RAF inhibitor and KRAS G12C inhibitor combination therapy

Abstract

A pharmaceutical combination comprising: a Raf inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof, (b) a KRAS G12C inhibitor, and / or (c) trametinib.

Description

[0001] CROSS-REFERENCE

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 478,888, filed January 6, 2023, and U.S. Provisional Application Serial No. 63 / 505,643, filed June 1, 2023, which are incorporated herein by reference in their entireties. BACKGROUND

[0003] The RAS / RAF / MEK / ERK or MAPK pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Dysregulation of this pathway is the basis of many tumorigenesis. The pathway is activated by extracellular signals, which in turn induce the small G protein RAS to exchange GDP for GTP. The activated RAS guanosine triphosphatase (GTPase) promotes the activation of the RAF (also referred to herein as Raf) family proteins (ARAF, BRAF, and CRAF (also known as RAF1)). The activated RAF proteins lead to the phosphorylation and activation of MEK1 / 2 proteins, which in turn phosphorylate and activate extracellular signal-regulated kinases (ERKs). The ERK1 / 2 proteins phosphorylate a variety of substrates, including a variety of transcription factors, and regulate key cellular activities, including proliferation, differentiation, migration, survival, and angiogenesis.

[0004] 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 different mechanisms, including activating mutations in RAS and BRAF (V-Raf murine sarcoma viral oncogene homolog Bl). RAS is a superfamily of GTPases, including 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, are detected in 9-30% of all cancers, with the highest rate of KRAS mutations (86%), followed by NRAS (11%), and the less common HRAS (3%) (Cox AD, et al. Nat Rev Drug Discov 2014; 13(11):828-51). Activating KRAS mutations are also common in melanoma (Fedorenko IV, et al. Br J Cancer 2015; 112(2):217-26), pancreatic cancer (di Magliano MP and Logsdon CD, Gastroenterology 2013; 144(6): 1220-9), colorectal cancer (Knickelbein K and 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

[0005] Embodiments herein relate to a pharmaceutical combination comprising: (a) a Raf inhibitor, which is a compound of Formula (I)

[0006]

[0007] or a pharmaceutically acceptable salt thereof,

[0008] and (b) a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof.

[0009] Embodiments herein further relate to a pharmaceutical combination comprising: (a) a Raf inhibitor, which is a compound of Formula (I)

[0010]

[0011] or a pharmaceutically acceptable salt thereof, (b) a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof, and (c) trametinib or a pharmaceutically acceptable salt thereof.

[0012] The embodiments further relate to a pharmaceutical combination for use in the treatment of proliferative diseases (particularly cancer), comprising (a) a Raf inhibitor (which is a compound of formula (I) as defined above) or a pharmaceutically acceptable salt thereof and a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof, and the use of such a combination for the preparation of a medicament for treating proliferative diseases (particularly cancer); further provided are methods for treating proliferative diseases (particularly cancer) in a subject in need thereof, comprising administering to the subject a combined therapeutically effective amount of the combination; further provided are the use of such a combination for treating proliferative diseases (particularly cancer); pharmaceutical compositions comprising such a combination and commercial packaging thereof.

[0013] The embodiments further relate to a pharmaceutical combination for use in the treatment of a proliferative disease (particularly cancer), comprising (a) a Raf inhibitor, which is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, (b) a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof, and (c) trametinib or a pharmaceutically acceptable salt thereof, and the use of such a combination for the preparation of a medicament for treating a proliferative disease (particularly cancer); further provided are methods for treating a proliferative disease (particularly cancer) in a subject in need thereof, comprising administering to the subject a combined therapeutically effective amount of the combination; further provided are the use of such a combination for treating a proliferative disease (particularly cancer); pharmaceutical compositions comprising such a combination and commercial packaging thereof. DETAILED DESCRIPTION

[0014] In some embodiments, a pharmaceutical combination is provided comprising (a) a Raf inhibitor, the Raf inhibitor being a compound of formula (I)

[0015]

[0016] or a pharmaceutically acceptable salt thereof,

[0017] and (b) KRAS G12C inhibitors.

[0018] In some embodiments, a pharmaceutical combination is provided comprising a Raf inhibitor, wherein the Raf inhibitor is a compound of formula (I)

[0019]

[0020] or a pharmaceutically acceptable salt thereof,

[0021] (b) KRAS G12C inhibitor, and (c) trametinib.

