Combination therapy of RAF inhibitor and KRAS G12C inhibitor

Abstract

Compounds of formula (I) [Formula 1] A pharmaceutical combination comprising: (a) a Raf inhibitor that is TIFF2026503267000030.tif4686 or a pharmaceutically acceptable salt thereof; (b) a KRAS G12C inhibitor T; and / or (c) trametinib.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 478,888, filed January 6, 2023, and U.S. Provisional Application No. 63 / 505,643, filed June 1, 2023, which are incorporated by reference in their entireties. [Background technology]

[0002] The RAS / RAF / MEK / ERK or MAPK pathway is a critical signaling cascade that drives cell proliferation, differentiation, and survival. Dysregulation of this pathway underlies many cases of tumorigenesis. This pathway is activated by extracellular signals, which then induce the small G protein RAS to exchange GTP for GDP. Activated RAS small guanidine triphosphatase (GTPase) promotes the activation of RAF (also referred to herein as RAF) family proteins (ARAF, BRAF, and CRAF, also known as RAF1). Activated RAF proteins lead to the phosphorylation and activation of MEK1 / 2 proteins, which then phosphorylate and activate extracellular signal-regulated kinases (ERKs). ERK1 / 2 proteins phosphorylate a variety of substrates, including multiple transcription factors, and regulate important cellular activities, including proliferation, differentiation, migration, survival, and angiogenesis.

[0003] Aberrant signaling or inappropriate activation of the MAPK pathway has been demonstrated in multiple tumor types, including colorectal, lung, and pancreatic cancers, and can occur through several different mechanisms, including activating mutations in RAS and BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B1). RAS, a superfamily of GTPases, includes KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), a regulatory signaling protein that can be turned on (activated) by a variety of single-point mutations 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 rarely 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 of the Invention

[0004] Embodiments herein include (a) a compound of formula (I)

[0005] [ka] or a pharmaceutically acceptable salt thereof; and (b) a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof.

[0006] Embodiments herein further include (a) a compound of formula (I)

[0007] [ka] or a pharmaceutically acceptable salt thereof; (b) a Raf inhibitor, which is a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof; and (c) trametinib or a pharmaceutically acceptable salt thereof.

[0008] Embodiments further relate to (a) a pharmaceutical combination comprising a Raf inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disease, particularly cancer, and the use of such a combination for the preparation of a medicament for the treatment of a proliferative disease, particularly cancer; further provided is a method of treating a proliferative disease, particularly cancer, in a subject in need thereof, the method comprising administering to the subject the combination, jointly, in therapeutically effective amounts; further provided is the use of such a combination for the treatment of a proliferative disease, particularly cancer, and provided are pharmaceutical compositions comprising such combinations and commercial packages therefor.

[0009] Embodiments further relate to a pharmaceutical combination comprising (a) a Raf inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of a proliferative disease, particularly cancer, and (b) a KRAS G12C 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, particularly cancer, as well as the use of such a combination for the preparation of a medicament for treating a proliferative disease, particularly cancer; further provided is a method of treating a proliferative disease, particularly cancer, in a subject in need thereof, the method comprising administering to the subject the combination, jointly, in therapeutically effective amounts; further provided is the use of such a combination for the treatment of a proliferative disease, particularly cancer, as well as pharmaceutical compositions comprising such a combination and commercial packages therefor.

[0010] In some embodiments, (a) a compound of formula (I)

[0011] [ka] or a pharmaceutically acceptable salt thereof; and (b) KRAS G12C inhibitor and Further provided is a pharmaceutical combination comprising:

[0012] In some embodiments, the pharmaceutical combination comprises a compound of formula (I)

[0013] [ka] or a pharmaceutically acceptable salt thereof; and (b) a KRAS G12C inhibitor; and (c) trametinib and A pharmaceutical combination comprising:

