTION

DEFINITIONS

[0044] As used herein, “Compound A” refers to the compound having the name of 5-

(((1R, 1 aS,6bR)- 1 -(6-(trifluorom ethyl)- lH-benzo(d)imidazol-2-yl)-l a,6b-dihydro- 1H- cyclopropa(b)benzofuran-5-yl)oxy)-3,4-dihydro-l,8-naphthyrid in-2(lH)-one, or the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof. Compound A is disclosed and claimed, along with pharmaceutically acceptable salts thereof, and also as solvates thereof, as being useful as an inhibitor of BRAF activity, particularly in treatment of cancer, in WO2013097224, the entire disclosure of which is incorporated herein by reference. Compound A is compound 2.2b in WO2013097224.

Compound A can be prepared as described in WO2013097224. The international nonproprietary name of Compound A is lifirafenib. In one embodiment, Compound A is a hydrate. Unless specifically stated, “Compound A” as used herein refers to Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof. [0045] As used herein, “Compound B” refers to the compound having the name ofN-((R)- 2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-pheny lamino)-benzamide, or the structure of formula (II): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof Compound B is disclosed and claimed, along with pharmaceutically acceptable salts thereof, and also as solvates thereof, as being useful as an inhibitor of MEK activity, particularly in treatment of cancer, in W02002/06213, the entire disclosure of which is incorporated herein by reference. Compound B is compound 49A in W02002/06213. Compound B can be prepared as described in W02002/06213. The international nonproprietary name of Compound B is mirdametinib. Unless specifically stated, “Compound B” as used herein refers to Compound B or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.

[0046] As used herein, the term “combination” refers to more than one therapeutically active agents, such as Compound A and Compound B, used in coordinated fashion but does not necessary mean that the more than one therapeutical active agents are in the same composition nor administered at the exact same time. The term “combination” as used herein as it relates to methods for treatment, one therapeutically active agent and the other therapeutically active agent can be administered simultaneously, consecutively, or sequentially. In some embodiments of a combination use, more than one therapeutically active agents can have separate dosing regimens, such as, one therapeutically active agent can be administered once a day while the other therapeutically active agent can be administered multiple times a day, or the different therapeutic agents can be dosed on different days.

[0047] As used herein the term “neoplasm” refers to an abnormal growth of cells or tissue and is understood to include benign, i.e., non-cancerous growths, and malignant, i.e., cancerous growths. The term “neoplastic” means of or related to a neoplasm. [0048] As used herein the term “agent” is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. Accordingly, the term “anti -neoplastic agent” is understood to mean a substance producing an anti -neoplastic effect in a tissue, system, animal, mammal, human, or other subject. It is also to be understood that an “agent” may be a single compound or a combination or composition of two or more compounds.

[0049] By the term “treating” and derivatives thereof as used herein, is meant therapeutic therapy. In reference to a particular condition, treating means: (1) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition. [0050] As used herein, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof. The skilled artisan would appreciate that “prevention” is not an absolute term. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.

[0051] As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0052] Compounds A and/or B may contain one or more chiral atoms, or may otherwise be capable of existing as enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or en anti omeri cal ly enriched mixtures. Also, it is understood that all tautomers and mixtures of tautomers are included within the scope of Compound A and Compound B.

[0053] As used herein, the term “solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, compounds of formula (I) or (II) or a salt thereof and a solvent. Also, it is understood that compounds A and B may be presented, separately or both, as solvates. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, dimethyl sulforide, ethanol and acetic acid. In one embodiment, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. In another embodiment, the solvent used is water (i.e., a hydrate).

[0054] Compounds A and B may have the ability to crystallize in more than one form, a characteristic, which is known polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of Compounds A and B. Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point. [0055] As used herein, and in the specification and the accompanying claims, the indefinite articles “a” and “an” and the definite article “the” include plural as well as single referents, unless the context clearly indicates otherwise.

[0056] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses, amounts, or weight percents of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 30%, within 20%, within 15%, within 10%, or within 5%, of the specified dose, amount, or weight percent.

[0057] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with a numeric value or range of values which is provided to characterize a particular solid form, e g., a specific temperature or temperature range, such as, for example, that describes a melting, dehydration, desolvation, or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in analysis by, for example, IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the solid form. Techniques for characterizing crystal forms and amorphous solids include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), singlecrystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In certain embodiments, the terms “about” and “approximately,” when used in this context, indicate that the numeric value or range of values may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. For example, in some embodiments, the value of an XRPD peak position may vary by up to ±0.2° 20 (or ±0.2 degrees 20) while still describing the particular XRPD peak.

[0058] As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compounds provided herein include, but are not limited to those well-known in the art, see for example, Remington ’s Pharmaceutical Sciences, 18 ^th eds., Mack Publishing, Easton PA (1990) ox Remington: The Science and Practice of Pharmacy, 19 ^th eds., Mack Publishing, Easton PA (1995).

[0059] As used herein and unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0060] The use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 332125 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN, 1972).

[0061] It should also be noted the compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of the E and Z isomers.

[0062] “Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other: [0063] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of the compounds provided herein are within the scope of the present invention.

[0064] It should also be noted the compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( ³ H), iodine-125 ( ¹²⁵ I), sulfur-35 ( ³⁵ S), or carbon-14 ( ¹⁴ C), or may be isotopically enriched, such as with deuterium ( ² H), carbon-13 ( ¹³ C), or nitrogen-15 ( ¹³ N). As used herein, an “isotopologue” is an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. ’’Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the compounds, for example, the isotopologues are deuterium, carbon-13, or nitrogen-15 enriched compounds.

[0065] “Treating” as used herein, means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In some embodiments, “treating” means an alleviation, in whole or in part, of a disorder, disease or condition, or a slowing, or halting of further progression or worsening of those symptoms.

[0066] “Preventing” as used herein, means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition. [0067] The term “effective amount” in connection with a compound means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein.

[0068] The term “subject” includes an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human.

[0069] While it is possible that, for use in therapy, Compounds A and B, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include a Compound A and/or a Compound B, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds A and B are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical composition including admixing a Compound A and/or Compound B, with one or more pharmaceutically acceptable carriers, diluents or excipients. Such elements of the pharmaceutical compositions utilized may be presented in separate pharmaceutical combinations or formulated together in one pharmaceutical composition. Accordingly, the invention further provides a combination of pharmaceutical compositions one of which includes Compound A and one or more pharmaceutically acceptable carriers, diluents, or excipients and a pharmaceutical composition containing Compound B and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0070] Compound A and Compound B described above may be utilized in any of the compositions described above.

[0071] Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. As is known to those skilled in the art, the amount of active ingredient per dose depends on the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.

[0072] Compounds A and B may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It is appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that the Compounds A and B may be compounded together in a pharmaceutical composition.

[0073] Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[0074] Unless otherwise defined, in all dosing protocols described herein, the regimen of compounds administered does not have to commence with the start of treatment and terminate with the end of treatment, it is only required that the number of consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or the indicated dosing protocol - including the amount of compound administered, occur at some point during the course of treatment.

[0075] Compounds A and B may be employed in combination in accordance with the disclosure by administration simultaneously in a unitary pharmaceutical composition including both compounds. Alternatively, the combination may be administered separately in separate pharmaceutical compositions, each including one of the compounds A and B in a sequential manner wherein, for example, Compound A or Compound B is administered first and the other second. Such sequential administration may be close in time (e.g., simultaneously) or remote in time.

[0076] Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g., one compound may be administered topically and the other compound may be administered orally. Suitably, both compounds are administered orally.

[0077] In one embodiment, one or more doses of Compound A are administered simultaneously or separately with one or more doses of Compound B. [0078] Unless otherwise defined, in all dosing protocols described herein, the regimen of compounds administered does not have to commence with the start of treatment and terminate with the end of treatment, it is only required that the number of consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or the indicated dosing protocol - including the amount of compound administered, occur at some point during the course of treatment.

[0079] In one embodiment, multiple doses of Compound A are administered simultaneously or separately with multiple doses of Compound B.

[0080] In one embodiment, multiple doses of Compound A are administered simultaneously or separately with one dose of Compound B.

[0081] In one embodiment, one dose of Compound A is administered simultaneously or separately with multiple doses of Compound B.

[0082] In one embodiment one dose of Compound A is administered simultaneously or separately with one dose of Compound B.

[0083] In all the above embodiments Compound A may be administered first or Compound B may be administered first.

[0084] The combinations may be presented as a combination kit. By the term “kit” “or kit of parts” as used herein is meant the pharmaceutical composition or compositions that are used to administer Compound A and Compound B according to the disclosure. When both compounds are administered simultaneously, the kit can contain Compound A and Compound B in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. When Compounds A and B are not administered simultaneously, the kit contains Compound A and Compound B in separate pharmaceutical compositions either in a single package or Compound A and Compound B in separate pharmaceutical compositions in separate packages.

[0085] In one aspect there is provided a kit of parts comprising components: Compound A in association with a pharmaceutically acceptable excipients, diluents or carrier; and Compound B in association with a pharmaceutically acceptable excipients, diluents or carrier.

[0086] In one embodiment, the kit of parts comprises the following components: Compound A in association with a pharmaceutically acceptable excipients, diluents or carrier; and Compound B in association with a pharmaceutically acceptable excipients, diluents or carrier, wherein the components are provided in a form which is suitable for sequential, separate and/or simultaneous administration.

[0087] In one embodiment, the kit of parts comprises: a first container comprising Compound A in association with a pharmaceutically acceptable excipient, diluent or carrier; and a second container comprising Compound B in association with a pharmaceutically acceptable excipient, diluent or carrier, and a container means for containing said first and second containers.

[0088] The kit can also be provided with instruction, such as dosage and administration instructions. Such dosage and administration instructions can be of the kind that are provided to a doctor, for example by a drug product label, or they can be of the kind that are provided by a doctor, such as instructions to a patient.

[0089] The term “lead-in dose(s)” as used herein is understood to mean one or more doses of Compound A or Compound B having a dosage lower than the maintenance dose administered to the subject to, for example, lower the increase of the plasma or blood concentration level of the drug. In some embodiments, the “lead-in dose” can increase the plasma or blood concentration of the drug to a therapeutically effective level. In some embodiments, the “lead-in dose” can increase the plasma or blood concentration of the drug to a therapeutically effective level in conjunction with a maintenance dose of the drug. The “lead-in dose” can be administered once per day, or more than once per day (e.g., up to 4 times per day). Suitably the “lead-in dose” is administered once a day. Suitably, the lead-in dose is an amount from about 40% to about 95% of the maintenance dose; suitably from about 55% to about 95%; suitably from about 65% to about 85%; suitably about 40%; suitably about 50%; suitably about 60%; suitably about 70%; suitably about 75%; suitably about 85%; suitably about 95%. Suitably, the lead-in dose of Compound A (based on weight of unsalted/unsolvated amount) administered as part of the combination is an amount selected from about 3 mg to about 60 mg; suitably, the amount is selected from about 5 mg to about 40 mg; suitably, the amount is selected from about 5 mg to about 30 mg; suitably, the amount is selected from about 5 mg to about 20 mg; suitably, the amount is selected from about 5 mg to about 15 mg; suitably, the amount is selected from about 5 mg to about 10 mg. For example, the amount of Compound A administered as part of the combination can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg; preferably about 5 mg, about 10 mg, or about 15 mg; more preferably about 10 mg.

[0090] The term “maintenance dose” as used herein is understood to mean a dose that is serially administered (for example; at least twice), and which is intended to either slowly raise plasma or blood concentration levels of the compound to a therapeutically effective level, or to maintain such a therapeutically effective level. The maintenance dose is generally administered with a daily dose higher than the total daily dose of the lead-in dose. Suitably, the maintenance dose of Compound A (based on weight of unsalted/unsolvated amount) administered as part of the combination is an amount selected from about 3 mg to about 60 mg; suitably, the amount is selected from about 5 mg to about 40 mg; suitably, the amount is selected from about 10 mg to about 30 mg; suitably, the amount is selected from about 15 mg to about 20 mg. For example, the amount of Compound A administered as part of the combination can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg; preferably about 10 mg, about 15 mg, about 20 mg, or about 25 mg; more preferably about 15 mg, or about 20 mg.

[0091] The term “maintenance dosing regimen” as used herein is understood to mean a time period, wherein the maintenance dose is administered per day.

[0092] The term “break day” as used herein is understood to mean the time period when Compound A or Compound B is not administered. In one embodiment, the break days comprise 1 to 14 days; suitably from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 5 days; suitably for 4 days; suitably for 3 day; suitably for 2 day; suitably for 1 day. In one embodiment, the break days are consecutive days or non-consecutive days.

[0093] The term “lead-in dosing period” as used herein is understood to mean the time period when the lead-in dose(s) may be administered. In one embodiment, the lead-in dosing period comprises 1 to 48 days. In one embodiment, the lead-in dosing period further comprises 0-14 break day(s), preferably 0-7 break day(s), preferably break day(s),0-4 break day(s), preferably 0-2 break day(s), wherein Compound A or Compound B is not administered in the break day(s). Suitably, the lead-in dose is administered for from 1 to 48 days; suitably from 1 to 28 days; suitably from 1 to 21 days; suitably from 1 to 14 days; suitably from 1 to 7 days; suitably from 1 to 5 days; suitably from 2 to 5 days; suitably for 5 days; suitably for 4 days; suitably for 3 day; suitably for 2 day; suitably for 1 day, followed by a maintenance dose. In one embodiment, the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the lead-in dose of Compound A is administered in the first 5 days of the 7-day cycle; and Compound A is not administered in the last 2 days of the 7-day cycle. In one embodiment, the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the lead-in dose of Compound A is administered in the first 5 days of the 7-day cycle; and Compound A or Compound B is not administered in the last 2 days of the 7-day cycle.

[0094] In one embodiment, the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A is administered in the first 10 days of the 12-day cycle; and Compound A is not administered in the last 2 days of the 12-day cycle. In one embodiment, the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A is administered in the first 10 days of the 7-day cycle; and Compound A or Compound B is not administered in the last 2 days of the 10-day cycle.

[0095] In one embodiment, the lead-in dosing period comprises 1 cycle. In one embodiment, the lead-in dosing period comprises 2 cycles. In one embodiment, the lead-in dosing period comprises 3 cycles. In one embodiment, the lead-in dosing period comprises 4 cycles.

[0096] The term “intermittent dosing regimen” as used herein is understood to mean a time period comprising break day(s). In one embodiment, the intermittent dosing regimen comprises 2 to 28 days. In one embodiment, the intermittent dosing regimen further comprises 1-14 break day(s); suitably 1 to 7 break days; suitably 1 to 5 break days; suitably 1 to 3 break days; suitably 5 break days; suitably 4 break days; suitably 3 break days; suitably 2 break day; suitably 1 break day, wherein Compound A or Compound B is not administered in the break day(s). In one embodiment, the maintenance dose is administered in the intermittent dosing regimen. In one embodiment, the intermittent dosing regimen comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the maintenance dose of Compound A is administered in the first 5 days of the 7-day cycle; and Compound A is not administered in the last 2 days of the 7-day cycle. In one embodiment, the intermittent dosing regimen comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the maintenance dose of Compound A is administered in the first 5 days of the 7-day cycle; and Compound A or Compound B is not administered in the last 2 days of the 7- day cycle. In one embodiment, the intermittent dosing regimen comprises 1 cycle. In one embodiment, the intermittent dosing regimen comprises 2 cycles. In one embodiment, the intermittent dosing regimen comprises 3 cycles. Tn one embodiment, the intermittent dosing regimen comprises 4 cycles.

[0097] Suitably, the amount of Compound A (based on weight of unsalted/unsolvated amount) administered as a part of the combination is an amount selected from about 3 mg to about 60 mg; suitably, the amount is selected from about 5 mg to about 60 mg; suitably, the amount is selected from about 5 mg to about 40 mg; suitably, the amount is selected from about 10 mg to about 40 mg; suitably, the amount is selected from about 15 mg to about 40 mg; suitably, the amount is selected from about 15 mg to about 30 mg; suitably, the amount is about 20 mg. For example, the amount of Compound A administered as a part of the combination can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg; preferably about 5 mg, about 10 mg, about 15 mg, or about 20 mg; more preferably about 10 mg, about 15 mg, or about 20 mg. Suitably, the selected amount of Compound A is administered from 1 to 4 times a day. Suitably, the selected amount of Compound A is administered twice a day. Suitably, the selected amount of Compound A is administered once a day.