[0022] In cell-based assays, the Raf inhibitor compound of Formula (I) exhibited anti-proliferative activity in cell lines containing various mutations that activate the MAPK signaling. In vivo, treatment with the compound of Formula (I) resulted in tumor regression in several KRAS mutant models, including Calu-6 (KRAS Q61K) and NCI-H358 (KRAS G12C) of NSCLC origin. Overall, the in vitro and in vivo MAPK pathway suppression and anti-proliferative activity of the compound of Formula (I) observed at well-tolerated doses suggest that the compound of Formula (I) can have anti-tumor activity in tumor patients with MAPK pathway activating lesions. In addition, the compound of Formula (I) is a type 2 ATP-competitive inhibitor of both B-Raf and C-Raf, which can keep the kinase pocket in an inactive conformation, thereby reducing paradoxical activation seen with many B-Raf inhibitors and blocking mutant Ras-driven signaling and cell proliferation. The compound of Formula (I) exhibited efficacy in a number of MAPK-driven human cancer cell lines and xenograft tumors that represent model tumors with human lesions in KRAS, NRAS, and BRAF oncogenes. The pharmaceutical combinations of the disclosed embodiments further comprise a KRAS G12C inhibitor. Further pharmaceutical combinations of the disclosed embodiments further comprise a KRAS G12C inhibitor and trametinib. The term “KRAS G12C inhibitor” is defined herein as a compound that targets, reduces, or inhibits a KRAS glycine 12 to cysteine mutation.

[0023] In some embodiments, a suitable KRAS G12C inhibitor is selected from sotorasib, adagrasib,

[0024]

[0025]

[0026]

[0027]

[0028] or a pharmaceutically acceptable salt or solvate thereof.

[0029] In some embodiments, other suitable KRAS G12C inhibitors are selected from:

[0030]

[0031]

[0032]

[0033]

[0034] or a pharmaceutically acceptable salt or solvate thereof.

[0035] Trametinib

[0036] Trametinib: Belongs to a class of pyrimidine compounds that are known inhibitors of mitogen-activated protein (MAP) kinase / extracellular signal-regulated (ERK) kinases (hereinafter referred to as MEK), such as MEK1 and MEK2. MEK inhibitory activity effectively induces the inhibition of ERK1 / 2 and the suppression of cell proliferation, which has shown effects on diseases caused by undesirable cell proliferation (such as tumors, etc.).

[0037] As used herein, the terms "combination," "therapeutic combination," or "pharmaceutical combination" refer to a fixed combination in the form of one dosage unit, or a non-fixed combination or kit for combined administration, wherein two or more therapeutic agents may be administered together, independently at the same time, or separately within time intervals, especially when these time intervals allow the combination partners to exhibit a synergistic (e.g., synergistic) effect.

[0038] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as with a single formulation of active ingredients in a fixed ratio or with a separate formulation (e.g., capsule and / or intravenous formulation) for each active ingredient. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential or separate manner at approximately the same time or at different times. Regardless of whether the active ingredient is administered in a single formulation or a separate formulation, these drugs are administered to the same patient as part of the same course of treatment. In any case, the treatment regimen will provide a beneficial effect in treating the conditions or disorders described herein.

[0039] In some embodiments, the combination is for simultaneous, sequential or separate administration.Simultaneous therapeutic use, within the meaning of the presently disclosed embodiments, refers to the administration of at least two active ingredients by the same route and at the same time or essentially the same time.

[0040] Within the meaning of the presently disclosed embodiments, separate use specifically refers to the administration of at least two active ingredients by different routes at the same time or essentially the same time.

[0041] Sequential therapeutic use means that the at least two active ingredients are administered at different times, either by the same or different routes of administration. More specifically, the method of administration refers to how the entire administration of one of the active ingredients is completed before the administration of another or more of the active ingredients is initiated.

[0042] 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 preparation" as used herein refer to a single carrier or vehicle or dosage form that is formulated for the delivery to a patient of both therapeutic agents in amounts that are jointly effective for the treatment of cancer. The single vehicle is intended to deliver an amount of each agent as well as any pharmaceutically acceptable carrier or excipient. In some embodiments, the vehicle is a tablet, capsule, pill, or patch. In other embodiments, the vehicle is a solution or suspension.