[0014] In cell-based assays, the Raf inhibitor compound of formula (I) exhibited anti-proliferative activity in cell lines containing various mutations that activate MAPK signaling. In vivo treatment with the compound of formula (I) resulted in tumor regression in several KRAS mutant models, including NSCLC-derived Calu-6 (KRAS Q61K) and NCI-H358 (KRAS G12C). Collectively, the in vitro and in vivo MAPK pathway suppression and anti-proliferative activity observed with the compound of formula (I) at well-tolerated doses suggests that the compound of formula (I) may have anti-tumor activity in patients with tumors involving activating lesions in the MAPK pathway. Furthermore, the compound of formula (I) is a type 2 ATP-competitive inhibitor of both B-Raf and C-Raf, maintaining 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. The compound of formula (I) has demonstrated efficacy in multiple MAPK-driven human cancer cell lines and in xenograft tumors representing model tumors with human lesions in the KRAS, NRAS, and BRAF oncogenes. The pharmaceutical combination of this embodiment further comprises a KRAS G12C inhibitor. A further pharmaceutical combination of this embodiment further comprises a KRAS G12C inhibitor and trametinib. The term "KRAS G12C inhibitor" is defined herein to refer to a compound that targets, reduces, or inhibits KRAS mutation of glycine 12 to cysteine.

[0015] In some embodiments, suitable KRAS G12C inhibitors include sotorasib, adagrasib,

[0016] [ka]

[0017] [ka]

[0018] [ka]

[0019] [ka]

[0020] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0021] In some embodiments, other suitable KRAS G12C inhibitors include:

[0022] [ka]

[0023] [ka]

[0024] [ka]

[0025] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0026] Trametinib Trametinib:

[0027] [ka] It belongs to a class of pyrimidine compounds known as mitogen-activated protein (MAP) kinase / extracellular signal-regulated (ERK) kinase (hereinafter referred to as MEK) inhibitors, such as MEK1 and MEK2. MEK inhibitory activity effectively induces inhibition of ERK1 / 2 and suppression of cell proliferation, which is effective against diseases caused by unwanted cell proliferation, such as tumors.

[0028] The terms "combination," "therapeutic combination," or "pharmaceutical combination," as used herein, refer to either a fixed combination in one dosage unit form, or a non-fixed combination, or a kit of parts for combined administration, wherein two or more therapeutic agents may be administered simultaneously, independently, or together separately within time intervals, particularly those time intervals that allow the combination partners to exhibit a cooperative, e.g., synergistic, effect.

[0029] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic disease or disorder described in this 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 for each active ingredient (e.g., capsules and / or intravenous formulations). In addition, such administration also encompasses the use of each type of therapeutic agent at approximately the same time or at different times, either sequentially or in a separate manner. Regardless of whether the active ingredients are administered as a single formulation or separate formulations, the drugs are administered to the same patient as part of the same course of treatment. In either case, the treatment regimen provides beneficial effects in the treatment of a disease or disorder described herein.

[0030] In some embodiments, the combination is for simultaneous, sequential, or separate administration. Simultaneous therapeutic use, within the meaning of this embodiment, means simultaneous or substantially simultaneous administration of at least two active ingredients by the same route.

[0031] Separate use, within the meaning of this embodiment, means in particular the simultaneous or substantially simultaneous administration of at least two active ingredients by different routes.

[0032] Sequential therapeutic use refers to the administration of at least two active ingredients at different times, with the same or different routes of administration. More specifically, the administration method refers to the administration of one of the active ingredients in its entirety before the administration of the other ingredient or ingredients begins.

[0033] 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, refer to a single carrier or vehicle or dosage form formulated to deliver both therapeutic agents, jointly, in therapeutically effective amounts to a patient for the treatment of cancer. The single vehicle is designed to deliver a certain amount of each agent, along with any pharmaceutically acceptable carriers or excipients. In some embodiments, the vehicle is a tablet, capsule, pill, or patch. In other embodiments, the vehicle is a solution or suspension.

[0034] The term "unfixed combination" or "kit of parts" means that the therapeutic agents of the combination disclosed herein are both administered to a patient as separate entities simultaneously, concurrently, or sequentially without specific time limits, such administration providing 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.

[0035] The term "pharmaceutically acceptable," as used herein, refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of a subject, e.g., a mammal or human, without undue toxicity, irritation, allergic response, and other problem or complication commensurate with a reasonable benefit / risk ratio.

[0036] 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, antifungal), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, as well as combinations thereof, as 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.

