EP4646209A1 - Raf inhibitor and erk1/2 and/or shp2 inhibitor combination therapy - Google Patents

Abstract

A pharmaceutical combination includes (a) a Raf inhibitor which is a Compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and/or a SHP2 inhibitor or a pharmaceutically acceptable salt thereof. A pharmaceutical combination includes (a) a Raf inhibitor which is a Compound of formula (I) or a pharmaceutically acceptable salt thereof, (b) an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and/or a SHP2 inhibitor or a pharmaceutically acceptable salt thereof, and (c) trametinib or a pharmaceutically acceptable salt thereof.

Description

WSGR Ref. 59457-781.601 RAF INHIBITOR AND ERK1/2 AND/OR SHP2 INHIBITOR COMBINATION THERAPY CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/478,890 filed January 6, 2023, and U.S. Provisional Application Serial No.63/505,646 filed June 1, 2023, which are hereby incorporated by reference in their entirety. BACKGROUND [0002] The RAS/RAF/MEK/ERK or MAPK pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Dysregulation of this pathway underlies many instances of tumorigenesis. This pathway is activated by extracellular signals that in turn induces the small G protein RAS to exchange GDP for GTP. The activated RAS small guanidine triphosphatase (GTPase) promotes the activation of the RAF (also referred to as Raf herein) family proteins (ARAF, BRAF and CRAF, also known as RAF1). Activated RAF proteins lead to the phosphorylation and activation of MEK1/2 proteins, which subsequently phosphorylate and activate extracellular signal regulated kinases (ERKs). ERKl/2 proteins phosphorylate a variety of substrates, including multiple transcription factors, and regulate key cellular activities, including proliferation, differentiation, migration, survival, and angiogenesis. [0003] Aberrant signaling or inappropriate activation of the MAPK pathway has been shown in multiple tumor types, including colorectal, lung and pancreatic cancer, and can occur through several distinct mechanisms, including activating mutations in RAS and BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B l). RAS which is a superfamily of GTPases includes KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), which is a regulated signaling protein that can be turned on (activated) by various single -point mutations, which are known as gain-of-function mutations. RAS mutations, particularly gain-of-function (GOF) mutations, have been detected in 9-30% of all cancers, with KRAS mutations having the highest prevalence (86%), followed by NRAS (11%), and, infrequently, HRAS (3%) (Cox AD, et al, Nat Rev Drug Discov 2014; 13(11):828-51). Activating KRAS mutations are also frequently found in melanoma (Fedorenko IV, et al, Br J Cancer 2015; 112(2):217-26), pancreatic cancer (di Magliano MP & Logsdon CD, Gastroenterology 2013;144(6): 1220-9), colorectal cancer (Knickelbein K & Zhang L, Genes Dis 2015;2(1):4-12) and ovarian cancer (Nakayama N, et al, Br J Cancer 2008;99(12):2020-8). SUMMARY [0004] Embodiments herein relate to a pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I) WSGR Ref. 59457-781.601 or a pharmaceutically acceptable salt thereof; and (b) an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof; a SHP2 inhibitor or a pharmaceutically acceptable salt thereof; or an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof. [0005] Embodiments herein further relate to a pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof; a SHP2 inhibitor or a pharmaceutically acceptable salt thereof; or an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof; and (c) trametinib or a pharmaceutically acceptable salt thereof. [0006] Embodiments further relate to a pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof; and (b) an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and/or a SHP2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a proliferative disease, in particular a cancer, uses of such combinations for the preparation of a medicament for the treatment of a proliferative disease, in particular a cancer; there are further provided methods of treating a proliferative disease, in particular a cancer, in a subject in need thereof comprising administering to said subject a jointly therapeutically effective amount of said combinations; there are further provided use of such combinations for the treatment of a proliferative disease, in particular a cancer; pharmaceutical compositions comprising such combinations and commercial packages thereto. [0007] Embodiments further relate to a pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof; (b) an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and/or a SHP2 inhibitor or a pharmaceutically acceptable salt thereof and (c) trametinib or a pharmaceutically acceptable salt thereof for use in the treatment of a proliferative disease, in particular a cancer, uses of such WSGR Ref. 59457-781.601 combinations for the preparation of a medicament for the treatment of a proliferative disease, in particular a cancer; there are further provided methods of treating a proliferative disease, in particular a cancer, in a subject in need thereof comprising administering to said subject a jointly therapeutically effective amount of said combinations; there are further provided use of such combinations for the treatment of a proliferative disease, in particular a cancer; pharmaceutical compositions comprising such combinations and commercial packages thereto. BRIEF DESCRIPTION OF THE DRAWINGS [0008] FIGs.1A-1E illustrate SHP2 inhibitor Compound B and a MEK inhibitor Trametinib combination showed synergy on cellular proliferation in NCI-H358 G12C KRAS mutated (FIG.1A), BRAF Class III Mutated NCI-H508 (FIG.1B) and NCI-H1666 (FIG.1C), and NF1LOF Mutated MeWo (FIG.1D) and NCI-H1838 (FIG.1E) Cells. DETAILED DESCRIPTION [0009] In some embodiments, there are provided pharmaceutical combinations comprising (a) a Raf inhibitor which is a Compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof; a SHP2 inhibitor or a pharmaceutically acceptable salt thereof; or an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof. [0010] In some embodiments, there are provided pharmaceutical combinations comprising (a) a Raf inhibitor which is a Compound of formula (I) or a pharmaceutically acceptable salt thereof; WSGR Ref. 59457-781.601 (b) an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof; a