[0043] The term "non-fixed combination" or "kit" refers to the therapeutic agents in the combinations disclosed herein are each administered to the patient as separate entities simultaneously, concurrently or sequentially, with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the subject in need thereof. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0044] 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 use in contact with the tissues of a subject (e.g., a mammal or a human) without an excessive level of toxicity, irritation, allergic response, and other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0045] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein 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 be known to one of ordinary skill in the art, except insofar as limited by the disclosure. The use of any and all such diluents, dispersants, solvents, and the like and combinations thereof in the treatment or pharmaceutical compositions is contemplated, except insofar as limited by the disclosure.

[0046] The term "pharmaceutical composition" is defined herein as a mixture or solution containing at least one therapeutic agent that is administered to a subject (e.g., a mammal or human) to treat or prevent a particular disease or condition affecting the subject. The pharmaceutical compositions of the present disclosure can be formulated into pharmaceutical compositions suitable for enteral or parenteral administration such as tablets, capsules, pills, or suppositories, or ampoules. These are prepared according to procedures known in the art using well-known and readily available ingredients. Unless otherwise specified, these are prepared in a manner fully within the capability of an ordinary skilled artisan (e.g., by various conventional mixing, granulation, direct compression, encapsulation, sugar coating, dissolution, lyophilization processes, or manufacturing techniques that are known to those skilled in the art). It will be appreciated that the unit content of the combination partners contained in each dosage form need not per se constitute an effective amount, since the necessary effective amount can be achieved via administration of a plurality of dosage units. The pharmaceutical composition can contain from about 0.1% to about 99.9%, or from about 1% to about 60%, of the therapeutic agent. One of ordinary skill in the art can select one or more of the foregoing carriers for a particular desired property of the dosage form by routine experimentation and without any undue burden of experimentation. The amount of each carrier used can vary within ranges conventional in the art. The following references disclose techniques and excipients for formulating oral dosage forms: The Handbook of Pharmaceutical Excipients, 4thEdition, Rowe et al. eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20thEdition, Gennaro ed., Lippincott Williams & Wilkins (2003). These optional additional conventional carriers can be incorporated into the oral dosage form by incorporating one or more conventional carriers into the initial mixture prior to granulation or during the process of granulation, or by combining one or more conventional carriers with the granules comprising the pharmaceutical agent combination or individual pharmaceutical agents of the pharmaceutical agent combination in the oral dosage form. In the latter embodiment, the combined mixture can be further mixed, e.g., by V-blender mixing, and then compressed or molded into tablets (e.g., monolithic tablets), encapsulated with a capsule, or filled into a sachet.

[0047] Pharmaceutical compositions can exist in unit dosage form, each unit dosage containing a predetermined amount of active ingredient. In some embodiments, a unit dosage includes one or more vehicles, such that each vehicle includes an effective amount of at least one therapeutic agent along with pharmaceutically acceptable carriers and excipients. In some embodiments, a unit dosage is one or more tablets, capsules, pills, injections, infusions, patches, etc. that are administered to a patient at the same time. The amount of active ingredient per dose depends on the condition to be treated, the route of administration, and the age, weight, and condition of the patient, as known to those skilled in the art. In some embodiments, unit dosage compositions are those containing active ingredient in the amount and dosage regimen that would be used in a daily dosage or a sub-dose, or an appropriate fraction thereof. Furthermore, such pharmaceutical compositions can be prepared by any of the methods well-known in the art of pharmacy.

[0048] Pharmaceutical compositions can include a "therapeutically effective amount" or "effective amount" of a compound disclosed herein. The terms "pharmaceutically effective amount," "therapeutically effective amount," or "clinically effective amount" of a therapeutic agent combination is an amount that is sufficient, at dosages and for periods of time necessary to provide an observable or clinically significant improvement relative to the baseline of clinically observable signs and symptoms of the disorder being treated by the combination. A therapeutically effective amount can vary depending on such factors as the disease state, age, sex, and body 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 the therapeutically beneficial effects.