[0098] Suitably, the amount of Compound B (based on weight of unsalted/unsolvated amount) administered as a part of the combination is an amount selected from about 1 mg to about 10 mg. Suitably, the amount is selected from about 2 mg to about 8 mg; suitably, the amount is selected from about 2 mg to about 4 mg. For example, the amount of Compound B administered as part of the combination is suitably selected from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, and about 8 mg; preferably about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 6 mg, or about 8 mg; more preferably about 2 mg, about 3 mg, or about 4 mg. Suitably, the selected amount of Compound B is administered from 1 to 4 times a day. Suitably, the selected amount of Compound B is administered twice a day. Suitably, the selected amount of Compound B is administered once a day.

[0(199] In certain embodiments, the treatment of a cancer may be assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (see Thereasse P., et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. J. of the National Cancer Institute; 2000; (92) 205-216 and Eisenhauer E. A., Therasse P , Bogaerts J., et al. New response evaluation criteria in solid tumors: Revised RECTST guideline (version 1.1). European J. Cancer; 2009; (45) 228-247). Overall responses for all possible combinations of tumor responses in target and nontarget lesions with or without the appearance of new lesions are as follows:

CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease. [00100] With respect to the evaluation of target lesions, complete response (CR) is the disappearance of all target lesions, partial response (PR) is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, progressive disease (PD) is at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions and stable disease (SD) is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.

[00101] With respect to the evaluation of non-target lesions, complete response (CR) is the disappearance of all non-target lesions and normalization of tumor marker level; incomplete response/stable disease (SD) is the persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits, and progressive disease (PD) is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

[00102] The procedures, conventions, and definitions described below provide guidance for implementing the recommendations from the Response Assessment for Neuro-Oncology (RANG) Working Group regarding response criteria for high-grade gliomas (Wen P., Macdonald, DR., Reardon, DA., et al. Updated response assessment criteria for high-grade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol 2010; 28: 1963- 1972). Primary modifications to the RANG criteria for Criteria for Time Point Responses (TPR) can include the addition of operational conventions for defining changes in glucocorticoid dose, and the removal of subjects’ clinical deterioration component to focus on objective radiologic assessments. The baseline MRI scan is defined as the assessment performed at the end of the post-surgery rest period, prior to initiating or re-initiating compound treatment. The baseline MRI is used as the reference for assessing complete response (CR) and partial response (PR). Whereas, the smallest SPD (sum of the products of perpendicular diameters) obtained either at baseline or at subsequent assessments are designated the nadir assessment and utilized as the reference for determining progression. For the 5 days preceding any protocol-defined MRI scan, subjects receive either no glucocorticoids or are on a stable dose of glucocorticoids. A stable dose is defined as the same daily dose for the 5 consecutive days preceding the MRI scan. If the prescribed glucocorticoid dose is changed in the 5 days before the baseline scan, a new baseline scan is required with glucocorticoid use meeting the criteria described above. The following definitions are used.

[00103] Measurable Lesions: Measurable lesions are contrast-enhancing lesions that can be measured bi-dimensionally. A measurement is made of the maximal enhancing tumor diameter (also known as the longest diameter, LD). The greatest perpendicular diameter is measured on the same image. The cross hairs of bi-dimensional measurements should cross and the product of these diameters are calculated.

[00104] Minimal Diameter: T1 -weighted image in which the sections are 5 mm with 1 mm skip. The minimal LD of a measurable lesion is set as 5 mm by 5 mm. Larger diameters may be required for inclusion and/or designation as target lesions. After baseline, target lesions that become smaller than the minimum requirement for measurement or become no longer amenable to bi-dimensional measurement are recorded at the default value of 5 mm for each diameter below 5 mm. Lesions that disappear are recorded as 0 mm by 0 mm.

] 001051 Multicentric Lesions: Lesions that are considered multicentric (as opposed to continuous) are lesions where there is normal intervening brain tissue between the two (or more) lesions. For multicentric lesions that are discrete foci of enhancement, the approach is to separately measure each enhancing lesion that meets the inclusion criteria. If there is no normal brain tissue between two (or more) lesions, they are considered the same lesion. [00106] Nonmeasurable Lesions: All lesions that do not meet the criteria for measurable disease as defined above are considered non-measurable lesions, as well as all non-enhancing and other truly nonmeasurable lesions. Nonmeasurable lesions include foci of enhancement that are less than the specified smallest diameter (i.e., less than 5 mm by 5 mm), non-enhancing lesions (e.g., as seen on Tl-weighted post-contrast, T2 -weighted, or fluid-attenuated inversion recovery (FLAIR) images), hemorrhagic or predominantly cystic or necrotic lesions, and leptomeningeal tumor. Hemorrhagic lesions often have intrinsic Tl-weighted hyperintensity that could be misinterpreted as enhancing tumor, and for this reason, the pre-contrast Tl-weighted image may be examined to exclude baseline or interval sub-acute hemorrhage.

[00107] At baseline, lesions are classified as follows: Target lesions: Up to 5 measurable lesions can be selected as target lesions with each measuring at least 10 mm by 5 mm, representative of the subject’s disease; Non-target lesions: All other lesions, including all nonmeasurable lesions (including mass effects and T2/FLAIR findings) and any measurable lesion not selected as a target lesion. At baseline, target lesions are to be measured as described in the definition for measurable lesions and the SPD of all target lesions is to be determined. The presence of all other lesions is to be documented. At all post-treatment evaluations, the baseline classification of lesions as target and non-target lesions are maintained and lesions are documented and described in a consistent fashion over time (e.g., recorded in the same order on source documents and eCRFs). All measurable and nonmeasurable lesions must be assessed using the same technique as at baseline (e.g., subjects should be imaged on the same MRI scanner or at least with the same magnet strength) for the duration of the study to reduce difficulties in interpreting changes. At each evaluation, target lesions are measured and the SPD calculated. Non-target lesions are assessed qualitatively and new lesions, if any, are documented separately. At each evaluation, a time point response is determined for target lesions, non-target lesions, and new lesion. Tumor progression can be established even if only a subset of lesions is assessed. However, unless progression is observed, objective status (stable disease, PR or CR) can only be determined when all lesions are assessed.

[00108] Confirmation assessments for overall time point responses of CR and PR are performed at the next scheduled assessment, but confirmation may not occur if scans have an interval of < 28 days. Best response, incorporating confirmation requirements, are derived from the series of time points [00109] As used herein, all amounts specified for Compound A and Compound B are indicated as the amount of free or unsalted compound.

COMBINATION

[00110] Provided here is a combination comprising:

(i) Compound A having the name of 5-(((lR,laS,6bR)-l-(6-(trifluoromethyl)-lH- benzo(d)imidazol-2-yl)-la,6b-dihydro-lH-cyclopropa(b)benzofu ran-5-yl)oxy)-3,4-dihydro-l,8- naphthyridin-2(lH)-one, or the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof; and

(ii) Compound B having the name of N-((R)-2,3-dihydroxy-propoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, or the structure of formula (II): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.

[00111] Provided here is a combination product comprising:

(i) Compound A having the name of 5-(((lR,laS,6bR)-l-(6-(trifluoromethyl)-lH- benzo(d)imidazol-2-yl)-la,6b-dihydro-lH-cyclopropa(b)benzofu ran-5-yl)oxy)-3,4-dihydro-l,8- naphthyridin-2(lH)-one, or the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof; and

(ii) Compound B having the name of N-((R)-2,3-dihydroxy-propoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, or the structure of formula (II): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.

[00112] In one embodiment, the combination comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 6 mg, or about 8 mg of Compound B. In one embodiment, the combination comprises about 2 mg, about 3 mg, or about 4 mg of Compound B. In one embodiment, the combination comprises about 2 mg of Compound B. In one embodiment, the combination comprises about 3 mg of Compound B. In one embodiment, the combination comprises about 4 mg of Compound B.

[00113] In one embodiment, the combination comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg of Compound A; preferably about 5 mg, about 10 mg, about 15 mg, or about 20 mg of Compound A; more preferably about 10 mg, about 15 mg, or about 20 mg of Compound A. In one embodiment, the combination comprises about 10 mg of Compound A. In one embodiment, the combination comprises about 15 mg of Compound A. In one embodiment, the combination comprises about 20 mg of Compound A.

KITS

[00114] Provided herein is a kit comprising a combination provided herein and means for monitoring patient response to administration of said combination provided herein. In certain embodiments, the patient has colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, thyroid tumor, and their complications; preferably melanoma, ovarian cancer, and non-small cell lung cancer. In particular embodiments, the patient response measured is inhibition of disease progression, inhibition of tumor growth, reduction of primary and/or secondary tumor(s), relief of tumor-related symptoms, improvement in quality of life, delayed appearance of primary and/or secondary tumors, slowed development of primary and/or secondary tumors, decreased occurrence of primary and/or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth or regression of tumor. [90115] In other embodiments, provided herein are kits comprising a combination provided herein and means for measuring the amount of inhibition of B-RAF or MEK in a patient. In certain embodiments, the kits comprise means for measuring inhibition of B-RAF or MEK in circulating plasma, blood, or tumor cells and/or skin biopsies or tumor biopsies/aspirates of a patient. In certain embodiments, provided herein are kits comprising a combination provided herein and means for measuring the amount of inhibition of B-RAF or MEK before, during and/or after administration of a combination provided herein. In certain embodiments, the patient has colorectal cancer, pancreatic cancer, melanoma, ovarian cancer, or non-small cell lung cancer.

[00116] In certain embodiments, the kits provided herein comprise an amount of a combination provided herein effective for treating or preventing colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, thyroid tumor, and their complications; preferably melanoma, ovarian cancer, and non-small cell lung cancer. In certain embodiments, the kits provided herein comprise an amount of a combination provided herein effective for treating or preventing colorectal cancer, pancreatic cancer, melanoma, ovarian cancer, or non-small cell lung cancer.

[00117] In certain embodiments, the kits provided herein further comprise instructions for use, such as for administering a combination provided herein and/or monitoring patient response to administration of the combination.

METHOD OF TREATMENT

[00118] Provided herein is a method of treating a cancer in a subject in need thereof, comprising administering to said subject the combination disclosed herein. [00119] In one embodiment, the treating begins with a lead-in dosing period; the lead-in dosing period comprises 2 to 48 days; and the dose of Compound A in the lead-in dosing period is lower than the dose of Compound A administered after the lead-in dosing period. In one embodiment, the method comprises administering a lead-in dose of Compound A in a lead-in dosing period; or the method comprises administering a lead-in dose of Compound A in a lead-in dosing period and administering a maintenance dose of Compound A in a maintenance dosing regimen; and the lead-in dose of Compound A during the lead-in dosing period is lower than the maintenance dose of Compound A administered during the maintenance dosing regimen.

[00120] In one embodiment, the lead-in dosing period further comprises 1 to 14 break day(s);

Compound A is not administered in the break day(s); and the break days are consecutive days or non-consecutive days.

[00121] In one embodiment, the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the lead-in dose of Compound A is administered in the first 5 days of each cycle; and Compound A or Compound B is not administered in the last 2 days of each cycle.

[00122] In one embodiment, the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A is administered in the first 10 days of the 12-day cycle; and Compound A is not administered in the last 2 days of the 12-day cycle. In one embodiment, the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A is administered in the first 10 days of the 7-day cycle; and Compound A or Compound B is not administered in the last 2 days of the 10-day cycle.

[00123] In one embodiment, in the lead-in dosing period, Compound A is administered about 5 or about 10 mg per day; preferably about 10 mg per day.

[00124] In one embodiment, in the lead-in dosing period, each of Compound A and Compound B is administered, together or separately, once per day.

[00125] In one embodiment, in the lead-in dosing period, Compound A is administered once per day; and Compound B is administered twice per day.

[00126] In one embodiment, the treating begins with an intermittent dosing regimen; the intermittent dosing regimen comprises 2 to 28 days; the intermittent dosing regimen further comprises 1 to 14 break days; Compound A is not administered in the break day(s); the break day(s) are consecutive days or non-consecutive days.

[00127] In one embodiment, the intermittent dosing regimen comprises 1 to 4 cycles, wherein every cycle consists of 7 days; Compound A is administered in the first 5 days of each cycle; and Compound A or Compound B is not administered in the last 2 days of each cycle.

[00128] In one embodiment, in the intermittent dosing regimen, Compound A is administered about 15 or about 20 mg per day.

[00129] In one embodiment, in the intermittent dosing regimen, each of Compound A and Compound B is administered, together or separately, once per day.

[00130] In one embodiment, in the intermittent dosing regimen, Compound A is administered once per day; and Compound B is administered twice per day.

[00131] In one embodiment, the combination is administered with a lead-in dosing period, or an intermittent dosing regimen at the beginning.

[00132] In one embodiment, Compound A is administered about 15 or about 20 mg per day after the lead-in dosing period, or an intermittent dosing regimen.

[00133] In one embodiment, each of Compound A and Compound B is administered, together or separately, once per day.

[00134] In one embodiment, Compound A is administered once per day; and Compound B is administered twice per day.

[00135] In one embodiment, the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, thyroid tumor, and their complications; preferably melanoma, ovarian cancer and non-small cell lung cancer.

[00136] In one embodiment, the cancer is characterized by a mutation in a gene selected from the group consisting of RAS, NRAS, KRAS, RAF, BRAF, CRAF, ARAF, and their combination thereof; preferably RAS, NRAS, KRAS, RAF, BRAF, and their combination thereof; more preferably NRAS, KRAS, BRAF, and their combination thereof.

[00137] In one embodiment, the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS GBR, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof; preferably NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof; more preferably NRAS 06 JR, NRAS Q6JK, NRAS Q61L, KRAS GJ 2D, KRAS GJ2V, and their combination thereof [00138] In one embodiment, the cancer is characterized by other MAPK pathway genomic aberration. In one embodiment, the other MAPK pathway genomic aberration is RAS Al splice isoform. In one embodiment, the other MAPK pathway genomic aberration is RASA1 chr5:86,587,807.

[00139] In one embodiment, the cancer is characterized by a mutation in a gene selected from the group consisting of ARAF, BRAF, RAFI, KRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, and their combination thereof.

[00140] In one embodiment, the cancer is characterized by a mutation selected from the group consisting of BRAF N20T, BRAF A33T, BRAF S36A, BRAF V47_G393del, BRAF