SHP2 inhibitor or a pharmaceutically acceptable salt thereof; or an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof; and (c) trametinib or a pharmaceutically acceptable salt thereof. [0011] In some embodiments, the ERK1/2 inhibitor is (S)-N-(2-amino-1-(3-chloro-5- fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole- 4-carboxamide: (compound A), or a pharmaceutically acceptable salt thereof. [0012] In some embodiments, the salt of compound A is the mandelic acid salt. In some embodiments, the salt of compound A is the benzenesulfonic acid salt. In some embodiments, the salt of compound A is the hydrochloride salt. In some embodiments, the salt of compound A is the p- toluenesulfonic acid salt. [0013] In some embodiments, the SHP2 inhibitor is (3-((3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H- pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazin-2-yl)methanol: (compound B) or a pharmaceutically acceptable salt thereof. [0014] In some embodiments, trametinib is N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)- 6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide: (compound C) or a pharmaceutically acceptable salt thereof. [0015] In cell-based assays, the Raf inhibitor which is a Compound of formula (I) demonstrated anti- proliferative activity in cell lines that contain a variety of mutations that activate MAPK signaling. In WSGR Ref. 59457-781.601 vivo, treatment with Compound of formula (I) generated tumor regression in several KRAS-mutant models including the NSCLC-derived Calu-6 (KRAS Q61K) and NCI-H358 (KRAS G12C). Collectively, in vitro, and in vivo MAPK-pathway suppression and anti-proliferative activity observed for Compound of formula (I) at well- tolerated doses suggest that Compound of formula (I) may have anti-tumor activity in patients with tumors harboring activating lesions in the MAPK pathway. Moreover, Compound of formula (I) are a Type 2 ATP-competitive inhibitor of both B-Raf and C-Raf that keeps the kinase pocket in an inactive conformation, thereby reducing the paradoxical activation seen with many B-Raf inhibitors, and blocking mutant Ras-driven signaling and cell proliferation. Compound of formula (I) exhibited efficacy in numerous MAPK-driven human cancer cell lines and in xenograft tumors representing model tumors harboring human lesions in KRAS, NRAS and BRAF oncogenes. Pharmaceutical combinations of the present embodiments further comprise an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof; a SHP2 inhibitor or a pharmaceutically acceptable salt thereof; or an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof. Further pharmaceutical combinations of the present embodiments further comprise an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof; a SHP2 inhibitor or a pharmaceutically acceptable salt thereof; or an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof; and trametinib. [0016] SHP2 plays important roles in fundamental cellular functions including proliferation, differentiation, cell cycle maintenance and motility, and regulates multiple intracellular signaling pathways in response to wide range of growth factors, cytokines, and hormones. Cell signaling processes in which SHP2 participates include MAPK, PI3K and JAK pathways. SHP2 inhibitors have the potential to attenuate upstream RTK signaling that often drives oncogenic signaling and adaptive tumor escape globally, and to become a broad-spectrum anticancer drug. [0017] The terms combination, therapeutic combination or pharmaceutical combination as used herein refer to either a fixed combination in one dosage unit form, or non-fixed combination, or a kit of parts for the combined administration where two or more therapeutic agents may be administered together, independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic, effect. [0018] The term combination therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of active ingredients or in separate formulations (e.g. , capsules and/or intravenous formulations) for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential or separate manner, either at approximately the same time or at different times. Regardless of whether WSGR Ref. 59457-781.601 the active ingredients are administered as a single formulation or in separate formulations, the drugs are administered to the same patient as part of the same course of therapy. In any case, the treatment regimen will provide beneficial effects in treating the conditions or disorders described herein. [0019] In some embodiments the combination is for simultaneous, sequential, or separate administration. By simultaneous therapeutic use, within the meaning of the present embodiments is meant an administration of at least two active ingredients by the same route and at the same time or at substantially the same time. [0020] By separate use, within the meaning of the present embodiments is meant in particular an administration of at least two active ingredients at the same time or at substantially the same time by different routes. [0021] By sequential therapeutic use is meant administration of at least two active ingredients at different times, the administration route being identical or different. More particularly by an administration method is meant according to which the whole administration of one of the active ingredients is carried out before administration of the other or others commences. [0022] In some embodiments, the combination is a fixed combination. In some embodiments, the combination is a non-fixed combination. The terms fixed combination, fixed dose and single formulation as used herein refers to a single carrier or vehicle or dosage form formulated to deliver an amount, which is jointly therapeutically effective for the treatment of cancer, of both therapeutic agents to a patient. The single vehicle is designed to deliver an amount of each of the agents along with any pharmaceutically acceptable carriers or excipients. In some embodiments, the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension. [0023] The term non-fixed combination or kit of parts means that the therapeutic agents of the combinations disclosed herein are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of a subject in need thereof. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients. [0024] The term pharmaceutically acceptable as used herein refers to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of a subject, e.g., a mammal or human, without excessive toxicity, irritation, allergic response and other problems or complications commensurate with a reasonable benefit/risk ratio. [0025] As used herein, the term pharmaceutically acceptable excipient or pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would WSGR Ref. 59457-781.601 be known to those skilled in the art. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. [0026] The term pharmaceutical composition is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order or treat a particular disease or condition affecting the subject. The present pharmaceutical combinations can be formulated in suitable pharmaceutical compositions for enteral or parenteral administration, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units. The pharmaceutical composition may contain, from about 0.1 % to about 99.9%, or from about 1 % to about 60 %, of the therapeutic agent(s). One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden. The amount of each carriers used may vary within ranges conventional in the art. The following references disclose techniques and excipients used to formulate oral dosage forms: The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003). These optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination of agents in the oral dosage form. In the latter embodiment, the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet. [0027] Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. In some embodiments, the unit dose includes one or more vehicles such that each vehicle includes an effective amount of at least one of the therapeutic agents along with pharmaceutically acceptable carriers and excipients. In some embodiments, the unit dose is one or more tablets, capsules, pills, injections, infusions, patches, or the like, administered to the patient at the same time. As is known to those skilled in the art, the amount of active ingredient per dose will depend on the condition being treated, the route of administration and the age, weight, and condition of the patient. In some embodiments, 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. WSGR Ref. 59457-781.601 [0028] The pharmaceutical compositions may include a therapeutically effective amount or effective amount of a compound disclosed herein. The term pharmaceutically effective amount, therapeutically effective amount or clinically effective amount of a combination of therapeutic agents is an amount sufficient, at dosages and for periods of time necessary, to provide an observable or clinically significant improvement over the baseline of clinically observable signs and symptoms of the disorders treated with the combination. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agents are outweighed by therapeutically beneficial effects. [0029] A therapeutically effective dosage can modulate a measurable parameter, such as tumor growth rate or disease progression in a desired manner. The ability of a compound to modulate a measurable parameter can be evaluated in an animal model system predictive of efficacy in human tumors to help establish suitable dosing levels and schedules. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to modulate an undesired parameter by using in vitro assays known to the skilled practitioner. [0030] The term jointly therapeutically active or joint therapeutic effect as used herein means that the therapeutic agents can be given jointly, separately or sequentially in such time intervals that they prefer such that the subject, especially human, to be treated, still show an (which can be synergistic) interaction (joint therapeutic effect). Whether this is the case can, inter alia, be determined by following the blood levels of the compounds, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals. [0031] 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. It is also to be understood that an agent may be a single compound or a combination or composition of two or more compounds. [0032] The term proliferative disease includes a cancer. [0033] As used herein, the term cancer refers to a disease characterized by the undesired and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. As used herein, the term cancer or tumor includes premalignant, as well as malignant cancers and tumors. The term cancer is used herein to mean a broad spectrum of tumors, including all solid and hematological malignancies. [0034] An oral dosage form includes a unit dosage form prescribed or intended for oral administration. As used herein, the terms treat, treatment and treating refer to the reduction or amelioration of the progression, severity and/or duration of a disorder, e.g., a proliferative disorder, or the amelioration of one or more symptoms, suitably of one or more discernible symptoms, of the disorder resulting from the administration of one or more therapies. In specific embodiments, the terms treat, treatment and treating refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the WSGR Ref. 59457-781.601 patient. In other embodiments the terms treat, treatment and treating refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms treat, treatment and treating refer to the reduction or stabilization of tumor size or cancerous cell count. [0035] Within the meaning of the present disclosure, the term treat also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease. The term protect is used herein to mean prevent, delay, or treat, or all, as appropriate, development, continuance, or aggravation of a disease in a subject, e.g., a mammal or human. [0036] The term subject or patient as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer. Examples of subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a proliferative disease, such as cancer. [0037] The term inhibition, inhibitor, or antagonist includes a reduction in a certain parameter, e.g., an activity, of a given molecule or pathway. For example, inhibition of an activity of a target (e.g., Raf, ERK1/2, or SHP2) by 5%, 10%, 20%, 30%, 40% or more is included by this term. Thus, inhibition may be, but need not be, 100%. [0038] As used herein, salts (which, what is meant by or salts thereof or or a salt thereof), can be present alone or in mixture with free compounds of the combinations disclosed herein, e.g., a Raf inhibitor which is a Compound with formula (I), ERK1/2 inhibitor, SHP2 