[0049] A "therapeutically effective dose" can modulate a measurable parameter, such as tumor growth rate or disease progression, in a desired fashion. The ability of a compound to modulate a measurable parameter can be assessed in animal model systems predictive of efficacy in human tumors to help establish appropriate dosage levels and schedules. Alternatively, the ability of a compound to modulate an undesirable parameter can be tested by using in vitro assays known to those skilled in the art to assess this property of the composition.

[0050] The terms "jointly therapeutic activity" or "jointly therapeutic effect" as used herein mean that the therapeutic agents can be given in conjunction, separately or sequentially in time intervals preferred by them, so that the subject to be treated, especially a human, still shows an interaction (jointly therapeutic effect), which can be synergistic. It can be determined, especially by following the blood levels of the compounds, whether this is the case, indicating that both compounds are present in the blood of the human to be treated at least for a certain time interval.

[0051] The term "agent" as used herein is understood to be a substance that produces a desired effect in a tissue, system, animal, mammal, human or other subject. It is also understood that an "agent" can be a single compound or a combination or composition of two or more compounds.

[0052] The term "proliferative disease" includes cancer.

[0053] As used herein, the term "cancer" refers to a disease characterized by the uncontrolled and undesirable 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 precancerous lesions as well as malignant cancers and tumors. The term "cancer" is used herein to refer to a broad range of tumors, including all solid and hematological malignancies.

[0054] "Oral dosage form" includes unit dosage forms prescribed or intended for oral administration. As used herein, the terms "treat," "treatment," and "treating" refer to reducing or alleviating the progression, severity and / or duration of a disorder, e.g., a proliferative disorder, or one or more symptoms thereof, suitably one or more perceptible symptoms thereof, by administration of one or more therapies. In particular embodiments, the term "treatment" refers to the alleviation of at least one measurable physical parameter of a proliferative disorder, such as tumor growth, that a patient in need of treatment can not necessarily perceive. In other embodiments, the term "treatment" refers to inhibiting the progress of a proliferative disorder, e.g., inhibiting the progression of a perceptible symptom, e.g., at a physical level, as by stabilizing a physical parameter, e.g., at a physiological level, or both. In other embodiments the term "treatment" refers to reducing or stabilizing tumor size or cancer cell count.

[0055] Within the meaning of the present disclosure, the term "treatment" also denotes arresting, delaying the onset (i.e., the period prior to clinical manifestation of a disease), and / or reducing the risk of developing or worsening a disease. The term "protecting" is used herein to refer to preventing, delaying or treating (or all) the development, persistence or aggravation of a disease in a subject (e.g., a mammal or a human) as appropriate.

[0056] The term "subject" or "patient" as used herein is intended to include an animal that can have or be afflicted with a cancer or any disorder that is directly or indirectly related to cancer. Examples of subjects include mammals, such as 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 having, at risk of having, or potentially likely to have a proliferative disease, such as a cancer.

[0057] The terms "inhibit," "inhibitor," or "antagonist" include a reduction in a particular parameter (e.g., activity) of a given molecule or pathway. For example, the term includes inhibition of activity of the targeted kinase (Raf or KRAS G12C) by 5%, 10%, 20%, 30%, 40% or more. Thus, inhibition can be 100%, but need not be.

[0058] As used herein, “salt” (which is referred to by “or a salt thereof”) can exist independently or in admixture with the free compounds in the combinations disclosed herein, e.g., in admixture with the Raf inhibitor (which is a compound of Formula (I)), the KRAS G12C inhibitor, and / or the trametinib, and includes pharmaceutically acceptable salts. Such salts are, for example, acid addition salts formed from compounds in the combinations disclosed herein having basic nitrogen atoms with organic or inorganic acids, particularly pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds and that are generally non-toxic and biologically or otherwise

[0059] A list of suitable salts can be found in, for example, “Remington's Pharmaceutical Sciences,” 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002) by Sahl and Wermuth. Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002) by Sahl and Wermuth.

[0060] For isolation or purification purposes, pharmaceutically unacceptable salts, such as picrates or perchlorates, can also be used. For therapeutic use, only pharmaceutically acceptable salts or the free compounds (if applicable to the form of the pharmaceutical preparation) can be employed. In view of the close relationship between the new compounds in the free form and the new compounds in the form of their salts, including the salts that can be used as intermediates, for example, in the purification or identification of the new 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 the compounds used in the combinations disclosed herein can be pharmaceutically acceptable salts; pharmaceutically acceptable salts formed with suitable counterions are known in the art. Unless otherwise stated or indicated herein, reference to a useful therapeutic agent in the pharmaceutical combinations provided herein includes both the free base of the compound and all pharmaceutically acceptable salts of the compound.

