combination

Abstract

The present application discloses combination therapy using a combination of a WEE1 inhibitor and a BRAF inhibitor, and optionally an EGFR inhibitor, for the treatment of diseases such as colorectal cancer.

Description

[Technical Field]

[0001] (Incorporation by reference of any priority application) Any and all applications for which a foreign or domestic priority claim is identified in an Application Data Sheet submitted with this application, including U.S. Provisional Patent Application No. 63 / 375,809, filed September 15, 2022, are expressly incorporated herein by reference under 37 CFR § 1.57 and Rules 4.18 and 20.6.

[0002] FIELD OF THE INVENTION This application relates to the fields of chemistry, biochemistry, and medicine. More specifically, disclosed herein are combination therapies and methods of treating diseases and / or conditions using the combination therapies described herein. [Background technology]

[0003] Cancer is a group of diseases involving abnormal cell growth that can invade or spread to other parts of the body. Today's cancer treatments include surgery, hormone therapy, radiation, chemotherapy, immunotherapy, targeted therapy, and combinations thereof. Survival rates vary depending on the type of cancer and the stage at which it is diagnosed. In 2021, approximately 1.9 million people will be diagnosed with cancer in the United States, and an estimated 600,000 will die from cancer. Therefore, there remains a need for effective cancer treatments. Summary of the Invention

[0004] Some embodiments described herein relate to a compound combination that may include an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof, and an effective amount of Compound (B) or a pharmaceutically acceptable salt of any of the foregoing. Other embodiments described herein relate to a compound combination that may include an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof, an effective amount of Compound (B) or a pharmaceutically acceptable salt thereof, and an effective amount of Compound (C) or a pharmaceutically acceptable salt thereof.

[0005] Some embodiments described herein relate to the use of a combination of compounds for treating a disease or condition, the combination comprising an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of Compound (B) or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a combination of compounds in the manufacture of a medicament for treating a disease or condition, the combination comprising an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of Compound (B) or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to the use of a combination of compounds in a method for treating a disease or condition, the combination comprising an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of Compound (B) or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments described herein relate to the use of a combination of compounds to treat a disease or condition, the combination comprising an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof, an effective amount of Compound (B) or a pharmaceutically acceptable salt thereof, and an effective amount of Compound (C) or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a combination of compounds in the manufacture of a medicament for treating a disease or condition, the combination comprising an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof, an effective amount of Compound (B) or a pharmaceutically acceptable salt thereof, and an effective amount of Compound (C) or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to the use of a combination of compounds in a method for treating a disease or condition, the combination comprising an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof. and an effective amount of Compound (B) or a pharmaceutically acceptable salt thereof, and an effective amount of Compound (C) or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the disease or condition may be a cancer as described herein. [Brief explanation of the drawings]