V47_G327del, BRAF V47_D380del, BRAF V47_M438del, BRAF N49I, BRAF M53I, BRAF L64I, BRAF G69S, BRAF A81_D380del, BRAF A81_M438del, BRAF G104E, BRAF T119S, BRAF P141L, BRAF S151A, BRAF P162S, BRAF V169_G327del, BRAF V169_D380del, BRAF R188T, BRAF Q201H, BRAF G203_G393del, BRAF K205Q, BRAF V226L, BRAF E228V, BRAF R239Q, BRAF T241P, BRAF T241M, BRAF L245F, BRAF A246P, BRAF F247L, BRAF Q257R, BRAF Q257H, BRAF G258V, BRAF F259L, BRAF Q262R, BRAF H269Y, BRAF R271H, BRAF E275K, BRAF D287H, BRAF F294L, BRAF T310I, BRAF A320T, BRAF I326V, BRAF P341S, BRAF R347*, BRAF P348T, BRAF S363F, BRAF S364L, BRAF P367S, BRAF P367R, BRAF P367L, BRAF D380H, BRAF R389C, BRAF T401I, BRAF A404Cfs*9, BRAF P407L, BRAF S419Y, BRAF G421V, BRAF R444W, BRAF D448Y, BRAF D449Y, BRAF W450*, BRAF W450L, BRAF E451K, BRAF E451Q, BRAF P453T, BRAF V459L, BRAF R462E, BRAF R462K, BRAF R462I, BRAF I463T, BRAF 1463 S, BRAF G464I, BRAF G464R, BRAF G464E, BRAF G464A, BRAF G464V, BRAF S465D, BRAF S465E, BRAF S465A, BRAF G466R, BRAF G466E, BRAF G466A, BRAF G466V, BRAF S467A, BRAF S467L, BRAF F468C, BRAF G469L, BRAF G469del, BRAF G469S, BRAF G469R, BRAF G469E, BRAF G469A, BRAF G469V, BRAF T470K, BRAF V471I, BRAF V471F, BRAF Y472dup, BRAF Y472S, BRAF Y472C, BRAF G478C, BRAF K483E, BRAF K483M, BRAF L485_P490del, BRAF L485Y, BRAF L485_P490delinsY, BRAF L485S, BRAF L485W, BRAF L485F, BRAF L485_P490delinsF, BRAF N486_Q494del, BRAF N486del, BRAF N486_T488del, BRAF N486_T491del, BRAF N486_L495del, BRAF N486D, BRAF N486 V487del, BRAF N486 _P490del, BRAF N486 A489delinsK, BRAF N486_T491delinsK, BRAF V487_P490del, BRAF V487_P492delinsA, BRAF T488_P492del, BRAF T488_Q493delinsK, BRAF A489_P490del, BRAF P490del, BRAF P490_Q494del, BRAF K499E, BRAF K499N, BRAF E501K, BRAF E501G, BRAF V504_R506dup, BRAF V504I, BRAF L505F, BRAF L505H, BRAF R509G, BRAF R509H, BRAF L514V, BRAF M517I, BRAF Q524L, BRAF L525R, BRAF T529M, BRAF T529N, BRAF T529I, BRAF W531C, BRAF G534D, BRAF Y538H, BRAF R558Q, BRAF G563D, BRAF H568D, BRAF H574N, BRAF H574Y, BRAF H574Q, BRAF N581D, BRAF N581Y, BRAF N581T, BRAF N581S, BRAF N581I, BRAF N581K, BRAF I582M, BRAF F583C, BRAF L584F, BRAF H585Y, BRAF E586K, BRAF D587A, BRAF D587G, BRAF D587E, BRAF V590I, BRAF V590G, BRAF I592V, BRAF I592M, BRAF G593D, BRAF D594N, BRAF D594H, BRAF D594Y, BRAF D594_T599dup, BRAF D594A, BRAF D594G, BRAF D594V, BRAF D594E, BRAF F595L, BRAF F595S, BRAF G596S, BRAF G596R, BRAF G596C, BRAF G596D, BRAF G596V, BRAF L597S, BRAF L597V, BRAF L597Q, BRAF L597P, BRAF L597R, BRAF A598T, BRAF A598S, BRAF A598V, BRAF A598_T599insARC, BRAF A598_T599insV, BRAF T599dup, BRAF T599A, BRAF T599K, BRAF T599R, BRAF T599I, BRAF T599_V600insTT, BRAF T599_V600insS, BRAF T599_V600insETT, BRAF T599_V600insEAT, BRAF V600_K601delinsEN, BRAF V600_S605delinsEISRWR, BRAF V600K, BRAF V600R, BRAF V600Q, BRAF V600dup, BRAF V600delinsYM, BRAF V600M, BRAF V600L, BRAF V600D, BRAF V600 K601delinsE, BRAF V600E, BRAF V600A, BRAF V600G, BRAF K601del, BRAF K601Q, BRAF K601E, BRAF K601_W604del, BRAF K601T, BRAF K601I, BRAF K601_S602delinsNT, BRAF K601N, BRAF S602T, BRAF S602Y, BRAF S602F, BRAF R603*, BRAF W604del, BRAF W604R, BRAF W604G, BRAF S605A, BRAF S605F, BRAF S605E, BRAF S605G, BRAF S605N, BRAF S605I, BRAF G606W, BRAF G606E, BRAF G606A, BRAF G606V, BRAF S607P, BRAF S607F, BRAF H608R, BRAF Q609E, BRAF Q609L, BRAF Q609H, BRAF E61 ID, BRAF L613F, BRAF G615R, BRAF L618F, BRAF W619R, BRAF S637*, BRAF V639I, BRAF E648Q, BRAF Y656D, BRAF R671Q, BRAF P676S, BRAF L678I, BRAF V681I, BRAF E695K, BRAF K698R, BRAF L71 IF, BRAF A712T, BRAF R719S, BRAF H725Y, BRAF A728V, BRAF P731T, BRAF P731S, BRAF P731L, BRAF A762E, BRAF A762V, and their combination thereof.

[00141] In one embodiment, the cancer is characterized by a mutation selected from the group consisting of KIAA1549-BRAF fusion, BCAS1-BRAF fusion, CCDC6-BRAF fusion, CDC42BPB-BRAF fusion, FAM131B-BRAF fusion, FXR1-BRAF fusion, GIT2-BRAF fusion, KLHL7-BRAF fusion, RNF130-BRAF fusion, TMEM106B-BRAF fusion, MKRN1-BRAF fusion, AGAP3-BRAF fusion, AGK-BRAF fusion, AKAP9-BRAF fusion, ARMCI 0-BRAF fusion, CUL1-BRAF fusion, GTF2I-BRAF fusion, PAPSS1-BRAF fusion, PCBP2-BRAF fusion, PPFIBP2-BRAF fusion, SND1-BRAF fusion, TRIM24-BRAF fusion, ZKSCAN1-BRAF fusion, SEPT3-BRAF fusion, and their combination thereof.

[00142] In one embodiment, the cancer is characterized by a mutation selected from the group consisting of NRAS G12A, NRAS G12C, NRAS G12D, NRAS G12N, NRAS G12P, NRAS G12R, NRAS G12S, NRAS G12V, NRAS G12Y, NRAS G13A, NRAS G13C, NRAS G13D, NRAS G13E, NRAS G13N, NRAS G13R, NRAS G13S, NRAS G13V, NRAS A18T, NRAS I24N, NRAS P34L, NRAS Y40*, NRAS Q43*, NRAS T50I, NRAS T58I, NRAS A59G, NRAS A59D, NRAS A59T, NRAS G60E, NRAS G60R, NRAS Q61E, NRAS Q61H, NRAS Q61H, NRAS Q61K, NRAS Q61L, NRAS Q61L, NRAS Q61P, NRAS Q61R, NRAS Q61R, NRAS Q61R, NRAS Q61*, NRAS E63K, NRAS Y64D, NRAS S65C, NRAS R68S, NRAS S89A, NRAS G115Efs*46, NRAS E132K, NRAS K135N, NRAS A146P, NRAS A146T, NRAS A146V, NRAS E162*, and their combination thereof.

[00143] In some embodiments, the cancer harbors the mutations as described herein. In some embodiments, the subject with the cancer harbors the mutations as described herein.

[00144] In one embodiment, the cancer is melanoma. In one embodiment, the melanoma is cutaneous melanoma. In one embodiment, the melanoma is metastatic melanoma. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is non-small cell lung cancer.

[00145] In one embodiment, each of Compound A or Compound B, independently, is administered one to three times a day. In one embodiment, Compound A is administered once a day. In one embodiment, Compound B is administered once or twice a day; preferably twice a day. [09146] In one embodiment, said administration of the combination results in an AUC24h of Compound A between about 16,686 ng*h/ml and about 25,030 ng*h/ml.

[00147] In one embodiment, said administration of the combination results in an AUC24h of Compound A between about 22,052 ng*h/ml and about 33,078 ng*h/ml.

[00148] In one embodiment, said administration of the combination results in an AUC2411 of Compound A between about 38,358 ng*h/ml and about 57,536 ng*h/ml.

[00149] In one embodiment, said administration of the combination results in an AUC2411 of Compound A between about 41,534 ng*h/ml and about 62,302 ng*h/ml.

[00150] In some embodiments, the AUC24h is measured in the subject’s plasma. In some embodiments, the AUC2411 is measured in the subject’s blood. In some embodiments, the AUC2411 is measured in the subject’s plasma or blood on Day 29. In some embodiments, the AUC2411 is measured in the subject’s plasma or blood on Day 29 with maintenance dose.

[00151] In one embodiment, the subject achieves a stable disease, a partial response, or a complete response. In one embodiment, the subject achieves a partial response or a complete response. In one embodiment, the subject achieves a complete response. In one embodiment, the subject does not experience a progressive disease. In one embodiment, the subject achieves a stable disease. In one embodiment, the subject achieves a partial response. In one embodiment, the subject achieves a stable disease, a partial response, or a complete response for 1 week, 2 weeks, 3 weeks, or 4 weeks. In one embodiment, the subject achieves a stable disease, a partial response, or a complete response for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months. In one embodiment, the subject achieves a stable disease, a partial response, or a complete response for 1 year, 2 years, 3 years or 4 years.

[90152] When Compound A and Compound B are administered in physical combination, the dosage form and administration route should be selected depending on the compatibility of the combined Compound A and Compound B. Thus, the administration of Compound A and Compound B is understood to include the administration of Compound A and Compound B concomitantly or sequentially, or alternatively as a fixed dose combination of the at least two active components. METHODS FOR MAKING COMPOUNDS

[00153] The present embodiments can be understood more fully by reference to the detailed description and examples, which were intended to exemplify non-limiting embodiments.

[00154] Compound A can be prepared as described in WO2013097224. In one embodiment, Compound A may be prepared according to the methods below:

[00155] Step A: (!S,laS,6bR)-ethyl 5-((7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-4-yl)oxy)- la,6b-dihydro- 1 H-cyclopropa(b)benzo

[00156] The mixture of (!S,laS,6bR)-Ethyl 5 -hydroxy- la,6b-dihydro-l H- cyclopropa(b)benzofuran-l-carboxylate (400 mg, 1.8 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120 °C for 2hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2x 10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 3: 1) to obtain the title compound (360 mg, 54.6%) as a white solid.

[00157] Step B: (!S,laS,6bR)-5-((7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-4 -yl)oxy)-la,6b- dihydro- 1 H-cyclopropa(b)benzofuran- 1 -carboxylic acid

[00158] To a stirred solution of ester product of Step A (360 mg, 0.98 mmol) in THF (3 mL) and methanol (3 mL) was added sodium hydroxide aqueous solution (1 mL, 2 M, 2 mmol) at room temperature. The mixture was stirred at 60 °C for 2hrs. The solvent was removed under reduced pressure and the residue was dissolved into water (5 mL). The solution was neutralized with HC1 (2 mol/L) to pH = 7 and white solid precipitated out of solution. The white solid was collected by filtration and dried in air to give the title compound (230 mg, 69.3 %).

[00159] Step C: 5-(((lR, 1 aS,6bR)- 1 -(6-(trifluoromethyl)- lH-benzo(d)imidazol-2-yl)- 1 a,6b-dihydro-lH-cyclopropa(b)benzofuran-5-yl)oxy)-3,4-dihydr o-l,8-naphthyridin-2(lH)-one [00160] The mixture of the product of Step B (50 mg, 0.15 mmol), 4- (trifluoromethyl)benzene-l,2-diamine (26 mg, 0.15 mmol), DIPEA (0.1 mL) and HATU (84 mg, 0.22 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate anhydrous, filtered and concentrated under reduced pressure. [00161] The residue was dissolved in acetic acid (1 mL). The mixture was stirred at 80 °C for 3hours. Solvent was removed and a solution of NaOH (2 mL, 2mol/L) was added to the residue. The mixture was extracted with EtOAc (2 ^A 5 mL). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate anhydrous, and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound (10 mg, 14.1% yield; 69.6% ee) as a white solid.

[00162] Compound B can be prepared as described in W02002/06213. In one embodiment, Compound B may be prepared according to the methods below:

[00163] Step A: To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (2.25 g, 5.10 mmol) in dry tetrahydrofuran under nitrogen atmosphere, at -15 °C was added diphenylphosphinic chloride (1.26 mL, 6.63 mole) dropwise.

[00164] After stirring 20 min., N-methyl morpholine (0.70 mL, 6.375 mmol) was added and the reaction stirred an additional 20 min. (R)-O-(2,2-dimethyl-(l,3)dioxolan-4-ylmethyl)- hydroxylamine (0.748 g, 5.1 mmol) was added and the reaction stirred for 1 hour, at which point N-methylmorpholine (0.7 mL, 6.37 mmol) was added. The mixture was warmed to ambient temperature and stirred for 12 h. The reaction was concentrated in vacuo and then diluted with EtOAc. The organic layer was washed with saturated NaHCOs (2x), brine (lx), dried over Na2SO4, filtered and concentrated. The crude product was purified on SiO2 using 4: 1 hexane/EtOAc as eluent to provide 1.82g (68%) of a brownish red solid.

[00165] Step B : N-((R)-2,2-Dimethyl-(l,3)dioxolan-4-ylmethoxy)-3,4-difluoro- 2-(2-fluoro-4- iodo-phenylamino)-benzamide (0.210 g, 0.40 mmol) was suspended in 10: 1 methanol/ELO and pTsOH’ELO (0.008 g, 0.04 mmol) was added. The mixture was stirred at ambient temperature for 18 hrs, during which all solids dissolved to give a colorless, clear solution. The solution was diluted with EtOAc. The organic solution was washed with sodium bicarbonate (2x), brine (lx) and dried over Na2SO4. After filtration, the filtrate was concentrated, and recrystallized from EtOAc and heptane. This solid was washed with heptane- CHCh (1:1 and dried in vacuo at 60 °C to give N-((R)-2,3-Dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iod o-phenylamino)- benzamide as a white solid, (0.136g, 70%). Product shrinks at 90.8C, melts at 115-117 °C. Analysis shows C 40.92, H 3.16, N 5.41, F 11.30, 123.92 (6.75% EtOAc, 0.96 % heptane).

[00166] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. EXAMPLES

[00167] The examples below were intended to be purely exemplary and should not be considered to be limiting in any way. Unless otherwise specified, the experimental methods in the Examples described below were conventional methods.

[00168] Table 1 : List of Abbreviations And Terms

EXAMPLE 1

[00169] Study Compound A was completed and reported without the results on ClinicalTrials.gov with an identifier of NCT02610361 and a title of “Study of the Safety and Pharmacokinetics of Compound A in Patients With Solid Tumors,” the entire disclosure of which is incorporated herein by reference.

[00170] Study Compound A was a Phase la/lb, open-label, multiple-dose, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and preliminary antitumor activities of the RAF dimer inhibitor Compound A in patients with solid tumors. This was a 2- stage study, consisting of a Phase la dose-escalation and dose-finding component to establish the MTD and recommended phase 2 dose (RP2D), followed by a Phase lb dose-expansion component, to investigate efficacy in selected tumor types and further evaluate safety and tolerability of Compound A.

[00171] Phase la

[00172] A total of 35 patients were enrolled in the 9 dose cohorts of Phase la at dose levels ranging from 5 mg once a day to 60 mg once a day, which included a 15 mg twice a day dose regimen, and also a 50 mg once a day dose regimen, given 1 week on followed by 1 week off. [00173] A total of 6 (19.4%) patients experienced DLTs during the DLT observation period (Cycle 1). Among the 6 patients who had DLTs, 5 patients had Grade 4 thrombocytopenia (the single patient in the 15 mg twice a day cohort, 2 of 9 patients in the 40 mg once a day cohort, and 2 of 3 evaluable patients in the 60 mg once a day cohort); 1 patient in the 40 mg once a day cohort experienced Grade 3 non-hematologic toxicity (Grade 3 gamma-glutamyl transferase increased that lasted 11 days, accompanied by a Grade 3 alanine aminotransferase increased that lasted < 7 days). All patients recovered after study treatment interruption or discontinuation. [00174] The 30 mg once a day dose regimen was deemed safe and at least 10 patients have been on 30 mg once a day for extended periods without experiencing a DLT. Compound A was better tolerated at dose levels of 30 mg and below when dosed once a day than at 40 mg once a day and higher dose levels in terms of DLTs.

[00175] The MTD of Compound A was determined as 40 mg once a day, and 30 mg once a day was chosen as the RP2D for the associated Phase lb study (indication-specific expansion cohorts).

[00176] Phase lb

[00177] In Phase lb, 96 patients were treated at 30 mg once a day in 10 different arms with different solid tumors and mutation types. Compound A was generally well tolerated. Treatment- emergent adverse events (TEAE) and treatment-emergent serious adverse events related to study treatment were summarized below.

[00178] TEAE: 87 (90.6%) patients experienced at least 1 TEAE assessed as related to Compound A by the investigator. The most commonly occurring TEAEs assessed as related to Compound A treatment were fatigue (38.5%), dysphonia (26.0%), palmar- plantar erythrodysaesthesia syndrome (20.8%), decreased appetite (21.9%), thrombocytopenia and rash (19.8%, each), diarrhea (18.8%), dermatitis acneiform (17.7%), nausea (16.7%), hypertension (12.5%), and glossodynia and vomiting (10.4%, each). There were no A Grade 3 TEAEs assessed as related to Compound A that occurred with 10% frequency.

[00179] Treatment-emergent serious adverse events: 20 patients (20.8%) had at least 1 treatment-related treatment-emergent serious adverse event. These were thrombocytopenia and pyrexia in 3 patients (3.1%), febrile neutropenia and hypothyroidism in 2 patients (2.1%), and fatigue, pneumonia, alanine aminotransferase increased, liver function test abnormal, stomatitis, hyperbilirubinaemia, hyponatraemia, syncope, drug reaction with eosinophilia and systemic symptoms, and hypertension in 1 patient each (1.0%).

[00180] The safety profile of vemurafenib (n=336) showed that the most common adverse reactions of any grade (^ 30%) in vemurafenib-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. The most common 5%) Grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash. Compared to vemurafenib, Compound A had less of the most common adverse reactions of any grade 30%) in the 30 mg cohort. Although the most frequently reported study treatment-related Grade 3 and 4 AEs by preferred term were hypertension, fatigue, thrombocytopenia, and hyponatremia, these AEs were manageable. No cutaneous squamous cell carcinoma was found with Compound A in this study. [00181] Antitumor activity was not only observed in patients with B-RAF mutated solid tumors including melanoma, thyroid cancer, papillary thyroid cancer, and ovarian cancer, with a highest objective response rate (ORR) of 57.1% in patients with B-RAF V600 mutated melanoma, but also in patients with K-RAS mutated NSCLC and endometrial cancer.