inhibitor, or trametinib and including pharmaceutically acceptable salts. Such salts are formed, for example, as acid addition salts, with organic or inorganic acids, from compounds of the combinations disclosed herein with a basic nitrogen atom, especially the pharmaceutically acceptable salts. The term pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compound and which typically are not biologically or otherwise undesirable. The compound may be capable of forming acid addition salts by virtue of the presence of an amino group. [0039] Lists of suitable salts can be found, e.g., in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2002). [0040] For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds can be employed (where applicable in the form of pharmaceutical preparations). In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or WSGR Ref. 59457-781.601 identification of the novel compounds, any reference to the free compounds is to be understood as referring also to the corresponding salts, as appropriate and expedient. The salts of compounds used in the combinations disclosed herein can be pharmaceutically acceptable salts; suitable counter-ions forming pharmaceutically acceptable salts are known in the field. Unless otherwise specified, or clearly indicated by the text, reference to therapeutic agents useful in the pharmaceutical combination provided herein includes both the free base of the compounds, and all pharmaceutically acceptable salts of the compounds. [0041] As used herein, the term solvate refers to a complex of variable stoichiometry formed by a solute or a salt thereof and a solvent. Such solvents for the purpose of embodiments herein may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, dimethylsulfoxide, ethanol, and acetic acid. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol, and acetic acid. [0042] The term synergistic effect as used herein, refers to action of two or more agents such as, for example, (a) a Raf inhibitor which is a Compound with formula (I), or a pharmaceutically acceptable salt thereof; and (b) an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and/or a SHP2 inhibitor or a pharmaceutically acceptable salt thereof, to produce an effect, for example, slowing the symptomatic progression of cancer or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves. [0043] In some embodiments, there are provided pharmaceutical compositions comprising the pharmaceutical combination disclosed herein and at least one pharmaceutically acceptable carrier, as described herein above. [0044] In some embodiments, there are provided pharmaceutical combinations or the pharmaceutical composition, as disclosed herein, for use in the treatment of a cancer. [0045] In some embodiments, the cancer expresses a MAPK mutation or wherein the cancer is N- RAS mutant, H-RAS mutant or K-RAS mutant, or combination thereof. Included are KRAS-mutant cancers or tumors. The term KRAS-mutant tumor or cancer includes any tumor that exhibits a mutated KRAS protein, in particular gain of function KRAS -mutation; especially any G12X, G13X, Q61X or A146X KRAS-mutant, where X is any amino acid other than the one naturally occurring at that position. E.g., a G12V mutation means that a Glycine is substituted with Valine at codon 12. Examples of KRAS mutations in tumors include Q61H, Q61K, G12V, G12C, G12D, G12R, G12S, G13D, and A146T. Thus KRAS-mutant NSCLC includes tumors having at least one KRAS mutation corresponding to G12X, G13X, Q61X or A146X, particularly at least one KRAS mutation selected from Q61K, G12V, G12C and A146T NSCLC. The cancer may be at an early, intermediate, or late stage. KRAS-mutant cancers include KRAS G12D-mutant ovarian cancer; KRAS G12V-mutant or G13D-mutant colorectal cancer; KRAS Q61H-mutant, KRAS Q61K- mutant, KRAS G12C-mutant, KRAS G12S-mutant or KRAS G12V-mutant NSCLC; KRAS G12D-mutant, G12V-mutant, or KRAS G12R-mutant pancreatic cancer. Included are NRAS mutant cancers or tumors. The term NRAS - WSGR Ref. 59457-781.601 mutant tumor or cancer includes any tumor that exhibits a mutated NRAS protein, in particular gain of function NRAS -mutation; especially any G13R, Q61K, Q61L, Q61R, NRAS-mutant tumor. Thus NRAS-mutant melanoma includes melanoma having at least one NRAS mutation corresponding to Q61K, Q61L or Q61R. The cancer may be NRAS QG13R- mutant melanoma. The cancer may be at an early, intermediate, or late stage. The cancer may be locally advanced or metastatic. [0046] In some embodiments, the cancer comprises a mutation at Q61 selected from Q61R, Q61L, and Q61M. [0047] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or pancreatic ductal adenocarcinoma (PDAC). [0048] In some embodiments, the cancer is colorectal cancer (CRC). [0049] In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). [0050] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). [0051] In some embodiments, the cancer is characterized by a mutation selected from the group consisting of BRAF, NRAS, KRAS mutation and combinations thereof. [0052] In some embodiments, the cancer is selected from the group consisting of KRAS-mutant NSCLC (non-small cell lung cancer), KRAS-mutant colorectal cancer (CRC), and KRAS-mutant pancreatic cancer KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). [0053] In some embodiments, the pharmaceutical combination or the pharmaceutical composition further comprises an anti-PD-1, anti-PD-L1, or anti-EGFR antibody. [0054] In some embodiments, there are provided methods of treating cancer expressing a MAPK mutation or wherein the cancer is N-RAS mutant, H-RAS mutant or K-RAS mutant, or combination thereof, the method comprising administering the pharmaceutical combinations or the pharmaceutical compositions described herein. [0055] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or pancreatic ductal adenocarcinoma (PDAC). [0056] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). [0057] In some embodiments, the cancer is colorectal cancer (CRC). [0058] In some embodiments, the cancer is selected from the group consisting of KRAS-mutant NSCLC (non-small cell lung cancer), KRAS-mutant colorectal cancer (CRC), and KRAS-mutant pancreatic cancer KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). [0059] In some embodiments, the cancer comprises a mutation at Q61 selected from Q61R, Q61L, and Q61M. [0060] In some embodiments, the cancer comprises a NF-1 Loss