[0008] [Figure 1-1]Figures 1-1 to 1-4 provide examples of BRAF inhibitors. [Figure 1-2] Figures 1-1 to 1-4 provide examples of BRAF inhibitors. [Figure 1-3] Figures 1-1 to 1-4 provide examples of BRAF inhibitors. [Figure 1-4] Figures 1-1 to 1-4 provide examples of BRAF inhibitors. [Figure 2-1] Figures 2-1 and 2-2 provide examples of EGFR inhibitors. [Figure 2-2] Figures 2-1 and 2-2 provide examples of EGFR inhibitors. [Figure 3] Representative data from the proliferation assay described herein using the WEE1 inhibitor (ZN-c3), encorafenib, and their dual combination in the HT-29 cell line are shown. Percent inhibition is relative to baseline proliferation upon treatment with 0.1% DMSO. [Figure 4] Representative data from the proliferation assay described herein using the WEE1 inhibitor (ZN-c3), encorafenib, and their dual combination in the LS411N cell line are shown. Percent inhibition is relative to baseline proliferation upon treatment with 0.1% DMSO. [Figure 5] Representative data from the proliferation assay described herein using the WEE1 inhibitor (ZN-c3), cetuximab, encorafenib, and combinations thereof (double and triple) in the HT-29 cell line are shown. Percent inhibition is relative to baseline proliferation upon treatment with 0.1% DMSO. [Figure 6] Representative data from the proliferation assay described herein using the WEE1 inhibitor (ZN-c3), cetuximab, encorafenib, and combinations thereof (double and triple) in the LS411N cell line are shown. Percent inhibition is relative to baseline proliferation upon treatment with 0.1% DMSO. [Figure 7]Representative data are shown from tumor volume measurements obtained during an HT-29 cell line-derived xenograft (CDX) study using a WEE1 inhibitor (ZN-c3), encorafenib, cetuximab, and their combinations (double and triple) in the HT-29 CDX model. [Figure 8] Representative data from body weight measurements taken during the HT-29 CDX study in Figure 7 using a WEE1 inhibitor (ZN-c3), encorafenib, cetuximab, and their combinations (dual and triple) are shown. [Figure 9] Representative data from tumor volume measurements obtained during LS411N CDX studies using a WEE1 inhibitor (ZN-c3), encorafenib, cetuximab, and combinations thereof (dual and triple) in the LS411N CDX model are shown. [Figure 10] Representative data from body weight measurements taken during the LS411N CDX study in Figure 9 using a WEE1 inhibitor (ZN-c3), encorafenib, cetuximab, and combinations thereof (dual and triple) are shown. [Figure 11] Representative data from tumor volume measurements obtained during a CRC769 patient-derived xenograft (PDX) study using a WEE1 inhibitor (ZN-c3), cetuximab, encorafenib, and their combinations (dual and triple) in a CRC769 PDX model are shown. [Figure 12] Representative data from body weight measurements taken during the CRC769 PDX study in FIG. 11 using a WEE1 inhibitor (ZN-c3), cetuximab, and combinations thereof (dual and triple) are shown. [Figure 13] Representative data from tumor volume measurements taken during a CRC563 PDX study using a WEE1 inhibitor (ZN-c3), cetuximab, encorafenib, and combinations thereof (dual and triple) in the CRC563 PDX model are shown. [Figure 14]Representative data from body weight measurements taken during the CRC563 PDX study in FIG. 13 using a WEE1 inhibitor (ZN-c3), cetuximab, and combinations thereof (dual and triple) are shown. [Figure 15] Representative data from tumor volume measurements taken during a CTG-1009 PDX study using a WEE1 inhibitor (ZN-c3), cetuximab, encorafenib, and combinations thereof (dual and triple) in the CTG-1009 PDX model are shown. [Figure 16] Representative data from body weight measurements taken during the CTG-1009 PDX study in FIG. 15 using a WEE1 inhibitor (ZN-c3), cetuximab, and combinations thereof (dual and triple) are shown. DETAILED DESCRIPTION OF THE INVENTION

[0009] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated. In the event that there are multiple definitions for a term herein, those in this section prevail unless stated otherwise.

[0010] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium, potassium, or lithium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a salt of carbonate, a salt of bicarbonate, a salt of an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and amino acids such as arginine and lysine. Those skilled in the art will recognize that when a salt is formed by protonation of a nitrogen-based group (e.g., NH), the nitrogen-based group may be associated with a positive charge (e.g., NH becomes NH3). + ), and the positive charge can be replaced by a negatively charged counterion (Cl - Understand that balance can be achieved by

[0011] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure compounds, enantiomerically enriched compounds, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. Similarly, the compounds described It is understood that in any compound all tautomeric forms are intended to be included as well.

[0012] When the compounds disclosed herein have unfilled valences, it is understood that the valences are filled with hydrogen or its isotopes, such as hydrogen-1 (protium) and hydrogen-2 (deuterium). The compounds described herein can also include all isotopes of atoms occurring in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0013] It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium can result in certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. At any position in a compound where a hydrogen atom can be present, the hydrogen atom may be any hydrogen isotope, including, but not limited to, hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0014] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystalline packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and may be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0015] The term "antibody" (Ab) is used herein in the broadest sense and encompasses a variety of antibody structures, including those generated by the immune system or synthetic variants thereof, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity. An "antigen-binding fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to the antigen bound by the intact antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab'), diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and single-domain antibodies. Monoclonal antibodies are a type of synthetic antibody. In cancer therapy, monoclonal antibodies can directly kill cancer cells, they can block the development of tumor blood vessels, and / or they can assist the immune system in killing cancer cells.

[0016] When a range of values ​​is provided, it is understood that the upper and lower limits, and every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0017] Terms and phrases used in this application and variations thereof, particularly in the appended claims, should be construed as open ended rather than limiting unless expressly stated otherwise. For example, the word "including" can be used to mean "including without limitation," "including and the like; as used herein, the term "comprising" is synonymous with "including," "containing," or "featuring," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term "having" should be interpreted as "having at least," and the term "including" should be interpreted as "including, but not limited to," the term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of the items under discussion, and the use of terms such as "preferably," "preferred," "desired," or "desirable," as well as words of similar import, should not be understood as implying that a particular feature is essential, essential, or even critical to its structure or function, but instead is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Additionally, the term "comprising" is intended to be interpreted as synonymous with the phrases "having at least" or "including at least." When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0018] With respect to the use of virtually any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly stated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope thereof.