[0061] As used herein, the term “solvate” refers to a complex of variable stoichiometry formed by a solute or a salt thereof and a solvent. For the purposes of embodiments herein, such a solvent can 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.

[0062] The term "synergistic effect" as used herein refers to an effect (e.g., slowing of symptomatic progression of cancer or symptoms thereof) that is greater than the simple addition of the effects of each drug administered by itself, such as for example, a Raf inhibitor, which is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, there is provided a pharmaceutical composition comprising a pharmaceutical combination disclosed herein and at least one pharmaceutically acceptable carrier, as described hereinabove.

[0064] In some embodiments, there is provided a pharmaceutical combination or a pharmaceutical composition as disclosed herein for use in the treatment of cancer.

[0065] 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 a combination thereof. KRAS mutant cancers or tumors are included. The term “KRAS mutant” tumor or cancer includes any tumor that exhibits a mutated KRAS protein, in particular a gain-of-function KRAS mutation; especially any G12X, G13X, Q61X, or A146X KRAS mutant, wherein X is any amino acid other than the naturally occurring amino acid at that position. For example, a G12V mutation refers to a substitution of a glycine with a 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, in particular at least one KRAS mutation selected from Q61K, G12V, G12C, and A146T NSCLC. The cancer can be in 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. NRAS mutant cancers or tumors are also included. The term “NRAS mutant” tumor or cancer includes any tumor that exhibits a mutated NRAS protein, in particular a 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 can be NRAS QG13R mutant melanoma. The cancer can be in an early, intermediate, or late stage. The cancer can be locally advanced or metastatic.

[0066] In some embodiments, the cancer comprises a mutation at Q61 selected from Q61R, Q61L, and Q61M.

[0067] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or pancreatic ductal adenocarcinoma (PDAC).

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

[0069] In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0070] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0071] In some embodiments, the cancer is characterized by a mutation selected from BRAF, NRAS, KRAS mutations, and combinations thereof.

[0072] In some embodiments, the cancer is selected from KRAS mutant NSCLC (non-small cell lung cancer), KRAS mutant colorectal cancer (CRC), and KRAS mutant pancreatic cancer KRAS mutant pancreatic ductal adenocarcinoma (PDAC).

[0073] In some embodiments, the pharmaceutical combination or pharmaceutical composition further comprises an anti-PD-1, anti-PD-L1, or anti-EGFR antibody.

[0074] In some embodiments, there is provided a method of treating a cancer expressing a MAPK mutation or wherein the cancer is N-RAS mutant, H-RAS mutant, or K-RAS mutant, or combinations thereof, the method comprising administering a pharmaceutical combination or pharmaceutical composition described herein.

[0075] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or pancreatic ductal adenocarcinoma (PDAC).

[0076] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0077] In some embodiments, the cancer is colorectal cancer (CRC).

[0078] In some embodiments, the cancer is selected from KRAS mutant NSCLC (non-small cell lung cancer), KRAS mutant colorectal cancer (CRC), and KRAS mutant pancreatic cancer KRAS mutant pancreatic ductal adenocarcinoma (PDAC).

[0079] In some embodiments, the cancer comprises a mutation at Q61 selected from Q61R, Q61L, and Q61M.

[0080] In some embodiments, the cancer comprises NF-1 loss of function.

[0081] In some embodiments, the cancer comprises a RAS G13R mutation.

[0082] In some embodiments, the cancer comprises a KRAS G12C mutation. In some such embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0083] In some embodiments, the cancer comprises a Class 2 BRAF mutation.

[0084] In some embodiments, the cancer comprises a Class 3 BRAF mutation.

[0085] In some embodiments, the pharmaceutical combination or pharmaceutical composition further comprises an anti-PD-1, anti-PD-L1, or anti-EGFR antibody. For example, a suitable pharmaceutical combination of the composition can comprise an anti-PD-1 antibody, including but not limited to pembrolizumab, nivolumab, pidilizumab, cemiplimab, SHR-1210, PDR001, or AMP-224. Suitable PD-L1 antibodies can 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.