of Function mutation. [0061] In some embodiments, the cancer comprises a RAS G13R mutation. [0062] In some embodiments, the cancer comprises a KRAS G12C mutation. In some such embodiments, the cancer is non-small cell lung cancer (NSCLC). [0063] In some embodiments, the cancer comprises a Class 2 BRAF mutation. WSGR Ref. 59457-781.601 [0064] In some embodiments, the cancer comprises a Class 3 BRAF mutation. [0065] In some embodiments, the pharmaceutical combination or the pharmaceutical composition further comprises an anti-PD-1, anti-PD-L1, or anti-EGFR antibody. For example, suitable pharmaceutical combinations of compositions may comprise an anti-PD-1 antibody including, without limitation, pembrolizumab, nivolumab, pidilizumab, cemiplimab, SHR-1210, PDR001, or AMP-224. Suitable PD-L1 antibodies may include, without limitation, atezolizumab, avelumab, durvalumab, BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. Suitable EGFR antibodies include, without limitation, cetuximab, panitumumab, nimotuzumab, or necitumumab. [0066] By way of non-limiting examples, pharmaceutical combinations or compositions to treat lung cancer, including non-small cell lung cancer (NSCLC), may comprise (a) the RAF inhibitor: compound of formula (I); (b) compound A and/or compound B; and (c) pembrolizumab. [0067] By way of further non-limiting examples, pharmaceutical combinations or compositions to treat colon cancer, including colorectal cancer (CRC), may comprise (a) the RAF inhibitor: compound of formula (I); (b) compound A and/or compound B; and (c) cetuximab. [0068] By way of yet further non-limiting examples, pharmaceutical combinations or compositions to treat pancreatic cancer, including pancreatic ductal adenocarcinoma (PDAC), may comprise (a) the RAF inhibitor: compound of formula (I); (b) compound A and/or compound B; and (c) panitumumab. [0069] In some embodiments, the Raf inhibitor which is a Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, is combined with an ERK1/2 inhibitor or a pharmaceutically acceptable salt thereof and/or a SHP2 inhibitor or a pharmaceutically acceptable salt thereof, and may be administered at a therapeutic or lower-than therapeutic dose relative to a single- agent dose level. In some embodiments, the concentration or dosage of the one therapeutic agent that is required to achieve inhibition, e.g., growth inhibition or tumor shrinkage is lower when the other therapeutic agent is used or administered in combination with the first therapeutic agent than when each therapeutic agent is administered individually. In some embodiments, in a combination therapy, the concentration or dosage of one therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40- 50%, 50-60%, 60-70%, 70-80%, or 80-90% lower. [0070] In determining a synergistic interaction between one or more components, the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different w/w ratio ranges and doses to patients in need of treatment. For humans, the complexity and cost of carrying out clinical studies on patients may render the use of this form of testing as a primary model for synergy impractical. However, the observation of synergy in certain experiments can be predictive of the effect in other species, and animal models exist that can be used to further quantify a synergistic effect. The observation of synergy in one species can be predictive of the effect in other species and using animal models, as described herein, a WSGR Ref. 59457-781.601 synergistic effect can be measured and the results of such studies can also be used to predict effective dose ratio ranges and the absolute doses and plasma concentrations required in other species by the application of pharmacokinetic/pharmacodynamic (PK/PD) methods. Established correlations between tumor models and effects seen in man suggest that synergy in animals may be demonstrated, for example, by xenograft models or in appropriate cell lines. It can be shown by established test models that combinations disclosed herein result in the beneficial effects described herein. The person skilled in the art is fully enabled to select a relevant test model to prove such beneficial effects. The pharmacological activity of the combinations disclosed herein may, for example, be demonstrated in a clinical study or in an in vivo or in vitro test procedure as essentially described herein. [0071] Administration of the combination includes administration of the combination in a single formulation or unit dosage form, administration of the individual agents of the combination concurrently but separately, or administration of the individual agents of the combination sequentially by any suitable route. The individual combination partners of the combinations disclosed herein may be administered separately at different times during the course of therapy, or sequentially in any order or concurrently in divided or single combination forms, e.g., simultaneously or in jointly therapeutically effective amounts, including synergistically effective amounts, e.g., in daily or intermittent (i.e., not daily) dosages corresponding to the amounts described herein. [0072] Compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the methods, treatments, combinations, and compositions disclosed herein are potent inhibitors of BRAF and CRAF. In some embodiments, Compound of formula (I), or a pharmaceutically acceptable salt thereof is administered orally. In one embodiment, Compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50-1200 mg (e.g., per day). Compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered at a unit dosage of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg or about 1200 mg. The unit dosage of Compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered once daily, or twice daily, or three times daily, or four times daily, with the actual dosage and timing of administration determined by criteria such as the patient's age, weight, and gender; the extent and severity of the cancer to be treated; and the judgment of a treating physician. In some embodiments, the unit dosage of Compound of formula (I) is administered once daily. In another embodiment, the unit dosage of Compound of formula (I) is administered twice daily. [0073] In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is administered 25 mg to 300 mg, 25 mg to 250 mg, or 25 mg to 150 mg, twice a day, once a week (BID-QW). In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount that is 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, WSGR Ref. 59457-781.601 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 200 mg, 225 mg, or 250 mg twice a day, once a week (BID-QW). In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg twice a day, once a week (BID-QW). [0074] In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 25 mg, 30 mg, 40 mg, 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg. In some embodiments, each of the above-recited amounts may be administered QD, QW, BID, BID-QD, or BID-QW. [0075] In some embodiments, compound B is administered in an amount of 20 mg to 120 mg, or 20 mg to 60 mg, or 20 mg to 40 mg, once a day for three weeks, followed by a one week break in at least one four-week cycle. In some embodiments, compound B is administered in an amount of 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg, once a day for three weeks, followed by a one week break in at least one four-week cycle. [0076] In some embodiments, compound B is administered in an amount of 20 mg to 120 mg, or 40 mg to 120 mg, or 40 mg to 80 mg, twice a day for three weeks, followed by a one week break in at least one four-week cycle. In some embodiments, compound B is administered in an amount of 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg, twice a day for three weeks, followed by a one week break in at least one four-week cycle. [0077] In some embodiments, compound B is administered in an amount of 20 mg to 120 mg, or 20 mg to 60 mg, or 20 mg to 40 mg, once a day for two weeks, followed by a one week break in at least one three-week cycle. In some embodiments, compound B is administered in an amount of 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg, once a day for two weeks, followed by a one week break in at least one three-week cycle. [0078] In some embodiments, compound B is administered in an amount of 20 mg to 120 mg, or 40 mg to 120 mg, or 40 mg to 80 mg, twice a day for two weeks, followed by a one week break in at least one three-week cycle. In some embodiments, compound B is administered in an amount of 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg, twice a day for two weeks, followed by a one week break in at least one three-week cycle. WSGR Ref. 59457-781.601 [0079] In some embodiments, the dosing regimen for compound B may be twice daily on days 1 and 2, for four weeks In some embodiments, the dosing amount for compound B may be, but is not limited to, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, or 160 mg per day. In some embodiments, the dosing amount for compound B may be twice daily, anywhere from 40 mg to 120 mg on days 1 and 2. In some embodiments, the dosing amount for compound B may be twice daily, anywhere from 40 mg to 80 mg on days 1 and 2. [0080] In some embodiments, the dosing regimen for compound B may be once daily on days 1, 2, and 3, for four weeks. In some embodiments, the dosing amount for compound B may be, but is not limited to, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, or 160 mg per day. In some embodiments, the dosing amount for compound B may be once daily, anywhere from 80 mg to 200 mg on days 1, 2, and 3. In some embodiments, the dosing amount for compound B may be once daily, anywhere from 80 mg to 120 mg on days 1, 2, and 3. [0081] When compound B is administered multiple times a week, the dose may be administered on any day or combination of days within the week. For example, administration three times per week may include administration on days 1, 3, and 5; days 1, 2, and 3; 1, 3, and 5; and so on. Administration two days per week may include administration on days 1 and 2; days 1 and 3; days 1 and 4; days 1 and 5; days 1 and 6; days 1 and 7; and so on. [0082] In some embodiments, the dosing regimen for compound B is once daily. In some embodiments, the once daily dosing regimen for compound B may be, but is not limited to, 10 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, or 160 mg/day. Compound B may be administered anywhere from 20 mg to 60 mg once a day. The dose may be any value or subrange within the recited ranges. [0083] In some embodiments, the dosing regimen for compound B is twice daily. In some embodiments, the twice daily dosing regimen for compound B may be, but is not limited to, 10 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, or 160 mg/day. Compound B may be administered anywhere from 5 mg to 80 mg twice a day. In some embodiments, WSGR Ref. 59457-781.601 compound B may be administered anywhere from 10 mg/day to 160 mg/day. The dose may be any value or subrange within the recited ranges. [0084] In some embodiments, trametinib (compound C), or a pharmaceutically acceptable salt thereof is administered orally. In one embodiment, trametinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.5-2.0 mg (e.g., per day). Trametinib, or a pharmaceutically acceptable salt thereof, can be administered at a unit dosage of about 0.5 mg, about 1.0 mg, or about 2.0 mg. The unit dosage of trametinib, or a pharmaceutically acceptable salt thereof, may be administered once daily, with the actual dosage and timing of administration determined by criteria such as the patient's age, weight, and gender; the extent and severity of the cancer to be treated; and the judgment of a treating physician. In some embodiments, the unit dosage of trametinib is administered once daily. EXAMPLES Example 1: Synergistic Combinations of Compound of Formula (I) and Compound A [0085] Naporafenib and Compound A demonstrate combination benefit in invitro cell lines. Cells, (1) MM415 (NRAS Q61L, melanoma), (2) WM209 (NRAS G12A; melanoma), (3) SK-NAS (NRAS Q61K; neuroblastoma), (4) HM-V-II (NRAS Q61K/BRAF G469V; melanoma), (5) HepG2 (NRAS Q61L; liver), (6) OCI-AML-3 (NRAS Q61L; haematopoietic) and (7) SKMEL-30 (NRAS Q61K; melanoma) were treated with a dilution matrix of naporafenib in combination with Compound A in 2D cell viability assays. Bliss synergy score is shown in the matrix. [0086] Cells were plated at a density of 5,000 cells per well in a 96-well plate (Corning #3903). Cells were allowed to adhere overnight, and compound was added in a matrix format using a HP Tecan D300e digital dispenser (Switzerland). Naporafenib was added in a 1:3 dilution series (8-point dose response) from bottom to top of plate at indicated concentration (nM) (rows B-H) and