[0037] The term "pharmaceutical composition" is defined herein to refer to a mixture or solution containing at least one therapeutic agent administered to a subject, e.g., a mammal or human, to treat a particular disease or disorder affecting the subject. The pharmaceutical combination can be formulated into pharmaceutical compositions suitable for enteral or parenteral administration, such as dragees, tablets, capsules, or suppositories, or ampoules. Unless otherwise indicated, they are prepared in a manner known per se, e.g., by various conventional mixing, milling, direct compression, granulation, sugar-coating, dissolving, lyophilizing processes, or manufacturing techniques readily apparent to those skilled in the art. It will be understood that the unit content of the combination partner contained in an individual dose of each dosage form need not constitute an effective amount per se, since the required effective amount can be reached by administering multiple dosage forms. The pharmaceutical composition may contain from about 0.1% to about 99.9%, or from about 1% to about 60%, of the therapeutic agent. Those skilled in the art can select one or more of the above-mentioned carriers according to the specific desired properties of dosage form without undue burden through routine experimentation.The amount of each carrier used can vary within the range conventional in the art.The following references: 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) disclose the techniques and excipients used to formulate oral dosage form.These optional additional conventional carriers can be incorporated into the oral dosage form by incorporating one or more conventional carriers into the initial mixture before or during granulation, or by combining one or more conventional carriers with granules containing the drug combination or individual drugs of the drug combination in the oral dosage form. In the latter embodiment, the combined mixture can be further blended, for example, in a V-blender, and subsequently compressed or molded into a tablet, for example, a monolithic tablet, coated with a capsule, or filled into a sachet.

[0038] Pharmaceutical compositions may be provided in unit dose forms containing a predetermined amount of active ingredient per unit dose. In some embodiments, a unit dose contains one or more vehicles, each vehicle containing an effective amount of at least one therapeutic agent, along with pharmaceutically acceptable carriers and excipients. In some embodiments, a unit dose is administered to a patient simultaneously as one or more tablets, capsules, pills, injections, infusions, patches, etc. As 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 disease of the patient. In some embodiments, a unit dose composition contains a daily dose or sub-dose, or an appropriate fraction thereof, of the active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any method well known in the art of pharmacy.

[0039] A pharmaceutical composition may comprise 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 therapeutic combination is an amount sufficient, at dosages and for periods of time necessary, to provide an observable or clinically significant improvement above baseline in clinically observable signs and symptoms of the disorder being 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 agent are outweighed by the therapeutically beneficial effects.

[0040] 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 appropriate dosing levels and schedules. Alternatively, this property of a composition can be evaluated by examining the compound's ability to modulate an undesirable parameter using in vitro assays known to those skilled in the art.

[0041] As used herein, the term "jointly therapeutically active" or "joint therapeutic effect" means that the therapeutic agents can be given jointly, separately, or sequentially at a time interval preferred by the subject, particularly a human, being treated, so that they still exhibit a (possibly synergistic) interaction (joint therapeutic effect). Whether this is the case can be determined, inter alia, by tracking the blood levels of the compounds, showing that both compounds are present in the blood of the treated human for at least a specified time interval.

[0042] 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 should also be understood that an "agent" can be a single compound or a combination or composition of two or more compounds.

[0043] The term "proliferative disease" includes cancer.

[0044] As used herein, the term "cancer" refers to a disease characterized by the unwanted and uncontrolled growth of abnormal 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 and malignant cancers and tumors. The term "cancer" is used herein to refer to a wide range of tumors, including all solid and hematologic malignancies.

[0045] An "oral dosage form" includes a unit dosage form formulated or intended for oral administration. As used herein, the terms "treat," "treatment," and "treating" refer to a reduction or amelioration of the progression, severity, and / or duration of a disorder, e.g., a proliferative disorder, or an improvement in one or more symptoms, suitably one or more discernible symptoms, of a disorder resulting from the administration of one or more therapies. In specific embodiments, the terms "treat," "treatment," and "treating" refer to an improvement in at least one measurable physical parameter of a proliferative disorder, such as tumor growth, not necessarily discernible by the patient. In other embodiments, the terms "treat," "treatment," and "treating" refer to an inhibition of progression of a proliferative disorder, either physically, e.g., by stabilization of a discernible symptom, physiologically, e.g., by stabilization of a physical parameter, or both. In other embodiments, the terms "treat," "treatment," and "treating" refer to a reduction or stabilization of tumor size or cancerous cell number.