[00182] Stage 1 and Stage 2 were conducted. Twenty -two solid tumor patients and 20 advanced melanoma patients were enrolled. Based on the acquired data of Compound A from Stage 1 study, 20 mg once a day was recommended in the dose expansion stage. In Stage 2 dose expansion, 20 patients with advanced melanoma harboring B-RAF mutation were treated and Compound A was tolerated at 20 mg once aday. Clinical and durable benefit was seen in several patients at Compound A monotherapy once a day dosing levels from 10 mg to 30 mg. However, the percentage of patients experiencing platelet decreased events at 20 mg was rising and, as noted by the Safety Monitoring Committee(SMC), had the potential to cause a risk/benefit ratio imbalance in these trial patients. It was also noted that, although decreased platelet events were being reported in a sistertrial conducted in Australia, the frequency and severity of the events were presenting differently, raising speculation that perhaps the management of this toxicity with respect to drug interruptionand/or therapeutic intervention differed regionally. As such, and based on preliminary pharmacokinetics (PK) and safety data, the SMC and the sponsor decided to stop further enrollment in the trial and begin a development strategy using Compound A in combination with other targeted agents to which may permit lower dosing and/or intermittent dosing of Compound A and toxicity management to be further investigated.

EXAMPLE 2

[00183] Study Compound A was completed and reported without the results on ClinicalTrials.gov with an identifier of NCT03641586 and a title of “The Study of Compound A in Chinese Subjects With Local Advanced or Metastatic Malignant Solid Tumor,” the entire disclosure of which is incorporated herein by reference.

[00184] Study Compound A was a 3-stage study consisting of a dose-escalation and dosefinding stage (Stage 1) to explore the MTD and to determine the RP2D, followed by a dose expansion stage (Stage 2) to explore the antitumor activity of Compound A by assessing the ORR of melanomausing Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The third stage (Stage 3) was an evaluation of the effect of food on single and multiple oral doses of Compound A. Stage 3 of the study was not carried out.

[00185] Stage 1 and Stage 2 were conducted. Twenty -two solid tumor patients and 20 advanced melanoma patients were enrolled. Based on the acquired data of Compound A from Stage 1 of the Compound A study, 20 mg once a day was recommended in the dose expansion stage. In Stage 2 dose expansion, 20 patients with advanced melanoma harboring B-RAF mutation were treated and Compound A was tolerated at 20 mg once aday. Clinical and durable benefit was seen in several patients at Compound A monotherapy once a day dosing levels from 10 mg to 30 mg.

[00186] In Phase 1 trial, PK analysis was conducted by using plasma concentrationsfrom 35 patients who received doses of 15 mg twice daily, 5, 10, 20, 30, 40, 50, or 60 mg oncedaily (Phase 1A), and 96 patients who received doses of 30 mg once daily (Phase IB).

[00187] The PK Analysis Set for both Phase 1A and Phase IB was defined as patients who had receivedat least the first dose of Compound A and provided PK samples per protocol following first dosing on Day 1.

[00188] For the Phase 1 A stage of the study, PK parameters were calculated by noncompartmental analysis methods and are presented in Table 2. Mean plasma concentrations over time by doselevel and cycle are presented graphically in Fig. 4 on a logarithmic scale.

[00189] In the Phase 1A stage of the study, there was an increase in systemic exposure to lifirafenib, as measured by Cmax, AUC0-9, and AUC0-24 for Cycle 1 Day 1 for dose levels from 10 to 60 mg/day. For Cycle 2 Day 1, there was an increase in systemic exposure to lifirafenib for dose levels from 10 to 50 mg/day.

[00190] The accumulation ratios (Phase 1A) of Cmax, AUC0-9, and AUC0-24 for (Cycle 2 Dayl)/(Cycle 1 Day 1) were similar for 10 mg to 50 mg dose levels, with average accumulation by dose level ranging from 3.3- to 6.1-fold for Cmax, and from 3.6- to 7.6-fold for AUC0-9 and AUCo-24. The terminal half-life was able to be measured for only three patients and ranged from 15 to 59 hours; however, because samples were not collected beyond 72 hours after dosing, the estimation of terminal half-life should be interpreted with caution.

[00191] In the Phase IB stage of the study, the average pre-dose concentrations were similar for Day 1 of Cycle 2 and Cycle 3.

[90192] Table 2 Summary of Pharmacokinetic Parameters, Phase 1A (PK Analysis Set)

[00193] However, the percentage of patients experiencing platelet decreased events at 20 mg was rising and, as noted by the Safety Monitoring Committee (SMC), had the potential to cause a risk/benefit ratio imbalance in these trial patients. It was also noted that, although decreased platelet events were being reported in a sistertrial conducted, the frequency and severity of the events were presenting differently, raising speculation that perhaps the management of this toxicity with respect to drug interruptionand/or therapeutic intervention differed regionally. As such, and based on preliminary pharmacokinetics (PK) and safety data, the SMC decided to stop further enrollment in the trial and begin a development strategy using Compound A in combination with other targeted agents to which may permit lower dosing and/or intermittent dosing of Compound A and toxicity management to be further investigated.

EXAMPLE 3

[00194] Study Compound A+Compound B was reported without the results on ClinicalTrials.gov with an identifier of NCT03905148 and a title of “Study of the Safety and Pharmacokinetics of Compound A (Lifirafenib) and Compound B (Mirdametinib) in Participants With Advanced or Refractory Solid Tumors,” the entire disclosure of which is incorporated herein by reference.

[00195] Study Compound A+Compound B was an open-label, multicenter, dose-escalation and expansion Phase lb study investigating the safety, pharmacokinetics, and preliminary antitumor activity of the RAF dimer inhibitor Compound A in combination with MEK inhibitor Compound B in patients with advanced or refractory solid tumors.

[00196] 40 patients had received study drug in 7 dose-escalation arms, as follows:

[00197] • Cohort 1 : Compound A 15 mg + Compound B 2 mg QD dosed continuously [00198] • Cohort 2: Compound A 20 mg + Compound B 2 mg QD dosed continuously

[00199] • Cohort 3a: Compound A 20 mg + Compound B 3 mg QD dosed intermittently*

[00200] • Cohort 3b: Compound A 20 mg + Compound B 3 mg QD dosed intermittently with lead-in**

[00201] • Cohort 3c: Compound A 15 mg + Compound B 2 mg BID dosed intermittently with lead-in**

[00202] • Cohort 4a: Compound A 20 mg + Compound B 4 mg QD dosed intermittently*

[00203] • Cohort 4c: Compound A 15 mg + Compound B 3 mg BID dosed intermittently with lead-in**

[00204] intermittent dosing was QD dosing for 5 days followed by a 2-day break.

[00205] ** Intermittent dosing with lead-in was similar to intermittent dosing but with 2 weeks of 10 mg Compound A QD and 3 mg QD, 2 mg BID, or 3 mg BID of Compound B during lead- in followed by scheduled regimen.

[00206] Protocol Title: A Phase lb, Open-Label, Dose-escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Antitumor Activities of a RAF Dimer Inhibitor Compound A in Combination with a MEK inhibitor Compound B in Patients with Advanced or Refractory Solid Tumors

[00207] Compound A in Combination with Compound B

[00208] Preliminary Clinical Experience from Compound A/Compound B

[00209] A total of 26 patients were treated across four dose levels and two regimens in the dose escalation portion of this study.

[00210] Level 1: 15 mg Compound A + 2 mg Compound B given QD (continuous dosing regimen); enrolled 6 patients with 5 completed and 1 ongoing.

[00211] Level 2: 20 mg Compound A + 2 mg Compound B given QD (continuous dosing regimen); enrolled 8 patients with 2 completed, 2 discontinued, and 4 ongoing.

[00212] Level 3a: 20 mg Compound A + 3 mg Compound B given QD for 5 days followed by a 2-day break (intermittent dosing regimen); enrolled 6 patients with 1 discontinued and 5 ongoing.

[00213] Level 4a: 20 mg Compound A + 4 mg Compound B given QD for 5 days followed by a 2-day break (intermittent dosing regimen); enrolled 6 patients with 4 discontinued and 2 ongoing. [00214] None of these initial 4 dose levels included a lead-in dose as part of the dose regimen. [00215] Two out of 6 patients enrolled in Level 4a experienced DLTs of Grade 4 thrombocytopenia with associated clinical bleeding events, necessitating platelet transfusions for both patients and packed red cell transfusions for one. Both patients recovered from the events. One patient was rechallenged at a reduced dose level (Compound A 15 mg and Compound B 3 mg, both given QD for 5 days followed by a 2-day break), with no recurrence of thrombocytopenia. Both patients have discontinued from the study due to disease progression, warranting study termination, while the other patient remains on study at a reduced dose level. [00216] Thus, the inventors surprising and unexpectedly discovered that a reduced dose level (e.g., Compound A 15 mg and Compound B 3 mg, both given QD for 5 days followed by a 2- day break) can prevent thrombocytopenia.

[00217] Overall, the combination has been well tolerated up to doses of Compound A 20 mg + Compound B 3 mg given intermittently for 5 days (QD) followed by a 2-day break. The most frequently reported toxicities were fatigue (46.2%); dermatitis (38.5%); diarrhea and rash (34.6% each); and constipation (26.9%).

[00218] Two DLTs (both Grade 4 thrombocytopenia events) were reported in Level 4a (20 mg Compound A + 4 mg Compound B given intermittently for 5 days (QD) followed by a 2-day break) to determine that it was not a tolerable dose regimen.

[00219] Table 3 details the DLTs observed.

[00220] Table 3: Dose-limiting Toxicities Observed in Part A

[00221] * In this patient with colorectal cancer, bowel obstruction was likely due to disease progression which contributed to the DLT.

[00222] OBJECTIVES AND ENDPOINTS

[00223] Part A

[00224] Primary Objectives

[00225] To assess the safety and tolerability of the combination of Compound A and Compound B.

[00226] To determine the MTD, if any, and RP2D for the combination.

[00227] Secondary Objectives

[00228] To characterize the PK of Compound B and Compound A in the combination.

[00229] To assess the preliminary antitumor activity of the combination of Compound A and

Compound B.

[00230] Exploratory Objectives

[00231 ] To determine potential predictive biomarkers of efficacy.

[00232] To assess potential PD biomarkers of target engagement, biological activity, and mechanism of action.

[00233] To explore mechanisms of treatment resistance in patients who fail to respond or develop resistance.

[00234] Part B

[00235] Primary Objectives

[00236] To assess the preliminary antitumor activity of the combination of Compound A and Compound B.

[00237] Secondary Objectives

[00238] To further assess the safety and tolerability of the combination of Compound A and Compound B.

[00239] To further characterize the PK of Compound B and Compound A in combination.

[00249] Exploratory Objectives

[00241] To explore potential predictive biomarkers of efficacy. [00242] To assess potential PD biomarkers of target engagement, biological activity, and mechanism of action.

[00243] To explore mechanisms of resistance in patients who fail to respond or develop resistance.

[00244] Study Endpoints for Part A

[00245] Primary Endpoints

[00246] Safety and tolerability of the combination of Compound A and Compound B were assessed throughout the study by the incidence and severity of AEs and SAEs (coded to system organ class (SOC) and preferred term (PT) using MedDRA) and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0), physical examination, ophthalmologic examination, vital signs, ECG, echocardiogram (ECHO), and laboratory tests.

[00247] The MTD, if any, were based on safety and tolerability

[00248] The RP2D were determined based on safety, tolerability, PK, preliminary efficacy, and other available data.

[00249] Secondary Endpoints

[00250] Pharmacokinetic profile for Compound B, its active metabolite Compound B’s metabolite, and Compound A in combination. PK parameters including but not limited to single dose: AUC, Cmax, and Tmax; steady state: AUClast,ss, Cmax,ss, and Tmax,ss.

[00251] Efficacy parameters including:

[00252] ORR, defined as the proportion of patients who had confirmed CR or PR assessed by investigator using RECIST 1.1.

[00253] Disease control rate, defined as the proportion of patients with best overall response of confirmed CR, PR, or stable disease.

[00254] Duration of response, defined as the time from the first determination of an objective response per RECIST 1.1, until the first documentation of progression or death, whichever occurs first.

[00255] Clinical benefit rate defined as the proportion of patients with best overall response of confirmed CR or PR or stable disease lasting 24 weeks.

[00256] PFS, defined as the time from first dose of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. [00257] Exploratory Endpoints

[00258] Predictive biomarkers of efficacy, including mitogen activated protein kinase (MAPK) signaling including phosphorylated extracellular signal-regulated kinase (phospho- ERK), v-RAF murine sarcoma viral oncogene homolog B (B-RAF), KRAS proto-oncogene, GTPase (K-RAS), NRAS proto-oncogene, GTPase (N-RAS), A-Raf proto-oncogene serine/threonine kinase (A-RAF), neurofibromin 1 (NF1) mutation, B-RAF or Raf-1 protooncogene serine/threonine kinase (C-RAF) amplification and other aberrations in, or affecting, the MAPK pathway.

[00259] Study Endpoints for Part B

[00260] Primary Endpoint

[00261] ORR as described in Part A. Also, duration of response, disease control rate, clinical benefit rate, and PFS were evaluated.

[00262] Secondary Endpoints

[00263] Safety and tolerability assessment of AEs, physical examination, ophthalmologic examination, vital signs, ECG, ECHO, and laboratory measurements as described in Part A. [00264] PK parameters for Compound B and the active metabolite PD-0315209, including but not limited to: AUC, Cmax, and Tmax.

[00265] PK parameters for Compound A, including but not limited to: AUC, Cmax, and Tmax.

[00266] STUDY DESIGN

[00267] Summary of Study Design

[00268] This was a 2-part Phase lb study of Compound A in combination with Compound B in patients with tumors harboring confirmed B-RAF or K-RAS/N-RAS mutations or MAPK pathway or other genomic aberrations that may potentially respond to a RAF dimer inhibitor or a MEK inhibitor (including v-RAF murine sarcoma viral oncogene homolog B (BRAF), A-Raf proto-oncogene serine/threonine kinase (ARAF), Raf-1 proto-oncogene, serine/threonine kinase (RAFI), KRAS proto-oncogene GTPase (KRAS), NRAS proto-oncogene GTPase (NRAS), HRAS proto- oncogene GTPase (HRAS), neurofibromin 1 (NF1), mitogen-activated protein kinase kinase 1(MAP2K1), mitogen-activated protein kinase kinase 2 (MAP2K2), mitogen- activated protein kinase 1 (MAPK1), epidermal growth factor receptor (EGFR), G protein subunit alpha 11 (GNA11), G protein subunit alpha q (GNAQ), phosphatidylinositol-4,5- bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB), phosphatase and tensin homolog (PTEN), AKT serine/threonine kinase 1 (AKT1), MET proto-oncogene, receptor tyrosine kinase (MET), KIT proto-oncogene, receptor tyrosine kinase (KIT), and insulin like growth factor 1 receptor (IGF1R)).

[00269] Part A consisted of a dose-escalation and dose-finding component to establish the MTD and/or RP2D and to evaluate the PK of Compound B (and its active metabolite PD- 0315209) in combination with Compound A (see Fig. 2 Study Schema). Part B consisted of a component to further evaluate the PK, safety, and tolerability of the combination of Compound B and Compound A and to assess the preliminary antitumor activity of the combination in patients in each of the 3 groups with selected tumor types.

[00270] As shown in Fig. 2, Levels 1 and 2 were dosed continuously; levels 3a and 4a were dosed on an intermittent schedule: QD doses for 5 days followed by a 2-day break. Other cohorts were dosed on the following intermittent schedule: QD doses for 5 days followed by a 2- day break/4-week cycles. Lead-in periods of 7 or 21 days may be considered based on emergent based on emergent data; DLT period was adjusted as appropriate to include lead-in days. Abbreviations: BID, twice a day; QD, once a day; RP2D, recommended phase 2 dose.

[00271] Baseline tumor tissue was mandatory for mutation and biomarker analysis, either from archived tumor tissue or fresh tumor biopsies. With the patient’s consent, a follow-up biopsy may be taken for the analysis of PD biomarkers, ideally from the same tumor lesion if it was readily accessible. For Group 2 in Part B, paired fresh tumor biopsies were mandatory and were collected within the 8 weeks before the first dose of study treatment and again at a time post-dose to assess PD biomarkers. In addition, blood samples were collected from all patients for mutation profiling by next generation sequencing. Additional biomarker analysis from the blood might also be conducted by other assay types.