Compound A was added in a 1:3 dilution series (11-point dose response) from right to left at indicated concentration (nM) (columns 2-11). Final DMSO concentration was normalized across the plate. Cell viability was assessed for 5-days post-treatment using Promega CellTiter-Glo 3D Cell Viability Assay reagent M3e (Molecular Devices, San Jose, CA) and combination benefit was calculated using the BLISS model in the Synergy software (https://doi.org/10.1093/bioinformatics/btaa826). [0087] The results of these experiments are indicated in Tables 1-7 below. WSGR Ref. 59457-781.601 Table 1: Naporafenib combination benefit with Compound A in MM415 cell line Compound A [nM] 0.13 0.38 1.14 3.43 10.29 30.86 92.59 277.78 833.33 2500.00 0.61 -9.882 -12.515 -12.342 -13.498 -7.422 -5.394 5.588 5.489 0.289 -14.394 2.44 -11.597 -10.488 -7.941 -8.082 -1.173 -1.956 3.477 6.216 -2.269 -13.313 ] M 9.77 n_[ -13.208 -17.716 -13.626 -6.938 8.132 -2.894 1.040 4.968 -1.459 -13.701 b_i n_e 39.06 f -7.684 -7.484 10.841 27.072 19.100 -1.022 -0.254 2.398 -3.450 -16.492 a r_o p_a 156.25 -1.373 2.159 3.449 4.618 -1.024 -7.999 -5.026 -3.250 -13.106 -24.939 N 625 -5.652 -4.833 -4.977 -4.312 -5.315 -6.772 -5.476 -8.649 -15.543 -29.223 2500.00 -1.165 -0.232 0.052 0.356 -0.973 -3.849 -5.405 -9.962 -16.195 -26.152 - Table 2: Naporafenib combination benefit with Compound A in WM209 cell line Compound A [nM] 0.13 0.38 1.14 3.43 10.29 30.86 92.59 277.78 833.33 2500.00 3.43 -15.848 -22.200 -24.278 -24.023 -19.413 -15.006 -5.679 0.688 -0.630 -5.766 10.29 -18.343 -22.870 -26.764 -27.533 -22.869 -19.258 -10.271 1.021 -0.460 -4.642 ] M 30.86 n_[ -21.722 -18.999 -25.038 -19.143 -17.985 -14.686 -3.944 1.326 0.369 -3.560 b_i n_e 92.59 f -8.495 -3.953 -8.866 -3.492 4.632 24.398 7.701 2.902 0.185 -3.485 a r_o p_a 277.78 -2.458 -1.864 3.132 9.818 28.516 36.480 8.872 0.367 -1.834 -6.945 N 833.33 -0.639 -3.878 -2.578 -0.798 5.853 6.806 -1.162 -3.517 -4.864 -10.082 2500.00 0.082 -0.942 -0.299 -0.349 0.535 0.246 -1.425 -2.466 -3.884 -8.054 Bliss Synergy; naporafenib vs Compound A in WM209 - WSGR Ref. 59457-781.601 Table 3: Naporafenib combination benefit with Compound A in SK-NAS cell line Compound A [nM] 0.05 0.15 0.46 1.37 4.12 12.35 37.04 111.11 333.33 1000.00 1.22 -7.430 -9.646 -12.017 -11.643 -15.537 -13.932 -8.794 -5.221 -0.976 -4.685 4.88 -11.086 -13.368 -14.165 -15.804 -16.615 -7.854 -5.360 -4.173 -2.498 -4.638 ] M 19.53 n_[ -15.135 -18.484 -19.683 -19.305 -11.595 -6.178 -6.061 -5.437 -1.211 -3.833 b_i n_e 78.13 f_a -7.495 -6.045 -9.229 -4.760 2.391 9.157 2.326 0.020 -0.471 -5.275 r_o p_a 312.50 -3.687 -4.061 -1.213 2.017 7.187 12.063 11.164 0.960 -3.875 -6.963 N 1250.00 -2.434 -1.523 -2.497 -1.836 0.273 0.999 -1.290 -6.839 -8.026 -7.988 5000.00 -0.634 -0.737 -0.921 -0.908 -0.977 -1.257 -2.185 -4.178 -4.976 -6.926 Bliss Synergy; naporafenib vs Compound A in SK- - Table 4: Naporafenib combination benefit with Compound A in HM-V-II cell line Compound A [nM] 0.03 0.08 0.23 0.69 2.06 6.17 18.52 55.56 166.67 500.00 1.22 8.316 -1.251 1.496 -1.052 2.640 9.420 3.501 2.368 0.623 -1.140 4.88 3.187 -1.814 -1.774 -4.683 2.813 12.052 7.932 0.696 0.488 -1.374 ] M 19.53 n_[ 0.979 8.054 5.963 5.849 17.249 25.618 8.023 -2.692 -0.517 -1.962 b_i n_e 78.13 f 2.250 3.280 6.467 5.675 10.462 12.355 0.470 -3.670 -2.277 -3.263 a r_o p_a 312.50 -0.059 0.605 0.318 -0.075 1.005 1.692 -3.950 -5.976 -3.126 -4.810 N 1250.00 0.519 0.026 0.723 0.726 0.477 -0.100 -3.313 -4.920 -4.117 -4.809 5000.00 1.170 1.009 1.400 1.007 1.141 0.380 -2.786 -4.458 -5.102 -5.581 Bliss Synergy; naporafenib vs Compound A in HM-V- - Table 5: Naporafenib combination benefit with Compound A in HepG2 cell line WSGR Ref. 59457-781.601 Compound A [nM] 0.05 0.15 0.46 1.37 4.12 12.35 37.04 111.11 333.33 1000.00 1.22 -4.175 -6.032 -12.113 -21.703 -12.963 -5.223 -0.890 3.955 2.755 1.395 4.88 -19.731 -15.737 -22.799 -13.088 -7.251 3.523 4.817 6.105 2.579 0.833 ] M 19.53 n_[ -11.260 -8.665 -0.510 4.086 13.744 16.99911.813 6.192 0.867 -0.075 b_i n_e 78.13 f 5.629 8.259 12.543 12.192 13.302 12.331 8.030 3.475 -3.066 -2.537 a r_o p_a 312.50 -1.729 0.685 -0.020 1.078 3.681 4.163 0.635 -4.523 -5.845 -6.729 N 1250.00 1.655 1.840 0.909 0.561 1.224 -1.269 -3.596 -5.202 -5.317 -6.253 5000.00 -0.119 -0.038 -0.188 -0.335 -0.642 -1.075 -1.853 -2.477 -3.675 -3.690 Bliss Synergy; naporafenib - Table 6: Naporafenib combination benefit with Compound A in OCI-AML-3 cell line Compound A [nM] 0.05 0.15 0.46 1.37 4.12 12.35 37.04 111.11 333.33 1000.00 6.86 -5.310 -0.227 -9.806 -4.220 5.250 -18.285 -5.487 0.118 1.541 0.642 20.58 5.031 4.980 0.857 2.358 16.079 -15.285 -7.306 -0.005 1.580 0.335 ] M 61.73 n_[ -2.013 0.424 -2.479 3.247 17.808 -6.362 -5.771 -0.385 0.855 -0.534 b_i n_e 185.19 f_a -3.209 -2.305 -2.485 0.507 4.278 -4.121 -4.487 -0.740 0.080 -1.380 r_o p_a 555.56 -1.878 -1.671 -1.239 -0.909 0.403 -3.168 -2.545 -0.617 -0.212 -1.661 N 1666.67 -0.440 -0.845 -1.040 -0.568 0.170 -1.978 -1.365 -0.309 -0.210 -1.717 5000.00 1.891 1.884 1.824 1.924 1.947 0.287 -0.012 0.012 -0.042 -1.213 Bliss Synergy; naporafenib vs Compound A in OCI-AML- - WSGR Ref. 59457-781.601 Table 7: Naporafenib combination benefit with Compound A in SKMEL-30 cell line Compound A [nM] 0.05 0.15 0.46 1.37 4.12 12.35 37.04 111.11 333.33 1000.00 1.37 -15.395 -15.146 -16.005 -13.220 -10.137 -3.053 -2.467 1.885 0.101 -2.766 4.12 -10.345 -19.026 -16.600 -14.079 -3.587 1.617 -3.824 1.850 -0.118 -2.721 ] M 12.35 n_[ -11.453 -15.191 -10.418 -4.812 6.566 10.211 -0.799 0.980 -0.290 -2.953 b_i n_e 37.04 f -7.930 -5.143 -1.767 5.467 12.466 6.874 -3.430 -0.086 -1.049 -3.094 a r_o p_a 111.11 -3.832 -4.573 -4.309 -2.721 -1.361 -4.012 -5.527 -1.750 -2.415 -4.701 N 333.33 -4.290 -5.288 -5.118 -4.246 -3.904 -4.540 -4.236 -1.972 -2.344 -4.392 1000.00 1.081 1.599 1.560 1.182 0.807 -0.951 -1.846 -1.667 -2.429 -4.027 Bliss Synergy; naporafenib vs Compound A in SKMEL- - Example 2: Synergistic Combinations of Compound B and Trametinib [0088] This Example demonstrates the synergistic combination of Compound B with KRAS G12C inhibitors. [0089] Combination cellular proliferation assays: NCI-H358 (KRAS G12C mutant), NCI-H508 and NCI-H1666 (Class III BRAF mutant), NCI-H1838 and MeWo (NF1 LOF mutant) cells (5000 cells per well) were plated onto 96-well plates in 100 ul cell culture medium. Cells were treated with the compound of Formula I with trametinib at concentrations varying from 0 to 10 uM by using the Tecan D300e Digital Dispenser combination matrix protocol.5 days after treatment, 100 ul of CellTiter-Glo (CTG) reagent (Promega) was added and the plates were incubated for 60 minutes with gentle shaking. After 60 minutes of incubation, the luminescent signal was determined according to the (Promega) and combination data was generated by the standard Loewe model using our proprietary combination analysis software. This was done in duplicate. The combination synergy was represented by positive numbers in the results table. The negative numbers represent antagonism of the combination. [0090] The results of these experiments are indicated in Figures 1A-1E. [0091] While specific embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the WSGR Ref. 59457-781.601 embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Ref. 59457-781.601 CLAIMS What is claimed is: 1. A pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) an ERK1/2 inhibitor. 