[0046] Within the meaning of this disclosure, the term "treat" also means to arrest, delay the onset (i.e., the period before clinical signs of disease) and / or reduce the risk of developing or worsening a disease. The term "protect" is used herein to mean to prevent, delay, or treat, or all, as appropriate, the onset, continuation, or worsening of a disease in a subject, e.g., a mammal or human.

[0047] The terms "subject" or "patient," as used herein, are intended to include animals that suffer from or may suffer from cancer or any disorder directly or indirectly related to 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 that suffers from, is at risk of suffering from, or may potentially suffer from a proliferative disease such as cancer.

[0048] The terms "inhibition," "inhibitor," or "antagonist" include a reduction in a particular parameter, e.g., activity, of a given molecule or pathway. For example, inhibiting the activity of a target kinase (Raf or KRAS G12C) by 5%, 10%, 20%, 30%, 40%, or more is encompassed by the term. Thus, inhibition can be, but need not be, 100%.

[0049] As used herein, "salts" (meaning "or salts thereof" or "or a salt thereof") may exist alone or in admixture with the free compounds of the combinations disclosed herein, e.g., the Raf inhibitors, KRAS G12C inhibitors, and / or trametinib, which are compounds having formula (I), and include pharmaceutically acceptable salts. Such salts are formed from compounds of the combinations disclosed herein that have a basic nitrogen atom, particularly pharmaceutically acceptable salts, for example, as acid addition salts with organic or inorganic acids. The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound and are typically not biologically or otherwise undesirable. Due to the presence of an amino group, the compounds can form acid addition salts.

[0050] Lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa., (1985), and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0051] For isolation or purification purposes, it is also possible to use pharmaceutically unacceptable salts, such as picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds can be employed (if applicable, in the form of pharmaceutical preparations). Considering the close relationship between the free form of the novel compounds and their salt forms, including salts that can be used as intermediates, for example, in the purification or identification of the novel compounds, any reference to the free compound should be understood to also refer to the corresponding salt, as appropriate and convenient. The salts of the compounds used in the combinations disclosed herein may be pharmaceutically acceptable salts, and suitable counterions forming pharmaceutically acceptable salts are known in the art. Unless otherwise specified or clearly indicated by the context, reference to the therapeutic agents useful in the pharmaceutical combinations provided herein includes both the free base of the compound and all pharmaceutically acceptable salts of the compound.

[0052] As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute or its salt and a solvent. For purposes of the embodiments herein, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, dimethyl sulfoxide, ethanol, and acetic acid. Examples of suitable pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, and acetic acid.

[0053] The term "synergistic effect," as used herein, refers to the action of two agents, such as, for example, a Raf inhibitor that is a compound having Formula (I) or a pharmaceutically acceptable salt thereof, and a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof, producing an effect, such as delaying the symptomatic progression of cancer or a symptom thereof, that is greater than the simple addition of the effects of each drug administered alone.

[0054] In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutical combination disclosed herein and at least one pharmaceutically acceptable carrier.

[0055] In some embodiments, there is provided a pharmaceutical combination or composition disclosed herein for use in the treatment of cancer.

[0056] In some embodiments, the cancer expresses a MAPK mutation, or the cancer is an N-RAS mutant, an H-RAS mutant, or a K-RAS mutant, or a combination thereof. KRAS-mutated cancers or tumors are included. The term "KRAS-mutant" tumor or cancer includes any tumor that exhibits a mutated KRAS protein, specifically a gain-of-function KRAS mutation, particularly any G12X, G13X, Q61X, or A146X KRAS mutation, where X is any amino acid other than the naturally occurring amino acid at that position. For example, a G12V mutation means that 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. Therefore, KRAS mutant NSCLC includes tumors with 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.Cancer can be early stage, intermediate stage, 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.NRAS mutant cancers or tumors are also included. The term "NRAS-mutant" tumor or cancer includes any tumor that exhibits a mutant NRAS protein, specifically a gain-of-function NRAS mutation, particularly any G13R, Q61K, Q61L, Q61R, NRAS-mutant tumor. Thus, NRAS-mutant melanoma includes melanoma with at least one NRAS mutation corresponding to Q61K, Q61L, or Q61R.The cancer may be NRAS QG13R mutant melanoma. The cancer may be early, intermediate, or late stage. The cancer may be locally advanced or metastatic.