[00272] Two dose escalation arms, Levels 3b and 3c, were planned to be opened in parallel. Subsequent dose levels were based on emergent data. Lead-in periods of 7 or 21 days may also be considered whereby the DLT period would adjust as appropriate to include the lead-in days. [00273] Level 3c and subsequent levels implemented BID dosing for Compound B.

[00274] Part A

[00275] Part A was a multicenter, open-label, multiple-dose, dose-escalation study in patients with tumors harboring B-RAF or K-RAS/N-RAS mutations or MAPK pathway or other genomic aberrations that may potentially respond to a RAF dimer inhibitor or a MEK inhibitor (including BRAF, ARAF, RAFI, KRAS, NRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, EGFR, GNA1 1, GNAQ, PIK3CA, PIK3CB, PTEN, AKT1, MET, KIT, or IGF1R).

[00276] In Part A, the study recruited no more than 50% of patients with CRC or pancreatic cancer with confirmed K-RAS mutations. Investigators were encouraged to enroll patients with non-small cell adenocarcinoma of the lung (NSCLC-adenoca) harboring any variants of KRAS, NRAS, or BRAF mutations or cutaneous melanoma harboring any variants of KRAS or NRAS mutations. The clinical data from patients with NSCLC-adenoca or cutaneous melanoma harboring the required mutation status facilitated the sponsor’s selection of the population(s) of likely responders in the Part B dose expansion cohorts. The SMC evaluated safety data after patients have completed at least 1 cycle of treatment and decide upon subsequent dose levels. The study followed a 3+3 dose-escalation schema. The DLT assessments were evaluated during the first cycle consisting of the first 28 days of concurrent Compound A and Compound B treatment. If a lead-in dose regimen was used, the DLT period were 6 weeks (2 weeks of lead-in plus 4 weeks of target dosing). DLT assessments were evaluated during the Lead-in Dosing Period (14 days prior to Cycle 1 Day 1) and the first cycle (the first 28 days of concurrent Compound A and Compound B treatment). Continuous safety evaluations were performed by the sponsor, the coordinating investigator, and the investigators.

[00277] If fewer than 2 patients with NSCLC-adenoca or cutaneous melanoma and harboring the required mutation status have been enrolled when the current dose escalation cohort becomes evaluable for the SMC review, then 2 additional patients with NSCLC-adenoca or cutaneous melanoma and harboring the required mutation status were enrolled in this cohort. Clinical review of the additional patients was implemented as follows:

[00278] If the SMC clears the current dose escalation cohort (dose escalation or expansion of the current cohort), then additional patients received the same dose level that was just cleared and were evaluated in parallel with the next dose escalation cohort.

[00279] If the SMC does not clear the current dose escalation cohort (study drugs were not tolerated at the current dose level), then additional patients was not enrolled at that dose level. [00280] The next SMC meeting may be scheduled irrespective of the enrollment of additional patients. However, all available safety, PK and tumor response data, including from the additional patients, were reviewed at the SMC meeting. [00281] Starting dose and dose-escalation rules

[00282] The starting dose for each agent and the starting dose level of the combination was based on the doses evaluated in the monotherapy dose-escalation study for each agent and was significantly lower than the MTD that has been identified to date. Dose escalation may occur in accordance with the following modified 3+3 dose escalation rules.

[00283] Dose escalation proceeded if no DLT was observed during the DLT period in a minimum of 3 DLT evaluable patients. If a DLT occurred within the DLT observation period at a given dose level, enrollment for that dose level may be expanded per the modified 3+3 design rules and as follows:

[00284] Dose escalation may proceed if the DLT rate was < 1/3

[00285] Dose escalation stopped if the first cycle DLT rate was /+ 1/3. A minimum of 6 patients were enrolled to the current dose level if the DLT rate was 1/3 or the next lower dose level if the DLT rate was > 1/3 (e.g., 2/3 or 3/3)

[00286] The MTD was defined as the highest dose level at which < 1/3 of the patients experience a DLT.

[00287] More than 3 patients may be enrolled for a given dose level in the absence of a DLT. In such cases, the dose escalation decision was made based on the above 3+3 rules.

[00288] The recommended Phase 2 dose and dosing regimen used in Part B were determined by the SMC and the sponsor based on the available data on safety, PK, preliminary antitumor activity, and other pertinent data. The SMC may decide to evaluate an intermediate, not predefined, previously evaluated or not previously evaluated dose or a less frequent dosing regimen that does not exceed the MTD level if evaluation of toxicity at such a dose or schedule was desired. A minimum of 6 patients were enrolled in Part A at the dosing level and regimen determined by the SMC to be utilized in Part B.

[00289] Evaluation of a lead-in dose

[00290] Additional dosing scenarios may be explored in Part A of this study based on the evaluation of all available study data by the sponsor in consultation with the SMC, including the evaluation of a lead-in dose to enable subsequent lower, intermediate, or higher-level dose administration, and/or BID dosing, either intermittently or continuously, for Compound A and/or Compound B. [00291] An initial lead-in dose (14 days with alternative options of 7 and 21 days) given prior to the target dose for one or both agents, may be proposed to facilitate subsequent dose escalation when evaluating the MTD of a dosing regimen and in consideration of a RP2D. The lead-in dose was at least one dose level lower than the target dose. The decision to evaluate a regimen that includes a lead-in dose were made by the sponsor in consultation with members of the SMC.

[00292] Part B

[00293] Part B was comprised of 3 indication expansion cohorts:

[00294] Group 1 : Non-small cell lung cancer with confirmed K-RAS mutations, approximately 15 patients

[00295] Group 2: Endometrial cancer with confirmed K-RAS mutations, approximately 15 patients

[00296] Group 3 : Tumor types of interest based on clinical data observed in Part A, approximately 15 patients

[00297] Part A and Part B

[00298] Patients were monitored for safety, tolerability, and efficacy throughout the study from the day of first administration of study treatment up to 30 days after the last administration of either study treatment. Radiological assessment of tumor response was performed once every 8 weeks (± 7 days) (from Cycle 1 Day 1) to assess all known disease in the first year and approximately every 12 (± 1) weeks thereafter.

[00299] Tumor response were assessed by investigators based on RECIST 1.1. For patients with ovarian cancer, tumor response was also assessed by investigators based on RECIST 1.1 and Gynecological Cancer Intergroup (GCIG CA-125) criteria. The RECIST criteria took priority regarding patient treatment and discontinuation decisions.

[00300] This study was considered complete once all patients have manifested disease progression, ceased study treatment due to death, intolerance, withdrawal of consent from the study, or completed a total of 2 years of treatment. Patients in each part of the study who continue to demonstrate clinical benefit and have no intolerable toxicity at the end of the 2-year treatment period may continue receiving treatment and be followed for safety and other clinically relevant information after discussion with the sponsor medical monitor.

[00301] Enrollment Priority [99302] The first priority was to enroll patients into Part A (dose ranging component of the study).

[00303] After completion of Part A and the R2PD for Compound A/Compound B combination therapy has been determined, patients may be enrolled to different groups of Part B (advanced solid tumors) in parallel.

[90304] Study Periods

[00305] This study consisted of the following 3 periods.

[00306] Screening Period

[00307] Screening evaluations were performed within 28 days prior to the first administration of study treatment. Patients who agreed to participate signed the informed consent form (IGF) prior to undergoing any screening procedure. Screening evaluations may be repeated as needed within the Screening Period; the investigator was to assess patient eligibility according to the latest screening assessment results. If a patient was rescreened, a new ICF were required.

[00308] A baseline tumor tissue was mandatory for mutation and biomarker analysis, either from archived tumor tissue or fresh tumor biopsies. With patient consent, a follow-up biopsy may be taken for the analysis of PD biomarkers, ideally from the same tumor lesion if it was readily accessible. For Group 2 in Part B, paired fresh tumor biopsies were mandatory and were collected within the 8 weeks before the first dose of study treatment and again at a time postdose to assess PD biomarkers (NOTE: fresh biopsies taken within 8 weeks of the first dose of study treatment but prior to signing the ICF were allowed if this was part of standard-of-care). [00309] Treatment Period

[00319] After completing all screening activities, patients confirmed eligible were treated with Compound A /Compound B.

[90311] All patients received study treatment until 1) they were no longer considered to be achieving clinical benefit; or 2) cessation of study treatment due to death, intolerable toxicity, or withdrawal of consent from the study. Patients who continue to demonstrate clinical benefit and have no intolerable toxicity at the end of the 2-year treatment may continue to receive therapy per protocol or may enter an expanded access protocol assuming drug availability.

[90312] The End of Treatment Visit was conducted within 7 days after the Investigator determines that the study treatments were no longer used. If routine laboratory tests (e.g., hematology, serum chemistry) were completed within 7 days before the End of Treatment Visit, these tests need not be repeated. Tumor assessment was not required at the End of Treatment Visit provided that fewer than 6 weeks have passed since the last assessment.

[00313] Safety Follow-Up Period

[00314] Patients who discontinued treatment for any reason returned for a follow-up visit at approximately 30 (± 7) days after the last dose of the study treatment. Beyond 30 days, investigators should report any SAEs that were believed to be related to study treatment if they became aware of them. Patients who discontinued study treatment due to a drug-related AE were followed until the resolution of the AE (to Grade 1, baseline or stabilization) or initiation of a new treatment, whichever came first.

[00315] Dose-Limiting Toxicity Definition

[00316] All DLTs in Part A were graded according to the CTCAE v5.0. The occurrence of any of the following toxi cities within 28 days after the first dose of Compound A /Compound B were considered a DLT, with the exclusion of toxicities clearly related to disease progression or intercurrent illness.

[00317] When evaluating a lead-in dose, the DLT window included all lead-in treatment days as well as 28 days at the target dose of the combination. For the patients who have completed the DLT window, they should have received 80% of the intended dose over each of the lead in and target dose periods of the DLT window or have experienced a DLT.

[00318] Hematologic:

[00319] Grade 4 or greater hematologic toxicity

[00320] Grade 3 febrile neutropenia (defined as absolute neutrophil count [ANC] < 1000/mm ³ with a single temperature of > 38.3°C (101°F) or a sustained temperature of 38°C (100.4°F) for > 1 hour)

[00321] Grade 3 thrombocytopenia with clinically significant bleeding

[00322] Non-hematologic:

[00323] Grade 3 or greater non-hematologic toxicity

[00324] Grade 2 or greater ocular toxicities such as blurred vision, decreased vision, glaucoma, retinal detachment, or retinal vascular disorder

[00325] New York Heart Association (NYHA) Functional Classification V class III left ventricular dysfunction

[00326] Grade 3 toxicity that was clinically significant with the following exceptions: [00327] Toxicity that started to resolve within 3 days of initiating optimal supportive care. [00328] Grade 3 to Grade 4 laboratory abnormalities that were not associated with clinical sequelae (e.g, lactose dehydrogenase elevation) or resolves within 3 days of initiating optimal supportive care.

[00329] In addition, clinically important or persistent toxicides that were not included above may also be considered a DLT following review and discussion between the SMC and the sponsor.

[00330] Patients who received less than 80% of the assigned dose of either Compound A or Compound B and did not experience a DLT were not considered in the assessment of the overall DLT rate for the particular dose level. Additional patients may be enrolled at the same dose levels to ensure an adequate number of DLT-evaluable patients.

[00331] Patients who received less than 80% of the assigned dose of either Compound A or Compound B and experience a DLT were considered in the assessment of the overall DLT rate for the particular dose level.

[00332] Patients who experienced a DLT during the DLT assessment window and patients who had clinically significant Grade 2 toxicides that were considered related to Compound A and/or Compound B after the DLT assessment window may temporarily or permanently suspend taking study treatment.

[00333] STUDY POPULATION

[00334] The specific eligibility criteria for the selection of patients were provided below. The sponsor did not grant eligibility waivers.

[00335] Inclusion Criteria

[00336] Each patient eligible to participate in this study must meet all of the following criteria:

[00337] Able to provide written informed consent and can understand and comply with the requirements of the study.

[00338] Age ^ 18 years (or the legal age of consent in the jurisdiction in which the study was taking place) on the day of signing the ICF.

[00339] Patients with advanced or metastatic, unresectable tumors (other than patients with tumors of the brain or central nervous system) who have experienced disease progression during or after at least 1 line of systemic therapy or for which treatment was not available, not tolerated, or was refused. Tn addition, patients must meet the following eligibility criteria for the corresponding part of the study:

[ 00340] In Part A of the study, patients must have a known mutation status and a histologically or cytologically confirmed advanced tumor including NSCLC, CRC, ovarian cancer, endometrial cancer, thyroid cancer, melanoma, pancreatic cancer, and any tumor harboring an oncogenic B-RAF or K-RAS/N-RAS mutation, or MARK pathway or other genomic aberrations that may potentially respond to a RAF dimer inhibitor or a MEK inhibitor (as described in inclusion criterion below) for which no effective standard therapy was available or acceptable to the patient.

[00341 ] In Part B of the study, patients recruited to 1 of the following expansion groups must have a known mutation status and histologically or cytologically confirmed advanced or refractory solid tumor (of the types described below) for which no effective standard therapy was available or acceptable to the patient:

[00342] Group 1 : Non-small cell lung cancer with confirmed K-RAS mutation

[00343] Group 2: Endometrial cancer with confirmed K-RAS mutation

[00344] Group 3 : Tumor types of interest based on clinical data observed in Part A

[00345] Patients must have archival tumor tissue or agree to a tumor biopsy at baseline for mutation and biomarkers analysis.

[00346] NOTE: Tumor samples were used to confirm mutation status by central laboratory assessment.

[00347] NOTE: Acceptable tumor mutations by local (for initial enrollment) or central (for confirmation) testing include: BRAE, ARAF, RAFI, KRAS, NRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, EGFR, GNA11, GNAQ, PIK3CA, PIK3CB, PTEN, AKT1, MET, KIT, IGF1R.

[00348] Patients must have measurable disease as defined per RECIST 1.1.

[00349] Eastern Cooperative Oncology Group (ECOG) performance status of 1 at screening.

[00350] Life expectancy ≥ l 2 weeks at the time of signing the ICF.

[00351] Patient must have adequate organ function as indicated by the following laboratory values without transfusion within 14 days of the first dosing of study treatment:

[00352] Absolute neutrophil count (ANC) ≥ 1500 cells/μL [00353] Platelets

[00354] Hemoglobin 5.6 mmol/L

[00355] Serum creatinine 1.5 x upper limit of normal (ULN) or estimated creatinine clearance S- 50 mL/min

[00356] Serum total bilirubin A 1.5 x ULN (total bilirubin must be < 3 * ULN for patients with Gilbert’ s syndrome)

[00357] Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) A 3 * ULN or < 5 x ULN for patients with liver metastases

[00358] Female patients were eligible to enter and participate in the study if they were of: [00359] Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who:

[00360] has had a hysterectomy

[00361] has had a bilateral oophorectomy (ovariectomy)

[00362] has had a bilateral tubal ligation

[00363] is postmenopausal (total cessation of menses for 1 year).

[00364] Childbearing potential, has a negative serum pregnancy test within 7 days of the first dosing of study treatment, was not breast feeding, and uses protocol-approved contraception before study entry and throughout the study until 7 months after the last study treatment administration.

[00365] Male patients were eligible to enter and participate in the study if they were vasectomized or agree to use protocol -approved contraception during the study treatment period and for at least 120 days after the last dose of study treatment.

[00366] Exclusion Criteria

[00367] Patients who meet any of the following criteria must be excluded from this study: [00368] Current or history of central nervous system metastasis.

[00369] NOTE: Patients must have a computed tomography (CT)/magnetic resonance imaging (MRI) scan of the brain at screening to confirm no central nervous system metastasis. [00370] History or evidence of retinal pathology on ophthalmologic examination that was considered a risk factor for central serous retinopathy, RVO, or neovascular macular degeneration Patients were excluded from study participation if they currently were known to have any of the following risk factors for RVO:

[00371] Intraocular pressure V 21 mmHg

[00372] Grade V 2 serum cholesterol

[00373] Grade A 2 hypertriglyceridemia

[00374] Grade A 2 or symptomatic hyperglycemia (fasting)

[00375] Grade 2 hypertension

[00376] History of glaucoma.

[00377] Has an active parathyroid disorder or a history of malignancy-associated hypercalcemia.

[00378] Has experienced any of the following within 6 months (24 weeks) of signing the informed consent form: clinically significant cardiac disease (New York Heart Association Class III or IV), myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism.

[00379] Has left ventricular ejection fraction (LVEF) V 50% as assessed by multigated acquisition (MUGA) scan or by ECHO.

[00380] Has abnormal QT interval corrected by Fridericia’s formula (> 470 msec) after electrolytes have been corrected at screening.