[0086] As a non-limiting example, a triple pharmaceutical combination or composition for treating KRAS G12C mutant lung cancer (including non-small cell lung cancer (NSCLC)) can comprise a RAF inhibitor: a compound of Formula (I), plus sotorasib, and pembrolizumab.

[0087] As a further non-limiting example, a triple pharmaceutical combination or composition for treating KRAS G12C mutant colon cancer (including colorectal cancer (CRC)) can comprise a RAF inhibitor: a compound of Formula (I), plus sotorasib, and cetuximab.

[0088] As a still further non-limiting example, a triple pharmaceutical combination or composition for treating KRAS G12C mutant pancreatic cancer (including pancreatic ductal adenocarcinoma (PDAC)) can comprise a RAF inhibitor: a compound of Formula (I), plus sotorasib, and panitumumab.

[0089] In some embodiments, the Raf inhibitor is a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in combination with a KRAS G12C inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and can be administered at a therapeutic dose or at less than a therapeutic dose relative to the single agent dose level. 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 the other therapeutic agent is used or administered in combination with the first therapeutic agent than when each therapeutic agent is administered alone. In some embodiments, in combination therapy, the concentration or dosage of one therapeutic agent required to achieve inhibition (e.g., growth inhibition) is lower than the therapeutic dose in monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower.

[0090] In determining synergistic interactions between one or more components, the optimal range of effects and the absolute dose range for each component for an effect can be explicitly measured by administering different w / w ratio ranges and doses of the components to patients in need of treatment. For humans, the complexity and cost of conducting clinical studies on patients can make it impractical to use this form of testing as the primary model for synergism. However, synergism observed in certain experiments can be predictive of effects in other species, and there are animal models that can be used to further quantify synergistic effects. Synergism observed in one species can be predictive of effects in other species, and synergistic effects can be measured using the animal models described herein, 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 applying pharmacokinetic / pharmacodynamic (PK / PD) methods. Established correlations between tumor models and effects seen in humans indicate that synergism in animals can be demonstrated, for example, by xenograft models or appropriate cell lines. The combinations disclosed herein can be demonstrated to produce the beneficial effects described herein by established test models. The relevant test models to demonstrate such beneficial effects are well within the abilities of those skilled in the art to select. The pharmacological activity of the combinations disclosed herein can be demonstrated by, for example, clinical studies or in vivo or in vitro test procedures substantially described herein.

[0091] Administration of the combinations includes administration of the combination in a single formulation or unit dosage form, administration of the individual agents in the combination simultaneously but separately, or administration of the individual agents in the combination sequentially. The individual combination partners in the combinations disclosed herein can be administered separately at different times during the course of therapy, or consecutively in any order, or concurrently in divided or single combination form, e.g., simultaneously, or in a jointly therapeutically effective amount, e.g., in daily or intermittent (i.e., not daily) doses corresponding to the amounts described herein.

[0092] The 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, 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 50-1200 mg (e.g., per day). The compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered in 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 the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered once daily, or twice daily, or three times daily, or four times daily, the actual dose and timing of administration being determined by standards such as the age, weight, and sex of the patient; the extent and severity of the cancer being treated; and the judgment of the attending medical practitioner. In some embodiments, the unit dose of the compound of Formula (I) is administered once daily. In another embodiment, the unit dose of the compound of Formula (I) is administered twice daily.

[0093] In some embodiments, the KRAS G12C inhibitor or pharmaceutically acceptable salt thereof is administered orally. In one embodiment, the KRAS G12C inhibitor or pharmaceutically acceptable salt thereof is administered at a dose of about 50-1200 mg (e.g., per day). The KRAS G12C inhibitor or pharmaceutically acceptable salt thereof can be administered in 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 the KRAS G12C inhibitor or pharmaceutically acceptable salt thereof can be administered once daily, or twice daily, or three times daily, or four times daily, the actual dose and timing determined by standards such as the patient’s age, weight, and gender; the extent and severity of the cancer to be treated; and the judgment of the attending physician. In some embodiments, the unit dose of the KRAS G12C inhibitor is administered once daily. In another embodiment, the unit dose of the KRAS G12C inhibitor is administered twice daily.