[0057] In some embodiments, the cancer comprises a mutation at Q61 selected from Q61R, Q61L, and Q61M.

[0058] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or pancreatic ductal adenocarcinoma (PDAC).

[0059] In some embodiments, the cancer is colorectal cancer (CRC).

[0060] In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0061] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0062] In some embodiments, the cancer is characterized by a mutation selected from the group consisting of a BRAF, NRAS, KRAS mutation, and combinations thereof.

[0063] 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).

[0064] In some embodiments, the pharmaceutical combination or composition further comprises an anti-PD-1, anti-PD-L1, or anti-EGFR antibody.

[0065] In some embodiments, a method of treating a cancer expressing a MAPK mutation is provided, wherein the cancer is an N-RAS mutant, an H-RAS mutant, or a K-RAS mutant, or a combination thereof, comprising administering a pharmaceutical combination or pharmaceutical composition described herein.

[0066] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or pancreatic ductal adenocarcinoma (PDAC).

[0067] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0068] In some embodiments, the cancer is colorectal cancer (CRC).

[0069] 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).

[0070] In some embodiments, the cancer comprises a mutation at Q61 selected from Q61R, Q61L, and Q61M.

[0071] In some embodiments, the cancer comprises NF-1 loss of function.

[0072] In some embodiments, the cancer comprises a RAS G13R mutation.

[0073] In some embodiments, the cancer comprises a KRAS G12C mutation. In some such aspects, the cancer is non-small cell lung cancer (NSCLC).

[0074] In some embodiments, the cancer comprises a class 2 BRAF mutation.

[0075] In some embodiments, the cancer comprises a class 3 BRAF mutation.

[0076] In some embodiments, the pharmaceutical combination or composition further comprises an anti-PD-1, anti-PD-L1, or anti-EGFR antibody. For example, a suitable pharmaceutical combination of the composition may include an anti-PD-1 antibody, including, but not limited to, pembrolizumab, nivolumab, pidilizumab, semilimab, SHR-1210, PDR001, or AMP-224. Suitable PD-L1 antibodies may include, but are not limited to, atezolizumab, avelumab, durvalumab, BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. Suitable EGFR antibodies include, but are not limited to, cetuximab, panitumumab, nimotuzumab, or necitumumab.

[0077] In a non-limiting example, a triple pharmaceutical combination or composition for treating KRAS G12C mutant lung cancer, including non-small cell lung cancer (NSCLC), may include a RAF inhibitor: the compound of formula (I), sotorasib, and pembrolizumab.

[0078] In a further non-limiting example, a triple pharmaceutical combination or composition for treating KRAS G12C mutant colon cancer, including colorectal cancer (CRC), may include a RAF inhibitor: a compound of formula (I), sotorasib, and cetuximab.

[0079] Also, in a further non-limiting example, a triple pharmaceutical combination or composition for treating KRAS G12C mutant pancreatic cancer, including pancreatic ductal adenocarcinoma (PDAC), may include a RAF inhibitor: a compound of Formula (I), sotorasib, and panitumumab.

[0080] In some embodiments, the Raf inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, and may be combined with a KRAS G12C inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and administered at therapeutic or subtherapeutic doses compared to single-agent dose levels. In some embodiments, the concentration or dosage of one therapeutic agent required to achieve inhibition, e.g., growth inhibition or tumor shrinkage, is lower when another therapeutic agent is used or administered in combination with the first therapeutic agent than when each therapeutic agent is administered individually. In some embodiments, the concentration or dosage of one therapeutic agent required to achieve inhibition, e.g., tumor inhibition, in combination therapy is lower than the therapeutic dose as a single-agent therapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower.