[00381] Current severe, uncontrolled systemic disease including, but not limited to, clinically significant cardiovascular, pulmonary, renal disease, or active infection.

[00382] History of human immunodeficiency virus (HIV) infection.

[00383] Any clinically significant active or known history of liver disease including but not limited to cirrhosis.

[00384] NOTE: Hepatitis serology and viral load were tested at screening. Patients who were hepatitis B surface antigen (HBsAg) positive or hepatitis C virus (HCV) antibody positive at screening must not be enrolled until further definite testing with hepatitis B virus (HBV) DNA titers was < 500 lU/mL or hepatitis C virus (HCV) RNA polymerase chain reaction test was negative. [00385] Any hemorrhage or bleeding event at CTCAE v5.0 Grade 3 or higher within 28 days of the first dose of study treatment.

[00386] Has a history of or has ongoing Von Willebrand disease and/or other past or present bleeding disorders, including congenital or acquired platelet function defects.

[00387] Has an increased serum calcium (> 1 * ULN) or serum phosphorus (> 1 x ULN) level.

[00388] Inability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening, or otherwise altering the study treatment formulation. Patients should not have gastrointestinal illnesses (e.g., absorption syndrome) that could potentially impact the absorption of Compound A or Compound B, which were oral agents.

[00389] Has ongoing radiation therapy or radio-cytotoxic therapy within prior 4 weeks; no chemotherapy, immunotherapy, biologic therapy, hormonal, or molecular targeted therapy within prior 2 weeks.

[00390] a. Use of prior bevacizumab was allowed following a 28-day washout period prior to the first dose of study treatment.

[00391] Use of concomitant systemic or ocular glucocorticoid therapy within 2 weeks; topical therapies do not require an exclusion window.

[00392] Major surgical procedure or significant traumatic injury within 4 weeks prior to the first dose of study treatment, or anticipation of the need for major surgery during the course of study treatment.

[00393] Patients receiving concomitant medicines that were strong cytochrome P450 (CYP) 3A inhibitors for 14 days (or 5 half-lives, whichever was longer) before the first dose of an investigational medicinal product.

[00394] Known history of toxicity from another RAF, MEK, or ERK inhibitor requiring discontinuation of treatment from these drugs.

[00395] Underlying medical conditions, laboratory abnormality, or alcohol or drug abuse or dependence that, in the investigator’s opinion, were unfavorable for the administration of study treatment or affect the explanation of drug toxicity or adverse events; or insufficient compliance during the study according to investigator’s judgment.

[00396] Has been administered a live vaccine within 4 weeks (28 days) of initiation of study treatment. NOTE: injectable seasonal vaccines for influenza and COVID-19 were generally inactivated vaccines and were allowed Tntranasal vaccines were live vaccines and were not allowed.

[00397] STUDY TREATMENT

[00398] Formulation, Packaging, and Handling

[00399] Compound A drug product was supplied as 5-mg units. Compound B was supplied as 1-mg units and 2-mg units.

[00400] Dosage, Administration, and Compliance

[00401] Patients were required to fast for 2 hours before and 1 hour after the administration of study treatment on all days throughout the study. Water was allowed freely. Grapefruit and grapefruit juice were not allowed throughout the study. No other dietary restrictions applied.

[00402] For patients receiving lead-in dosing, the first lead-in doses of Compound A and Compound B were co-administered on Lead-in Dose Day 1. For patients who do not receive lead-in dosing, the first doses of Compound A and Compound B were co-administered on Day 1 of Cycle 1. Lead-in Dose Day 1 and Cycle 1 Day 1 were completed in the clinic.

[00403] On all visits to the study center, patients were questioned in regard to compliance with study medications. Patients were provided with a patient diary to record the date and time they took the study treatment on each occasion, as well as record any missed doses. They were instructed to bring the diary with them to every clinic visit, where it was reviewed for compliance by the study site staff.

[00404] Part A

[00405] Dose levels for evaluation were outlined below.

[00406] Level 1 : Compound B at 2 mg QD and Compound A at 15 mg QD

[00407] Level 2: Compound B at 2 mg QD and Compound A at 20 mg QD

[00408] Level 3a: Compound B at 3 mg and Compound A at 20 mg given QD for 5 days followed by a 2-day break (intermittent dosing regimen)

[00409] Level 4a: Compound B at 4 mg and Compound A at 20 mg given QD for 5 days followed by a 2-day break (intermittent dosing regimen)

[00410] Following review of all available safety, efficacy, PK, and PD clinical data from patients treated in Levels 1 and 2, and in accordance with an SMC recommendation, an intermittent dosing regimen was incorporated into Part A where treatment was given for 5 days, followed by a 2- day break every week (Levels 3a and 4a). [00411] Level 4a with Compound A 20 mg + Compound B 4 mg intermittent dosing (both agents given QD for 5 days followed by a 2-day break every week) was determined to not be a tolerable dose regimen based on observed 2 events of Grade 4 thrombocytopenia with associated bleeding. To mitigate the risk of thrombocytopenia, cohorts may include a lead-in dosing period for Compound A with or without Compound B.

[99412] Following Level 4a, 2 new dose levels, including lead-in dosing periods, were explored as follows:

[00413] Level 3b: included a lead-in dose of Compound B 3 mg + Compound A 10 mg given QD for 5 days followed by a 2-day break (intermittent dosing regimen) for 14 days, followed by Compound B 3 mg + Compound A 20 mg given QD for 5 days followed by a 2-day break (intermittent dosing regimen) for each 28-day cycle.

[00414] Level 3c: included a lead-in dose of Compound B 2 mg BID + Compound A 10 mg QD given for 5 days followed by a 2-day break (intermittent dosing regimen) for 14 days, followed by Compound B 2 mg BID + Compound A 15 mg QD given for 5 days followed by a 2-day break (intermittent dosing regimen) for each 28-day cycle.

[00415] Compound B BID dosing was evaluated as it provided more consistent study drug exposure as observed in prior clinical studies. Compound B has been administered as a monotherapy at doses ranging from 1 mg QD to 30 mg BID utilizing several different dosing regimens. At doses < 10 mg BID given on a 3 weeks on/1 week off schedule, the safety profile of single-agent Compound B in patients with advanced cancer (N=19) or with NF1-PN (N=19; 3 mg or 4 mg BID) has been characterized by mostly manageable and reversible toxicides. The most frequently reported adverse events have been rash, nausea, vomiting, diarrhea, and fatigue, with most events being mild-to-moderate in severity.

[90416] These doses and schedules of the combination regimen were chosen based on an overall assessment of available clinical data (including safety, tolerability, PK, and other clinical findings).

[00417] The dose levels in subsequent cohorts may be modified by the sponsor in consultation with the SMC based on the evaluation of all available study data. Additional dose levels or dosing regimens (with or without the lead-in, along with lower, intermediate, or higher doses, and/or BID dosing, either intermittently or continuously, for Compound A and/or Compound B) may be considered. Any modification of dose levels or dosing regimens were reviewed and approved by the SMC and the sponsor.

[00418] Part B

[00419] The sponsor made a recommendation on the selection of the Compound A /Compound B dose and schedule based on available safety, tolerability, efficacy, PK, and other clinical data from Part A.

[00420] Overdose

[00421] In a suspected overdose situation, emergency and supportive care should be initiated. [00422] Any overdose or incorrect administration of study treatment should be noted on the study treatment administration electronic case report form (eCRF). Adverse events associated with an overdose or incorrect administration of study treatment were recorded on the Adverse Event eCRF. If an overdose or incorrect administration of study treatment takes place, the sponsor was required to be immediately notified (within 24 hours of awareness).

[00423] Dose Delay and Modification

[00424] Every effort was made to administer the study treatment according to the planned dose and schedule. In the event of significant toxicides, dosing may be delayed based on the guidelines provided below. Reasons for dose delays, the supportive measures taken, and the outcome were documented in the patient's chart and recorded in the eCRF. The tumor assessment schedule was not altered even if the administration of study treatment was delayed.

[00425] Study treatment may not occur until all treatment-related AEs have returned to baseline or Grade 1 severity except for alopecia or AEs that, in the opinion of the investigator, were not considered a safety risk for the patient. If a treatment delay was due to worsening of hematologic or biochemical parameters, the frequency of relevant blood tests should be increased as clinically indicated.

[00426] If treatment-related AEs were persistent without any improvement for more than 21 days, permanent discontinuation of the study treatment should be considered. If the patient recovers from the treatment-related AE, re-initiation of study treatment was permitted only in patients who were deemed to be deriving clinical benefit per the opinion of the investigator and needs to be agreed between the investigator and the sponsor’s medical monitor or designee. Two occurrences of dose delays due to treatment-related AEs were permitted. In the event of a third occurrence of a toxicity which would require dose delay, permanent discontinuation of study treatment should be considered after consultation with the sponsor’s medical monitor or designee.

[00427] Dose Delay, Modification, and Permanent Discontinuation of Study Treatment

[00428] Every effort was made to administer study treatment as described in the proposed dose levels for Part A and for Part B, upon declaration of the RP2D for expansion cohorts [90429] However, in the event of significant toxicity, dosing may be interrupted and / or dose (s) modified. After any interruption lasting less than 21 days, study treatment may be resumed at the same dose or at a reduced dose depending on the toxicity, grade, prior events and number of dose reductions.

[00430] In general, a dose was reduced to the next immediate lower dose level that has been previously determined to be tolerable; a patient may have a maximum of 2 dose reductions for either or both study drugs. For patients experiencing toxicity requiring dose reduction during a lead-in period, discussion with the medical monitor must occur prior to resumption of treatment. [00431] Given the safety profiles of Compound A and Compound B, it was reasonable to assume that some toxicides may be attributable to one of the study drugs in the combination. In this case, following discussion with the medical monitor, it may be appropriate to reduce only the dose of the study drug to which the toxicity was attributed.

[00432] A patient must discontinue treatment with Compound A and Compound B if, after treatment was resumed at a lower dose, the toxicity recurs with the same or worse severity. [00433] Patients requiring more than 2 dose reductions of either or both study drugs discontinued study treatment except when, in the judgment of the treating investigator, a patient was benefitting from treatment. For these patients, treatment may be continued after consultation with and approval by the sponsor.

[90434] If considered in the best interest of the patient and consistent with local practice, investigators may use supportive measures or treatment and/or secondary prophylaxis instead of dose reductions for the next treatment.

[00435] An interruption of study treatment for more than 21 days due to any toxicity may require permanent discontinuation. However, in the judgment of the treating investigator, if the patient was deriving benefit from therapy, study treatment may be resumed only after discussion with the medical monitor and approval by the sponsor. [00436] An unscheduled visit may be performed at any time during the study. Assessments to be performed at the visit after treatment interruption were determined by the investigator, but additional PK sampling at the onset of a significant toxicity (or during its evaluation) was encouraged.

[00437] Treatment and dose modification guidelines are presented in Table 4.

[00438] Table 4: Guidelines for Toxicity Management and Dose Modifications of Study Treatment

[09439] Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; CMV, cytomegalovirus; DILI, drug- induced liver injury; EBV, Epstein-Barr virus; ECG, electrocardiogram; Hgb, hemoglobin; LVEF, left ventricular ejection fraction; QTc, corrected QT; RPED, retinal pigment epithelial detachment; RVO, retinal vein occlusion.

[90440] ^a If hepatic failure, DILI/Hy’s Law occurs, study treatment should be discontinued.

[00441] Additional Evaluations for Thrombocytopenia

[00442] For Grades 3 and 4 thrombocytopenia, additional evaluations may be done as clinically indicated. This may include anti-platelet antibody testing (prior to platelet transfusion or other empiric treatment such as glucocorticoids or IVIG, or other, if possible); a peripheral blood smear; thrombopoietin level testing; platelet-derived growth factor level and other (von Willebrand factor, fibrin) testing; and a bone marrow biopsy. These tests may be carried out locally or centrally as available and as per institutional practice and procedures.

[00443] Patient Dose Escalation

[00444] In Part A, if a patient progressed on Compound A /Compound B without other safety concerns, the patient may be treated with a higher dose of Compound A /Compound B after consultation with the medical monitor. The higher dose must be determined to be well tolerated by previous SMC recommendation.

[00445] In Part B, no dose escalation within a given patient was allowed.

[00446] Discontinuation From Study Treatment

[00447] Patients had the right to voluntarily withdraw from the study or discontinue study treatment at any time for any reason. In addition, the investigator had the right to discontinue a patient from the study treatment at any time. Patients who discontinued study treatment early was followed for assessments of antitumor activity, safety, and survival, if possible. Every effort was made to obtain information on patients who discontinue the study treatment.

[00448] Patients discontinued study treatment for reasons, which may include, but were not limited to the following:

[00449] Patient withdrawal of consent

[00459] Pregnancy

[00451] Any medical condition that the investigator or sponsor determines may j eopardize the patient’s safety, if he or she were to continue the study treatment (i.e., RVO) [00452] Use of any concurrent anti neoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, or standard or investigational agents (including herbal medicine) for the treatment of cancer)

[00453] Patient noncompliance

[00454] STUDY ASSESSMENTS AND PROCEDURES

[00455] Patients were closely monitored for safety and tolerability throughout the study. All assessments must be performed and documented in the medical record for each patient.

[00456] Dosing occurred only if the clinical assessment and local laboratory test values (that must be available before any dosing) have been reviewed and found to be acceptable per protocol guidelines.

[00457] Screening

[00458] Screening evaluations were performed within 28 days prior to the first administration of study treatment. Patients who agree to participate signed the ICF prior to undergoing any screening procedure. Screening evaluations may be repeated as needed within the Screening Period; the investigator was to assess patient eligibility according to the latest screening assessment results.

[00459] Results of standard of care tests or examinations performed prior to obtaining informed consent and 28 days prior to the first dose of the study treatment(s) may be used for the purposes of screening rather than repeating the standard of care tests, unless otherwise indicated.

[00460] Procedures conducted at the Screening Visit only were described in this section. For the description of other assessments that were conducted at Screening as well as throughout the study.

[00461] Rescreening under limited conditions (e g., when a patient narrowly misses a laboratory criterion and it was correctable and not due to rapidly deteriorating condition or disease progression) may be allowed after consultation with medical monitor. Rescreening was allowed only once.

[00462] Demographic Data and Medical History

[00463] Demographic data included age or year of birth, sex, and self-reported race/ethnicity. [00464] Medical history includes any history of clinically significant disease, surgery, or cancer history; reproductive status (i.e., of childbearing potential or no childbearing potential); history of alcohol consumption (i.e., presence or absence); and all medications (i.e., prescription drugs, over-the- counter drugs, herbal or homeopathic remedies, nutritional supplements) used by the patient within 28 days before the first dose of study treatment.

[00465] Cancer history included cancer diagnosis, prior surgery, prior radiotherapy; prior drug therapy including start and stop dates, best response, and reason for discontinuation.

[90466] Radiographic studies performed prior to study entry may be collected for review by the investigator.

[00467] Confirmation of Eligibility

[00468] The investigator assessed and the sponsor confirmed the eligibility of each patient.

All screening procedure results and relevant medical history must be available before eligibility can be determined. Eligible patients must meet all inclusion criteria and patients who meet any of the exclusion criteria were not eligible to enroll. No eligibility waivers were granted.

[00469] After a patient was screened and the investigator determines the patient was eligible for enrollment, study site personnel completed a Treatment Authorization Packet and send it to the medical monitor or designee to approve the enrollment. Study site personnel should ensure that a medical monitor approval has been received before dosing the patient with the study treatment.

[00470] Safety Assessments

[00471 ] Vital signs, weight, physical examination, ophthalmological examination, ECOG performance status, ECG, ECHO and laboratory safety tests were obtained and assessed at designated intervals throughout the study. Adverse events and SAEs were assessed throughout the study.

[00472] The continuous safety evaluation was performed by the sponsor or designee. An SMC recommended dose levels and/or dosing regimens to be administered during dose escalation and for Part B portion of this study.

[00473] Vital Signs

[00474] Vital signs included measurements of temperature, heart rate, respiratory rate, and blood pressure (systolic and diastolic) after the patient has been sitting for at least 5 minutes. Vital signs should be taken within 60 minutes pre-dose and within 60 minutes post-dose at each specified visit. [00475] Height and weight were to be recorded. Weight was to be recorded using the same scales at each time point.

[00476] Physical Examinations

[00477] During the Screening Visit, a complete physical examination was conducted, including evaluation of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 4) musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) neurological systems. Any abnormality identified at baseline were recorded on the Medical History eCRF with appropriate disease/condition terms.

[00478] At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations were performed. Changes from baseline were recorded. New or worsened clinically significant abnormalities were to be recorded as AEs on the Adverse Event eCRF.

[00479] Eastern Cooperative Oncology Group Performance Status

[00480] Eastern Cooperative Oncology Group Performance Status were assessed during the study.