2. A pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) an ERK1/2 inhibitor; and (c) trametinib. 3. The pharmaceutical combination according to claim 1 or 2, wherein the ERK1/2 inhibitor is (compound A), or a pharmaceutically acceptable salt or solvate thereof. 4. A pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I) WSGR Ref. 59457-781.601 or a pharmaceutically acceptable salt thereof; and (b) a SHP2 inhibitor. 5. A pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) a SHP2 inhibitor; and (c) trametinib. 6. The pharmaceutical combination according to claim 4 or 5, wherein the SHP2 inhibitor is (compound B), or a pharmaceutically acceptable salt or solvate thereof. 7. A pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) an ERK1/2 inhibitor; and (c) a SHP2 inhibitor. WSGR Ref. 59457-781.601 8. A pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) an ERK1/2 inhibitor; (c) a SHP2 inhibitor; and (d) trametinib. 9. The pharmaceutical combination according to claim 7 or 8, wherein the ERK1/2 inhibitor is (compound A), or a pharmaceutically acceptable salt or solvate thereof. 10. The pharmaceutical combination according to any one of claims 7-9, wherein the SHP2 inhibitor (compound B), or a pharmaceutically acceptable salt or solvate thereof. 11. The pharmaceutical combination according to any one of claims 1-10, wherein the combination is for simultaneous, sequential, or separate administration. 12. The pharmaceutical combination according to any one of claims 1-11, wherein the combination is a fixed combination. 13. The pharmaceutical combination according to any one of claims 1-11, wherein the combination is a non-fixed combination. 14. A pharmaceutical composition comprising the pharmaceutical combination according to any one of claims 1-13 and at least one pharmaceutically acceptable carrier. 15. The pharmaceutical combination according to any one of claims 1-13, or the pharmaceutical composition according to claim 14 for use in the treatment of a cancer. WSGR Ref. 59457-781.601 16. The pharmaceutical combination or the pharmaceutical composition for use according to claim 15, wherein the cancer expresses a NF-1 loss of function mutation, wherein the cancer expresses a MAPK mutation or wherein the cancer is N-RAS mutant, H-RAS mutant or K- RAS mutant, or combination thereof. 17. The pharmaceutical combination or the pharmaceutical composition for use according to claim 15 or 16, wherein the cancer comprises a mutation at Q61 selected from Q61R, Q61L, and Q61M. 18. The pharmaceutical combination or the pharmaceutical composition for use or the pharmaceutical composition for use according to any one of claims 15 to 17, wherein the cancer is non- small cell lung cancer (NSCLC), colorectal cancer (CRC), or pancreatic ductal adenocarcinoma (PDAC). 19. The pharmaceutical combination or the pharmaceutical composition for use or the pharmaceutical composition for use according to any one of claims 15 to 17, wherein the cancer is colorectal cancer (CRC). 20. The pharmaceutical combination or the pharmaceutical composition for use or the pharmaceutical composition for use according to any one of claims 15 to 17, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). 21. The pharmaceutical combination or the pharmaceutical composition for use or the pharmaceutical composition for use according to any one of claims 15 to 17, wherein the cancer is non-small cell lung cancer (NSCLC). 22. The pharmaceutical combination or the pharmaceutical composition for use or the pharmaceutical composition for use according to any one of claims 15-21, wherein the cancer is characterized by a mutation in BRAF, NRAS, KRAS, NRAS, or NF-1 or combinations thereof. 23. The pharmaceutical combination or the pharmaceutical composition for use according to any one of claims 15 to 17, wherein the cancer is selected from the group consisting of KRAS- mutant NSCLC (non-small cell lung cancer), KRAS-mutant colorectal cancer (CRC), and KRAS-mutant pancreatic cancer KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). 24. The pharmaceutical combination or the pharmaceutical composition for use according to any one of claims 15 to 23, wherein the combination or composition further comprises an anti- PD-1, anti-PD-L1, or anti-EGFR antibody. 25. A method of treating cancer expressing a MAPK mutation or wherein the cancer is N-RAS mutant, H-RAS mutant or K-RAS mutant, or combination thereof, the method comprising administering the pharmaceutical combination according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 14. 26. The method of claim 25, wherein the cancer is non- small cell lung cancer (NSCLC), colorectal cancer (CRC), or pancreatic ductal adenocarcinoma (PDAC). WSGR Ref. 59457-781.601 27. The method of claim 25, wherein the cancer is non-small cell lung cancer (NSCLC). 28. The method of claim 25, wherein the cancer is colorectal cancer (CRC). 29. The method of claim 25, wherein the cancer is selected from the group consisting of KRAS- mutant NSCLC (non-small cell lung cancer), KRAS-mutant colorectal cancer (CRC), and KRAS-mutant pancreatic cancer KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). 30. The method of any one of claims 25 to 29, wherein the cancer comprises a mutation at Q61 selected from Q61R, Q61L, and Q61M. 31. The method of any one of claims 25 to 30, wherein the pharmaceutical combination or the pharmaceutical composition further comprises an anti-PD-1, anti-PD-L1, or anti-EGFR antibody.