[0081] When determining synergistic interactions between one or more components, the optimal range of effect and absolute dose ranges of each component for effect can be definitively determined by administering the components across different w / w ratio ranges and doses to patients in need of treatment. In humans, the complexity and cost of conducting clinical studies on patients can make this form of testing impractical as a primary model of synergy. However, observations of synergy in specific experiments can predict effects in other species, and animal models exist that can be used to further quantify synergy. Observations of synergy in one species can predict effects in other species, and animal models can be used to measure synergy as described herein. The results of such studies can also be used to predict effective dose ratio ranges and absolute doses and plasma concentrations required in other species by applying pharmacokinetic / pharmacodynamic (PK / PD) methods. The established correlation between the effects observed in tumor models and humans suggests that synergistic effects in animals can be demonstrated, for example, by xenograft models or in appropriate cell lines.The combinations disclosed herein can be shown to produce the beneficial effects described herein by established test models.Those skilled in the art are fully capable of selecting relevant test models to demonstrate such beneficial effects.The pharmacological activity of the combinations disclosed herein can be demonstrated, for example, in clinical trials or in in vivo or in vitro test procedures essentially as described herein.

[0082] Administration of a combination includes administration of the combination in a single formulation or unit dosage form, simultaneous but separate administration of the individual agents of the combination, or sequential administration of the individual agents of the combination by any suitable route. The individual combination partners of the combinations disclosed herein can be administered separately at different times during the course of treatment, or sequentially in any order, or simultaneously in divided or single combination forms, e.g., simultaneously or jointly, in therapeutically effective amounts, including synergistically effective amounts, e.g., in dosages corresponding to the amounts described herein, daily or intermittently (i.e., not daily).

[0083] The compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the methods, treatments, combinations, and compositions disclosed herein is a potent inhibitor of BRAF and CRAF. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered orally. In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 to 1200 mg (e.g., per day). The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in 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 dose of the compound of formula (I) or its pharmaceutically acceptable salt can be administered once a day, twice a day, three times a day, or four times a day, and the actual dosage and timing of administration are determined by criteria such as the age, weight, and sex of the patient, the level and severity of the cancer being treated, and the judgment of the treating physician.In some embodiments, the unit dose of the compound of formula (I) is administered once a day.In another embodiment, the unit dose of the compound of formula (I) is administered twice a day.

[0084] In some embodiments, the KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof is administered orally. In one embodiment, the KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 to 1200 mg (e.g., per day). The KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof may be administered at a unit dose 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 dose of KRAS G12C inhibitor or its pharmaceutically acceptable salt can be administered once a day, twice a day, three times a day, or four times a day, and the actual dosage and timing of administration are determined by criteria such as patient's age, weight, and sex, the level and severity of the cancer being treated, and the judgment of the treating physician.In some embodiments, the unit dose of KRAS G12C inhibitor is administered once a day.In another embodiment, the unit dose of KRAS G12C inhibitor is administered twice a day.

[0085] In some embodiments, trametinib 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 to 2.0 mg (e.g., per day). Trametinib or a pharmaceutically acceptable salt thereof can be administered in unit doses of about 0.5 mg, about 1.0 mg, or about 2.0 mg. A unit dose of trametinib or a pharmaceutically acceptable salt thereof can be administered once daily, with the actual dosage and timing of administration determined by factors such as the patient's age, weight, and sex, the extent and severity of the cancer being treated, and the treating physician's judgment. In some embodiments, a unit dose of trametinib is administered once daily. [Example]

[0086] Example 1: Synergistic combination of compounds of formula (I) This example demonstrates the synergistic combination of a compound of Formula I with a KRAS G12C inhibitor.

[0087] Combination cellular proliferation assay: MIA PaCa-2 cells (5000 cells / well) were seeded onto 96-well plates in 100 μl of cell culture medium. Cells were treated with either sotorasib or the KRAS G12C inhibitor compound (12), a compound of Formula I, at concentrations ranging from 0 to 1 μM using a Tecan D300e Digital Dispenser combination matrix protocol. On day 5, 100 μl of CellTiter-Glo (CTG) reagent (Promega) was added, and the plate was incubated for 60 minutes with gentle shaking. After the 60-minute incubation, the luminescent signal was determined according to the supplier's instructions (Promega), and combination data were generated using the inventors' proprietary combination analysis software with a standard HSA model. This was performed in duplicate. Combination synergy was represented by a positive number in the results table. Negative numbers represent combination antagonism.

[0088] The KRAS G12C inhibitor compound (12) has the following structure:

[0089] [ka] It has.

[0090] The results of these experiments are shown in Tables 1 and 2 below.