[00481] Laboratory Safety Test

[00482] Laboratory assessments (serum chemistry, hematology, coagulation, and urinalysis) were shown. A local or central laboratory may be used. If a central laboratory was used, details about sample collection and shipment were provided in a separate instruction manual.

[00483] Investigators may use results from local laboratories for safety monitoring and dosing decision. Local testing was preferred for all sites and were determined during the site set up.

[00484] If laboratory tests at screening were not performed within 96 hours prior to the first initiation of study treatment, these tests should be repeated and reviewed within 72 hours before study treatment administration. For subsequent cycles, complete blood count with differential and serum chemistry should be performed and results reviewed within 72 hours before study treatment administration.

[00485] Electrocardiograms

[00486] A centralized ECG laboratory may be used in this study in selected study sites. Calibrated ECG machines were provided to these sites and ECG collected from the sites were reviewed centrally. In other sites, local ECG machines were used. [09487] For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. Paper or electronic copies of ECG tracings were kept as part of the patient's study fde at the site.

[00488] At each time point, 3 consecutive 12-lead ECGs were performed approximately 2 minutes apart to determine the mean QTcF interval. When coinciding with blood draws, ECG assessment should be performed after vital signs were collected and prior to blood draws.

[00489] Patients rested in semi-recumbent supine position for at least 5 minutes prior to ECG collection.

[00490] Echocardiogram

[00491] An ECHO or multigated acquisition (MUGA) scan to assess left ventricular ejection fraction (LVEF) were conducted in both the escalation and expansion cohorts. Specifically, this were performed at screening, at 4 (± 1) and 12 (± 1) weeks after Cycle 1 Day 1 of Compound A/Compound B , and every 12 (± 1) weeks thereafter. The modality of the cardiac function assessments must be consistent within each patient (e.g., if an ECHO was performed for the screening assessment, then an ECHO also should be performed for subsequent scans). The patient also should be examined using the same machine and operator whenever possible.

[90492] Ophthalmology Examination

[00493] Full ophthalmic assessment, including slit lamp examination, was performed at screening, every 8 (± 1) weeks after the first dose of Compound A/Compound B during the first year, and every 12 (± 1) weeks thereafter. If a patient experiences any visual symptoms (including blurred vision) or signs and symptoms of toxicity, an ophthalmic examination should be performed as soon as possible to address any ophthalmic signs and symptoms. Additional tests were conducted if clinically indicated. Any clinically significant findings and symptoms, including those confirmed by the ophthalmologist, must be reported as an AE.

[00494] Adverse Events

[00495] Adverse events were graded and recorded throughout the study. Characterization of toxicities included severity, duration, and time to onset.

[00496] All AEs, including SAEs, were collected. At the end of treatment, ongoing AEs considered related to study treatment were followed until the event has resolved to baseline or Grade 1, the event was assessed by the investigator as stable, the patient was lost to follow-up, the patient withdraws consent, or it has been determined that study treatment or participation was not the cause of the AE.

[00497] Tumor and Response Evaluations

[00498] Tumor imaging were performed within 28 days prior to the first study treatment. Results of standard-of-care tests or examinations performed prior to obtaining informed consent 28 days prior to the first administration of study treatment may be used for the purposes of screening rather than repeating the standard of care tests. Radiological assessment of tumor response was performed approximately every 8 (± 1) weeks after Cycle 1 Day 1 in the first year and approximately every 12 (± 1) weeks thereafter.

[00499] Tumor assessments must include CT scans (with oral/IV contrast, unless contraindicated) or MRI, with preference for CT, of the chest, abdomen, and pelvis. All measurable and evaluable lesions were assessed and documented at the Screening Visit and reassessed at each subsequent tumor evaluation. The same radiographic procedure used to assess disease sites at screening was required to be used throughout the study (i.e., the same contrast protocol for CT/MRI scans).

[00500] Imaging of the brain (MRI or CT) was required during screening.

[00501] If a patient was known to have a contraindication to CT contrast media or develops a contraindication during the study, a non-contrast CT of the chest plus a

[00502] contrast-enhanced MRI (if possible) of abdomen and pelvis should be performed.

[00503] If a CT/MRI scan for tumor assessment was performed in a positron emission tomography (PET)/CT scanner, the CT/MRI acquisition must be consistent with the standards for a full contrast diagnostic CT/MRI scan.

[00504] CT scans of the neck or extremities should also be performed if clinically indicated and followed throughout the study, if there was evidence of metastatic disease in these regions at screening. At the investigator’s discretion, other methods of assessment of target lesion and nontarget lesions per RECIST 1.1 may be used.

[00505] Tumor response were assessed by the investigators using RECIST 1.1. The same evaluator should perform assessments, if possible, to ensure internal consistency across visits. [00506] After the first documentation of response (CR or PR), confirmation of tumor response should occur at 4 weeks or later 4 weeks) after the first response or at the next scheduled assessment time point. [00507] Patients who discontinued study treatment early for reasons other than disease progression (e.g., toxicity) continued to undergo tumor assessments following the original plan until the patient began a subsequent anticancer treatment, experiences disease progression, withdraws consent, dies, or until the study terminated, whichever occurred first.

[00508] All patients’ files and radiologic images must be available for source verification and for potential peer review.

[00509] Pharmacokinetic Assessment

[00510] The following assessments were performed at a bioanalytical laboratory:

[00511] PK assay: plasma samples were assayed for Compound A (and possibly its major metabolites), Compound B, and Compound B’s metabolite concentrations with use of a validated chromatography assay.

[00512] Shipping, storage, and handling of samples for the assessment of PK assays were managed through a central laboratory. Instruction manuals and supply kits were provided for all laboratory assessments.

[00513] Biomarkers

[00514] Shipping, storage, and handling of tumor tissues and blood samples for the assessment of biomarkers were managed through a central laboratory. Refer to the laboratory manual for details of sample handling.

[00515] Patient eligibility was determined based on a tumor mutation identified by central laboratory testing or by a local assay result obtained in the tumor tissue sample collected at any time prior to screening.

[00516] If a patient in Part A was enrolled based on the result of a local assay, the result should be confirmed by the central laboratory at any time. When possible, the tumor sample tested centrally should be from the same block as the sample tested locally.

[00517] If a patient in Part B was enrolled based on the result of a local assay, the result must be confirmed by the central laboratory within 45 days of the first dose of study treatment. When possible, the tumor sample tested centrally should be from the same block as the sample tested locally.

[00518] If there was non-concordance between the local and central laboratory results, or if the local result cannot be confirmed by central laboratory (e.g., inadequate sample or poor sample quality) within 45 days of first dose, patients may continue receiving study treatment provided there was no clinical deterioration or disease progression and the patient was benefitting from study treatment, as determined by the investigator and in consultation with the sponsor medical monitor. In such cases, patients were informed as soon as possible that their mutation status was unconfirmed.

[00519] Definitive central laboratory mutation results (positive or negative) cannot be repeated. If a sample was determined to be inadequate or the result was indeterminate on central testing, an additional sample may be resubmitted to the laboratory for retesting.

[00520] Mutation status and patient responses were analyzed together to enable potential development of companion diagnostics for patients most likely to benefit from treatment in the future.

[00521] Baseline tumor tissue sample was mandatory for mutation and biomarker analysis, either from archived tumor tissue or fresh tumor biopsies. A follow-up biopsy may be taken (ideally from the same tumor lesion if it was readily accessible) at Cycle 3 and when the patient stops treatment due to disease progression. For Group 2 in Part B paired fresh tumor biopsies to assess PD biomarkers were mandatory; the first biopsy was collected during the 8 weeks before the first dose and again at a time post-dose to assess PD biomarkers. In addition, blood samples were collected from all patients for mutation profiling by next generation sequencing. Additional biomarker analysis from the blood might also be conducted by other assay types, such as RNA- Seq.

[00522] Tumor tissue was of good quality based on total and viable tumor content. Fine needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples were not acceptable.

[00523] Fresh biopsies were limited to readily accessible tumor lesions (i.e., skin; peripheral lymph nodes; lung, liver or internal lymph node metastases which can be readily accessed using CT guidance). If performed, a tissue cylinder should be obtained that has a proper size for histological examination and biomarker analysis (i.e., pERK; genomic profiling).

[00524] Archival tumor tissues (formalin-fixed paraffin-embedded block with tumor tissue or approximately 15 unstained slides) and fresh tumor biopsies were sent to a central laboratory for central immunohistochemistry assays and mutation profiling. In addition to BRAF, ARAF, RAFI, KRAS, NRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, EGFR, GNA11, GNAQ, PIK3CA, PTK3CB, PTEN, AKT1 , MET, KIT, and TGF1R mutations, other markers that were related to response or clinical benefit of Compound A/Compound B may also be evaluated. [00525] Visit Windows

[00526] All visits occurred at the scheduled date, unless otherwise noted. Assessments scheduled on the day of study treatment administration (Day 1) of each cycle were performed prior to study treatment unless otherwise noted. Laboratory results were required to be reviewed prior to dosing. If the timing of a protocol -mandated study visit coincided with a holiday, weekend, or other events, the visit was scheduled on the nearest feasible date.

[00527] STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION

[00528] The statistical analyses were performed by the sponsor or designee after the study was completed and the database was locked and released.

[00529] Statistical Analysis

[00530] Analysis Sets

[00531] Safety Analysis Set included all patients who received at least 1 dose of study treatment (either Compound A or Compound B).

[00532] Efficacy Evaluable Analysis Set included all dosed patients who have evaluable disease at baseline, and at least 1 evaluable postbaseline tumor response assessment.

[00533] DLT Evaluable Analysis Set included patients who received at least 80% of the assigned dose of Compound A and Compound B during the dose-escalation phase (Part A) or who experienced a DLT during the dose-escalation phase (Part A).

[00534] PK Analysis Set included all dosed patients for whom valid Compound A or Compound B PK parameters can be estimated.

[00535] PD Analysis Set includes all patients with valid PD sampling after treatment with Compound A/Compound B.

[00536] Patient Disposition

[00537] The number of patients treated, discontinued from study treatment and/or study, and those with critical and/or major protocol deviations were counted. The primary reason for study treatment and/or study discontinuation were summarized according to the categories in the eCRF. The end of study status (alive, dead, withdrew consent, or lost to follow-up) at the data cutoff date were summarized using the data from the eCRF. [00538] Critical and/or major protocol deviations were summarized and listed by each category.

[00539] Efficacy Analysis

[00540] The efficacy endpoints were analyzed using the Efficacy Evaluable Analysis Set except for PFS which were analyzed using the Safety Analysis Set.

[00541] Summaries were provided for each dose level in Part A if deemed appropriate and for each patient group in Part B.

[00542] For the analysis of ORR, disease control rate, and clinical benefit rate, summary tables presenting the number and proportion of responders and non-responders, together with the two- sided exact (Clopper-Pearson) 95% Cis for response rates were presented. A summary of each response category of the best overall response (confirmed CR, confirmed PR, unconfirmed CR, unconfirmed PR, stable disease, or PD) were presented as well. Waterfall plots of maximum tumor shrinkage per patient were presented.

[00543] The time-to-event endpoints, including PFS and duration of response were analyzed by Kaplan-Meier methods. The survival functions of the time-to-event endpoints were summarized for the 25th percentile, median, and 75th percentile and their 95% Cis. The rates of [00544] PFS and duration of response at Month 3 and every subsequent 3 months as appropriate and their 95% Cis were derived based on Kaplan-Meier estimates. In addition, the graphs of Kaplan- Meier estimates of survival functions were presented.

[00545] Safety Analysis

[00546] Safety endpoints (other than DLTs) were summarized using the Safety Analysis Set. All summaries of safety were by dose level for Part A and by group for Part B.

[00547] Extent of Exposure

[00548] Treatment exposure were summarized descriptively for each of the 2 study treatments. Measures of extent of exposure included the number of treatment cycles received, duration of exposure, dose intensity, relative dose intensity and cumulative dose received. The number of patients with dose delay and reason for dose discontinuation were summarized as well, as appropriate.

[00549] Adverse Events

[00550] Adverse events were coded using MedDRA, and AE data were summarized by system organ class and preferred term. The frequency and percentage of patients by reported system organ class /preferred term were summarized, with the number of AEs counted as well. Adverse events were also summarized by worst AE severity/grade and AE relationship to each study treatment. In addition, the number of SAEs and TEAEs that lead to discontinuation of study treatment was also summarized.

[00551] For Part A, DLTs were summarized for the DLT Evaluable Analysis Set.

[00552] All AE summaries were restricted to TEAEs only. Treatment-emergent AEs were defined as AEs which commence on or after the time of start of study treatment.

[00553] A by-subject AE data listing, including verbatim term, MedDRA system organ class and preferred term, severity, outcome and relationship to study treatment, were provided. Separate listings were generated for serious AEs and AEs leading to discontinuation of study treatment.

[00554] Laboratory Analyses

[00555] Clinical laboratory (e.g., hematology, serum chemistry) values were evaluated for each laboratory parameter as appropriate. Abnormal laboratory values were flagged and identified as those outside (above or below) the normal range. Reference (normal) ranges for laboratory parameters were included in the clinical study report for this protocol. Descriptive summary statistics (e.g., n, mean, standard deviation, median, minimum, maximum for continuous variables; n (%) for categorical variables) for laboratory parameters and their changes from baseline were calculated. Laboratory values were summarized by visit and by worst postbaseline visit.

[00556] Laboratory parameters were summarized by CTCAE Grade. In the summary of laboratory parameters by CTCAE Grade, parameters with CTCAE grading in both high and low directions (e.g., glucose, potassium, sodium) were summarized separately.

[00557] Vital Signs

[00558] Vital sign measurements and change from baseline were summarized at each protocol scheduled time point. Actual values and changes from baseline were presented.

[00559] Physical Examination

[00560] Newly occurring or worsening clinically significant abnormalities identified on physical examination were captured as AEs, and was not summarized or listed separately. [00561] 12-lead ECG [09562] Descriptive statistics were calculated for 12-lead ECG parameters, including change from baseline for all time points assessed. In addition, the overall interpretation of 12-lead ECG results was classified using frequency counts and percentages for the categories of normal, abnormal not clinically significant and abnormal clinically significant for all time points assessed, as applicable. Markedly abnormal QT interval corrected for heart rate (QTc) were also [90563] summarized as per the Food and Drug Administration guidance for Industry E14. Further details were provided in the Statistical Analysis Plan.

[00564] ECOG Performance Status

[00565] Shifts from baseline in ECOG performance status were summarized descriptively using frequency counts and percentages at all postbaseline protocol scheduled time points. [00566] Echocardiogram

[00567] Descriptive statistics were calculated for left ventricular ejection fraction (LVEF), including change from baseline for all time points assessed. In addition, abnormal clinically significant for all time points was also assessed, as applicable. Further details were provided in the Statistical Analysis Plan.

[00568] Ophthalmology Examination

[00569] Newly occurring or worsening clinically significant abnormalities after the first dose of study treatment identified on ophthalmology examination were captured as AEs and was not summarized separately.

[00570] Pharmacokinetic Analysis

[00571] PK variables (e.g., AUC, Cmax, and Tmax) were calculated for Compound B, its active metabolite Compound B’s metabolite, and Compound A as appropriate using noncompartmental methods. Summary statistics were provided. Additional PK parameters, including those of the potential metabolite(s) of Compound A, may also be calculated if available. The plasma concentration data and PK parameters were tabulated and summarized for each cycle at which pharmacokinetics were to be measured in Part A and Part B. Descriptive statistics included means, medians, minimums, maximums, standard deviation, coefficient of variation (CV), geometric mean, and geometric CV as appropriate. Mean plasma concentrations was also plotted against time for each dose level. Additional PK analyses may be conducted as appropriate. [00572] Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. Results of such analyses may be reported separately from the clinical study report.

[00573] Other Exploratory Analyses

[00574] Summary statistics were provided for PD biomarkers, including but not limited to immune cell subtypes in the blood. An exploratory analysis on a potential correlation of these pharmacodynamic markers with the dose, safety, and antitumor activity were performed as appropriate.

[00575] Exploratory predictive biomarker analyses were performed in an effort to understand the association of these markers with study treatment response, such as efficacy. Exploratory analyses of other candidate predictive biomarkers were conducted similarly.

[00576] Sample Size Consideration

[00577] The study planned to enroll approximately 75 to 105 patients.

[00578] Part A: Approximately 30 to 60 patients for the dose-escalation phase until MTD and/or RP2D determination

[00579] Part B: Approximately 45 patients for expansion in 3 selected groups (15 patients per group). Each group were evaluated separately and can be closed due to lack of clinical efficacy based on statistical evaluation or insufficient patient recruitment. If promising preliminary efficacy results have been observed in 1 of the groups after treating all planned patients (i .e., higher ORR or longer PFS), more numbers of patients could be added to the group to further assess the efficacy of the combination before moving into Phase 2/3 clinical development or regulatory discussions.