[0094] In some embodiments, the trametinib or pharmaceutically acceptable salt thereof is administered orally. In one embodiment, the trametinib or pharmaceutically acceptable salt thereof is administered at a dose of about 0.5-2.0 mg (e.g., per day). The trametinib or pharmaceutically acceptable salt thereof can be administered in a unit dose of about 0.5 mg, about 1.0 mg, or about 2.0 mg. The unit dose of the trametinib or pharmaceutically acceptable salt thereof can be administered once daily, the actual dose and timing determined by standards such as the patient’s age, weight, and gender; the extent and severity of the cancer to be treated; and the judgment of the attending physician. In some embodiments, the unit dose of the trametinib is administered once daily.

[0095] Example

[0096] Example 1: Synergistic combination of compounds of Formula (I)

[0097] This example demonstrates the synergistic combination of compounds of Formula I with a KRAS G12C inhibitor.

[0098] Combination cell proliferation assay: MIA PaCa-2 cells (5000 cells per well) were seeded in 100 ul cell culture medium in 96 well plates. Using Tecan D300e Digital Dispenser combination matrix protocol, cells were treated with compound of Formula I with Sotorasib or KRAS G12C inhibitor compound (12) at different concentrations from 0 to 1 uM. On day 5, 100 ul of CellTiter-Glo (CTG) reagent (Promega) was added and the plate was incubated for 60 minutes with gentle shaking. After 60 minutes of incubation, luminescent signal was determined according to the provider’s (Promega) instructions and combination data was generated by standard HSA model using our proprietary combination analysis software. The above was performed in duplicate. In the result table, combination synergy is represented by positive numbers. Negative numbers represent combination antagonism.

[0099] KRAS G12C inhibitor compound (12) has the following structure:

[0100]

[0101] The results of these experiments are shown in Tables 1 and 2 below.

[0102] Table 1: Benefit of the combination of naporaafenib with the KRAS G12C inhibitor sotorasib in KRAS G12C mutant cell line MIA PaCa-2 Table 2: Benefit of the combination of naporaafenib with the KRAS G12C inhibitor compound (12) in KRAS G12C mutant cell line MIA PaCa-2

[0103] N=2; HSA synergy and antagonism; model: Sotorasib with Compound (12) in MIA PaCa-2; ‘+’ synergy and ‘-’ antagonism

[0104] Table 2: Benefit of the combination of naporaafenib with the KRAS G12C inhibitor compound (12) in KRAS G12C mutant cell line MIA PaCa-2 ​ ​

[0105] N=2; HSA synergy and antagonism; model: Sotorasib with Compound (12) in MIA PaCa-2; ‘+’ synergy and ‘-’ antagonism

[0106] While specific embodiments of the application have been shown and described herein, it is to be understood that such embodiments are merely illustrative of the many possible specific embodiments which have been contemplated by the inventors. Numerous and varied embodiments have been contemplated as being within the scope of the present application. Various substitutions, alterations, and changes can be made to the specific embodiments described herein without departing from the spirit and scope of the application. It should be understood that various alternatives to the embodiments of the application described herein can be employed in practicing the application. It is the intent, therefore, to be limited only as indicated by the scope of the claims appended hereto.

Claims

1. A pharmaceutical combination comprising (a) a Raf inhibitor, wherein the Raf inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) KRAS G12C inhibitors.

2. A pharmaceutical combination comprising (a) a Raf inhibitor, wherein the Raf inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof, (b) KRAS G12C inhibitors, and (c) trametinib.

3. The pharmaceutical combination according to claim 1 or 2, wherein the KRAS G12C inhibitor is selected from the group consisting of sotolacizumab, adagraciba, or a pharmaceutically acceptable salt or solvate thereof.

4. The pharmaceutical combination according to any one of claims 1 to 3, wherein the KRAS G12C inhibitor The inhibitor is selected from: or a pharmaceutically acceptable salt or solvate thereof.

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

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

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

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

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

10. The pharmaceutical combination or pharmaceutical composition for use according to claim 9, wherein the cancer expresses an 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 a combination thereof.

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

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

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

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

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

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

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

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

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

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

23. The method of claim 19, wherein the cancer is selected from 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 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 according to any one of claims 19 to 24, wherein the drug combination or the pharmaceutical composition further comprises an anti-PD-1, anti-PD-L1 or anti-EGFR antibody.

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