[0091] [Table 1]

[0092] [Table 2]

[0093] While specific embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. (a) a compound of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof; and (b) a KRAS G12C inhibitor; 10. A pharmaceutical combination comprising:

2. (a) a compound of formula (I) 【Chemistry 2】 or a pharmaceutically acceptable salt thereof; and (b) a KRAS G12C inhibitor; and (c) trametinib and 10. A pharmaceutical combination comprising:

3. The KRAS G12C inhibitor is sotorasib, adagrasib, 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 [Chemistry 3-4] [Transformation 3-5] 3. The pharmaceutical combination according to claim 1 or 2, wherein the pharmaceutical combination is selected from:

4. The inhibitor of the KRAS G12C inhibitor is 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 The pharmaceutical combination according to any one of claims 1 to 3, wherein the pharmaceutical combination is selected from:

5. The pharmaceutical combination according to any one of claims 1 to 4, wherein said pharmaceutical combination is for simultaneous, sequential or separate administration.

6. The pharmaceutical combination according to any one of claims 1 to 5, wherein said pharmaceutical combination is a fixed combination.

7. The pharmaceutical combination according to any one of claims 1 to 5, wherein said pharmaceutical combination is a non-fixed combination.

8. A pharmaceutical composition comprising the pharmaceutical combination of any one of claims 1 to 7 and at least one pharmaceutically acceptable carrier.

9. A pharmaceutical combination according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 8, for use in the treatment of cancer.

10. 10. The pharmaceutical combination or pharmaceutical composition of claim 9, wherein the cancer expresses an NF-1 loss-of-function mutation, the cancer expresses a MAPK mutation, or the cancer is an N-RAS mutant, an H-RAS mutant, or a K-RAS mutant, or a combination thereof.

11. 11. The pharmaceutical combination or composition of claim 9 or 10, wherein the cancer comprises a mutation at Q61 selected from Q61R, Q61L, and Q61M.

12. The pharmaceutical combination or composition or pharmaceutical composition according to any one of claims 9 to 11, wherein the cancer is non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or pancreatic ductal adenocarcinoma (PDAC).

13. The pharmaceutical combination or composition or pharmaceutical composition according to any one of claims 9 to 11, wherein the cancer is colorectal cancer (CRC).

14. The pharmaceutical combination or composition or pharmaceutical composition according to any one of claims 9 to 11, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

15. The pharmaceutical combination or composition or pharmaceutical composition according to any one of claims 9 to 11, wherein the cancer is non-small cell lung cancer (NSCLC).

16. 16. The pharmaceutical combination or composition of any one of claims 9 to 15, wherein the cancer is characterized by mutations in BRAF, NRAS, KRAS, NRAS, or NF-1, or a combination thereof.

17. 12. The pharmaceutical combination or pharmaceutical composition of any one of claims 9 to 11, wherein the cancer is selected from the group consisting of KRAS mutated NSCLC (non-small cell lung cancer), KRAS mutated colorectal cancer (CRC), and KRAS mutated pancreatic cancer, KRAS mutated pancreatic ductal adenocarcinoma (PDAC).

18. 18. The pharmaceutical combination or composition of any one of claims 9 to 17, wherein the pharmaceutical combination or composition further comprises an anti-PD-1, anti-PD-L1, or anti-EGFR antibody.

19. 10. A method of treating a cancer expressing a MAPK mutation, wherein the cancer is N-RAS mutant, H-RAS mutant, or K-RAS mutant, or a combination thereof, said method comprising administering a pharmaceutical combination according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 8.

20. 20. The method of claim 19, wherein the cancer is non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or pancreatic ductal adenocarcinoma (PDAC).

21. 20. The method of claim 19, wherein the cancer is non-small cell lung cancer (NSCLC).

22. 20. The method of claim 19, wherein the cancer is colorectal cancer (CRC).

23. 20. The method of claim 19, 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. 24. The method of any one of claims 19 to 23, wherein the cancer comprises a mutation at Q61 selected from Q61R, Q61L, and Q61M.

25. The method of any one of claims 19 to 24, wherein the pharmaceutical combination or the pharmaceutical composition further comprises an anti-PD-1, anti-PD-L1, or anti-EGFR antibody.

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