[00580] The probability of observing at least 2 responders in the first 15 patients from an expansion group was approximately 83% when the underlying ORR was 20%. The lower bound of 90% CI using the exact method was 9.1% when the observed ORR was 20% in 30 patients. [00581] Interim Analyses

[00582] No formal inference related interim analysis was conducted. However, sponsor may request interim descriptive analyses of safety and preliminary efficacy data. The interim analyses were for the purpose of safety monitoring and planning of future studies and were not impact on the conduct of this study. Every effort was made to keep the bias possibly associated with interim analyses to a minimal level. [00583] Safety results

[00584] A TEAE was defined as an AE that had an onset date or a worsening in severity from baseline (pretreatment) on or after the first dose of study drug and A 30 days after the last dose of study drug or initiation of new anticancer therapy, whichever occurs first.

[00585] The most commonly occurring TEAEs by PT 10%) were fatigue (23 patients, 60.5%); dermatitis acneiform (17 patients, 44.7%); diarrhea (15 patients, 39.5%); constipation (12 patients, 31.6%); alopecia (11 patients, 28.9%); headache (10 patients, 26.3%); rash maculopapular and muscle spasms (each in 9 patients, 23.7%); abdominal pain, dry mouth, nausea, and vomiting (each in 8 patients, 21.1%); pyrexia, dry skin, rash, decreased appetite, and thrombocytopenia (each in 7 patients, 18.4%); alanine aminotransferase increased and hypertension (each in 6 patients, 15.8%); gastrooesophageal reflux disease, aspartate aminotransferase increased, dizziness, cough, and neutropenia (each in 5 patients, 13.2%); and influenza-like illness, photosensitivity reaction, arthralgia, myalgia, pain in extremity, hypokalaemia, urinary tract infection, dysphonia, dyspnoea, and anaemia (each in 4 patients, 10.5%).

[00586] Treatment-Emergent Adverse Events by Severity

[00587] Treatment-emergent AEs 2 ^s Grade 3 occurring in patients overall by SOC and PT were presented overall and by Cohort.

[00588] As of the data cutoff date of 12 November 2021, a total of 15 (39.5%) patients had at least 1 ^Grade 3 TEAEs; 1 patient (16.7%) in Cohort 1 (Compound A 15 mg + Compound B 2 mg), 6 patients (75.0%) in Cohort 2 (Compound A 20 mg + Compound B 2 mg), 3 patients (42.9%) in Cohort 3a (Compound A 20 mg + Compound B 3 mg), and 5 patients (83.3%) in Cohort 4a (Compound A 20 mg + Compound B 4 mg). No patients (0%) reported Grade 3 TEAEs in Cohort 3b (Compound A 20 mg + Compound B 3 mg lead-in), Cohort 3c (Compound A 15 mg + Compound B 2 mg BID lead-in), and Cohort 4c (Compound A 15 mg + Compound B 3 mg BID lead-in). Overall, the most commonly occurring Grade 3 TEAEs were thrombocytopenia, small intestinal obstruction, and alanine transferase increased (each in 3 patients, 7.9%); small intestinal obstruction was related to underlying disease in each case.

[00589] Treatment-Emergent Adverse Events Assessed as Related to Study Treatment [00590] TEAEs assessed as related to any treatment (Compound A or Compound B) occurred in 33 patients (86.8%).

[00591] A total of 32 patients (84.2%) experienced at least 1 TEAE assessed as being related to Compound A . There were 5 patients (83.3%) in Cohort 1 (Compound A 15 mg + Compound B 2 mg), 8 patients (100%) in Cohort 2 (Compound A 20 mg + Compound B 2 mg), 7 patients (100%) in Cohort 3a (Compound A 20 mg + Compound B 3 mg), 5 patients (83.3%) in Cohort 4a (Compound A 20 mg + Compound B 4 mg), 4 patients (66.7%) in Cohort 3b (Compound A 20 mg + Compound B 3 mg with lead-in), 3 patients (100%) in Cohort 3c (Compound A 15 mg + Compound B 2 mg BID with lead-in), and no patients (0%) in Cohort 4c (Compound A 15 mg + Compound B 3 mg BID with lead-in) who experienced TEAEs assessed as being related to Compound A . Overall, the most frequent events occurred in the SOCs skin and subcutaneous tissue disorders (26 patients, 68.4%), general disorders and administration site conditions (19 patients, 50.0%), gastrointestinal disorders (15 patients, 39.5%), and investigations (12 patients, 31.6%). Common TEAEs (^ 10% of patients) assessed by investigator as related to Compound A were dermatitis acneiform and fatigue (15 patients, 39.5%); alopecia, diarrhea, and thrombocytopenia (each in 7 patients, 18.4%); rash, pyrexia, alanine aminotransferase increased, and neutropenia (each in 5 patients, 13.2%); dry skin, nausea, aspartate aminotransferase increased, and hypertension (each in 4 patients, 10.5%).

[00592] Treatment-Emergent Adverse Events Assessed as Related to Compound A by Severity

[00593] Treatment-emergent AEs Grade 3 assessed as related to Compound A by SOC and PT were presented overall.

[00594] As of the data cutoff date of 12 November 2021, a total of 8 (21.2%) patients had at least 1 Grade 3 TEAEs assessed by investigator as related to Compound A , including 1 patient (16.7%) in Cohort 1 (Compound A 15 mg + Compound B 2 mg), 3 patients (37.5%) in Cohort 2 (Compound A 20 mg + Compound B 2 mg), 1 patient (14.3%) in Cohort 3a (Compound A 20 mg + Compound B 3 mg), and 3 patients (50.0%) in Cohort 4a (Compound A 20 mg + Compound B 4 mg).

[00595] No patients (0%) in Cohort 3b (Compound A 20 mg + Compound B 3 mg with lead- in), Cohort 3c (Compound A 15 mg + Compound B 2 mg BID with lead-in), and Cohort 4c (Compound A 15 mg + Compound B 3 mg BID with lead-in) reported any TEAEs Grade 3. [00596] Overall, the SOC with the most patients with at least 1 2s Grade 3 TEAE that were assessed by investigator as being related to Compound A was blood and lymphatic system disorders (5 patients, 13.2%). Three (7.9%) of those patients experienced thrombocytopenia. One (2.6%) patient experienced anaemia and febrile neutropenia.

[00597] Treatment-Emergent Serious Adverse Events

[00598] Serious TEAEs occurring in the Safety Analysis Set were presented by SOC and PT for overall and by Cohort.

[00599] Overall, the most frequent serious TEAEs (in 2s 5% patients) occurred in the SOCs gastrointestinal disorders (6 patients, 15.8%), blood and lymphatic system disorders (5 patients, 13.2%), general disorders and administration site conditions and infections and infestations (each had 4 patients, 10.5%), and investigations (2 patients, 5.3%).

[00600] Of the 38 patients, 17 patients (44.7%) experienced at least 1 serious TEAE, including 2 patients (33.3%) in Cohort 1 (Compound A 15 mg + Compound B 2 mg), 5 patients (62.5%) in Cohort 2 (Compound A 20 mg + Compound B 2 mg), 4 patients (57.1%) in Cohort 3a (Compound A 20 mg + Compound B 3 mg), 4 patients (66.7%) in Cohort 4a (Compound A 20 mg + Compound B 4 mg), 1 patient (16.7%) in Cohort 3b (Compound A 20 mg + Compound B 3 mg with lead-in), 1 patient (33.3%) in Cohort 3c (Compound A 15 mg + Compound B 2 mg BID with lead-in), and no patients (0%) in Cohort 4c (Compound A 15 mg +Compound B 3 mg BID with lead-in) reported serious TEAEs.

[00601] Overall, the most common serious TEAEs (2= 10%) were thrombocytopenia in 4 patients (10.5%), occurring in 2 patients (33.3%) in Cohort 4a, 1 patient each in Cohort 1 (16.7%) and Cohort 2 (12.5%), and no patients (0%) in Cohort 3a, Cohort 3b, Cohort 3c, and Cohort 4c.

[00602] Serious Treatment-Emergent Adverse Events by Severity

[00603] Serious TEAEs 2s Grade 3 by SOC and PT occurring in the Safety Analysis Set were presented overall and by Cohort.

[00604] A total of 13 (34.2%) patients had at least 1 serious TEAEs 2s Grade 3; 1 patient (16.7%) in Cohort 1 (Compound A 15 mg + Compound B 2 mg), 5 patients (62.5%) in Cohort 2 (Compound A 20 mg + Compound B 2 mg), 3 patients (42.9%) in Cohort 3a (Compound A 20 mg + Compound B 3 mg), and 4 patients (66.7%) in Cohort 4a (Compound A 20 mg + Compound B 4 mg). No patients in Cohort 3b (Compound A 20 mg + Compound B 3 mg with lead-in), Cohort 3c (Compound A 15 mg + Compound B 2 mg BID with lead-in), and Cohort 4c (Compound A 15 mg + Compound B 3 mg BID with lead-in) reported any serious TEAEs Grade 3.

[00605] Overall, the most common iA Grade 3 serious TEAEs 10% patients) by SOC were gastrointestinal disorders (5 patients, 13.2%) and blood lymphatic system disorders (4 patients, 10.5%).

[00606] Overall, the most common A Grade 3 serious TEAEs 5% patients) by PT were thrombocytopenia (3 patients, 7.9%); 1 patient (12.5%) in Cohort 2 and 2 patients (33.3%) in Cohort 4a, and small intestinal obstruction (3 patients, 7.9%); 1 patient each in Cohort 2, Cohort 3a, and Cohort 4a (12.5%, 14.3%, and 16.7% respectively).

[00607] Conclusion for safety assessment

[00608] The inventors surprising and unexpectedly discovered that the inclusion of the lead-in dose regimen reduced the severity and occurrence of the side effects, and thus, achieved tolerable toxicity. The inventors further surprising and unexpectedly discover that the inclusion of the intermittent dosing regimen reduced the severity and occurrence of the side effects as well, and thus, achieved tolerable toxicity.

[00609] Conclusion for therapeutic effects

[00619] Of the 37 patients, 11 patients had objective response including 1 complete response, and 10 partial responses. Thus, the objective response rate was 29.7%.

[00611] Of the 37 patients, 36 patients had disease control including 1 complete response, 10 partial responses, and 15 stable disease responses. Thus, the disease control rate was 70.3%.

[00612] Of the 37 patients, 11 patients had responses including 1 complete response, and 10 partial responses. Thus, the overall response rate was 29.7%.

[00613] Table 5 provides details with respect to the objective response data and disease control data. [00614] Table 5: Disease response (Evaluable Population)

00615] BOR: Best Overall Response; CR: Complete Response; PR: Partial Response; SD: Stable Disease; PD: Progressive Disease; NE/NA: Not Evaluable/Not Assessed; CI: Confidence Interval; ORR: Objective Response Rate (ORR ~ CR+PR); DCR: Disease Control Rate (DCR ~ CR+PR+SD); CBR: Clinical Benefit Rate; DOR: Duration of Response

[00616] For DOR, Percentages are based on number of Responders

[00617] Durable SD is stable disease lasting 24 weeks

[00618] Objective response rate (ORR) = 11/37 (29.7%): 1 CR + 10 PR

[00619] Disease control rate (DCR) = 26/37 (70.3%): 1 CR + 10 PR + 15 SD

[00620] Fig. 1 describes the best change (%) from baseline in sum of diameters per

RECIST 1.1 (efficacy in total 37 evaluable patients). Fig. 1 showed the following:

[00621] 11/37 (29.7%) overall response rate

[00622] 17/37 (45.9%) efficacy evaluable pts are ovarian

[00623] 11/17 (64.7%) ovarian patients have LGSOC

[00624] 7/11 (63.6%) responders in evaluable LGSOC

[00625] Other ovarian cancer did not show response

[00626] 1 NSCLC showed PR

[00627] Fig. 3 describes the best change (%) from baseline in sum of diameters per RECIST 1. 1 LGSOC patients.

[00628] Thus, the inventors surprising and unexpectedly discovered the combination of Compound A and Compound B showed therapeutic effects on cancers in a clinical trial with tolerable toxicity.

EXAMPLE 4

[00629] 9 dose levels, with a DLT window in Cycle 1 of 28 days, with and without lead-in dosing, as follows:

[00630] Continuous dosing

• Level 1 : M 2 mg QD + L 15 mg QD

• Level 2: M 2 mg QD + L 20 mg QD

[00631] 5 days on, 2 -day off (5/2-day intermittent)

• Level 3a: M 3 mg QD + L 20 mg QD

• Level 4a: M 4 mg QD + L 20 mg QD

[00632] Lead-in dosing (5/2-day intermittent) for 14 days, then 5/2-day intermittent dosing for each 28-day cycle

• Level 3b: (lead-in dose of M 3 mg QD + L 10 mg QD) M 3 mg QD + L 20 mg QD • Level 3c: (lead-in dose of M 2 mg BID + L 10 mg QD) M 2 mg BID + L 15 mg QD

• Level 4b: (lead-in dose of M 2 mg BID + L 10 mg QD) M 2 mg BID + L 20 mg QD

• Level 4c: (lead-in dose of M 3 mg BID + L 10 mg QD) M 3 mg BID + L 15 mg QD

• Level 5c: (lead-in dose of M 4 mg BID + L 10 mg QD) M 4 mg BID + L 15 mg QD

[00633] BID, twice a day; DLT, dose-limiting toxicity; L, lifirafenib; M, mirdametinib;

MTD, maximum tolerated dose; PK, pharmacokinetic(s); QD, once a day; RP2D, recommended phase 2 dose.

[00634] Overall Summary of Safety results are provided in the following table.

[00635]

[00636] 5.2, 5 days dosing followed by a 2-day break; BID, twice a day; DLT, dose limiting toxicity; L, lifirafenib QD, once a day; SAE, serious adverse event; TEAE, treatment-emergent adverse event. a Lead-in dosing occurred for 14 days as follows: DL 3b (M 3 mg QD + L 10 mg QD),

DL3c (M 2 mg BID + L 10 mg QD),

DL 4b (M 2 mg BID + L 10 mg QD), and DL 4c (M 3 mg BID + L 10 mg QD). Grade 3 TEAEs were reported in 42.9% of patients and SAEs in 41.1%; treatment-related TEAEs were seen in 89.3% of patients for each agent.

[00637] The most frequently reported treatment-related TEAEs for both study treatments were fatigue (L, 33.9%), diarrhea (L, 25.0%), and nausea (L, 16.1%). [00638] The most frequently reported SAEs and treatment-related SAEs were thrombocytopenia and pyrexia (each 7.1%); no thrombocytopenia was reported after the lead-in dose.

[00639] The incidence of DLT events was low; DLTs occurring in more than 1 patient included thrombocytopenia and febrile neutropenia (2 patients each); no DLTs occurred after the lead-in approach.

[00640] The incidence of TEAEs leading to treatment discontinuation was low (5.4%). [00641] There were no safety issues observed for skin and ocular toxicity.71 patients were treated across 9 dose levels evaluating different dosing regimens. Results suggest that lifirafenib in combination with mirdametinib demonstrated a favorable safety profile, with low incidence of dose limiting toxicities and treatment-emergent adverse events that led to dose discontinuations. The most common treatment-related adverse events related to lifirafenib and/or mirdametinib (>15%) were dermatitis acneiform (42%), fatigue (32%), diarrhea (27%), platelet count decreased (18%), alopecia (18%), nausea (17%) and alanine aminotransferase increased (16%).

[00642] The combination showed antitumor activity in patients with various KRAS, NRAS, and BRAF mutations across several solid tumor types, including low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC), and endometrial cancer. Among 62 efficacy-evaluable patients, 14 patients (23%) had confirmed objective responses. Of 17 patients with LGSOC treated, 10 patients (59%) had objective responses, with median duration of treatment of approximately 26 months. Of the 4 endometrial cancer patients treated, 2 (50%) had objective responses in tumors that harbor BRAF fusion mutation or KRAS mutation, respectively. Of the 11 patients with NSCLC treated, 2 (18%) had objective responses in tumors that harbor NRAS mutation or BRAF V600E mutation, respectively. These data support the advancement of this combination into the dose-expansion portion of the study, which will focus on a biomarker selected patient population with a tumor agnostic approach.

[00643] The findings indicate that the combination of lifirafenib and mirdametinib treatment demonstrated antitumor activity in patients with various KRAS, NRAS, and BRAF mutations across several solid tumor types known to be driven by the MARK pathway and for which current treatment options are limited.

[00644] A number of references have been cited, the disclosures of which were incorporated herein by reference in their entirety.