[0019] Compounds for Combination Therapy Current first-line treatment options for BRAF V600E-mutated metastatic colorectal cancer (mCRC) are limited to chemotherapy with or without bevacizumab. Following prior therapy, the BEACON study (ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35) represents the only phase 3 trial to demonstrate a response and survival benefit for patients with BRAF V600E-mutated mCRC who have received prior therapy. Despite approval of encorafenib plus cetuximab combination therapy in previously treated BRAF V600E-mutated mCRC, second- and third-line treatment remains highly unmet need. For example, triple combinations have been investigated in BRAF-mutated mCRC, and while they have shown some improvement in response rates and / or disease control compared with double combinations, they have been associated with higher toxicity. Specifically, the combinations of dabrafenib plus panitumumab, trametinib plus panitumumab, and dabrafenib plus trametinib plus panitumumab have been investigated in recent trials, which have shown improved objective response rates (ORR) for triple therapy compared with doublet combination regimens. RR), but was associated with an increase in certain adverse events, such as grade 3 / 4 diarrhea.

[0020] Combining dual combinations with orthogonal pathway inhibitors may enable additive or synergistic combined effects with clinically meaningful responses and / or durability of response without the toxicity observed with other triple combinations, such as those described herein. Inhibition of WEE1 with ZN-c3 (compound (A)) or a pharmaceutically acceptable salt thereof is an attractive option given that WEE1 targeting is particularly effective in cancer cells with oncogene-driven replication stress, such as occurs in RAS / RAF-mutated or MYC-amplified cells. Accordingly, some embodiments disclosed herein are useful for the treatment of diseases or conditions. Regarding the use of a combination of compounds, the combination may comprise an effective amount of compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of compound (B) or a pharmaceutically acceptable salt thereof, wherein compound (A) is

[0021] [ka] or a pharmaceutically acceptable salt thereof, and compound (B) is a BRAF inhibitor or a pharmaceutically acceptable salt thereof.

[0022] Some embodiments disclosed herein relate to a combination of compounds for use in treating a disease or condition, the combination may include an effective amount of compound (A), or a pharmaceutically acceptable salt thereof, and an effective amount of compound (B), or a pharmaceutically acceptable salt thereof, wherein compound (A) is

[0023] [ka] or a pharmaceutically acceptable salt thereof, and compound (B) is a BRAF inhibitor or a pharmaceutically acceptable salt thereof.

[0024] Compound (A), (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, along with its pharmaceutically acceptable salts, can be prepared according to the procedures provided in WO 2019 / 173082. As provided in WO 2019 / 173082, compound (A), including its pharmaceutically acceptable salts, is active against WEE1.

[0025] Examples of BRAF inhibitors include vemurafenib, dabrafenib, encorafenib (cncorafenib), agerafenib (agcrafenib), AZ-628, belvarafenib (bclvarafenib), BMS-908662, CHIR-265, DP-4978, and GDC-0 879, GW5074, lifirafenib, SB590885, naporafenib, PLX-4720, PLX-8394, ABM-1310, ASN-003, JZP815, and and KIN-2787, or a pharmaceutically acceptable salt of any of the foregoing. Figure 1 provides further information regarding BRAF inhibitors.

[0026] The combinations described herein may further include compound (C) (including pharmaceutically acceptable salts thereof), where compound (C) may be an EGFR inhibitor or a pharmaceutically acceptable salt thereof. Accordingly, some embodiments disclosed herein relate to the use of a combination of compounds for treating a disease or condition, where the combination may include an effective amount of compound (A) or a pharmaceutically acceptable salt thereof, an effective amount of compound (B) or a pharmaceutically acceptable salt thereof, and an effective amount of compound (C) or a pharmaceutically acceptable salt thereof, where compound (A) is

[0027] [ka] or a pharmaceutically acceptable salt thereof, compound (B) is a BRAF inhibitor or a pharmaceutically acceptable salt thereof, and compound (C) is an EGFR inhibitor or a pharmaceutically acceptable salt thereof. Further, some embodiments disclosed herein relate to a combination of compounds for use in treating a disease or condition, wherein the combination can include an effective amount of compound (A) or a pharmaceutically acceptable salt thereof, an effective amount of compound (B) or a pharmaceutically acceptable salt thereof, and an effective amount of compound (C) or a pharmaceutically acceptable salt thereof, wherein compound (A) is

[0028] [ka] or a pharmaceutically acceptable salt thereof, compound (B) is a BRAF inhibitor or a pharmaceutically acceptable salt thereof, and compound (C) is an EGFR inhibitor or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the EGFR inhibitor can be a tyrosine kinase inhibitor (TKI). In other embodiments, the EGFR inhibitor can be a monoclonal antibody. The antibody may be an antibody, such as, but not limited to, a human monoclonal antibody, or an antigen-binding fragment thereof. Examples of EGFR inhibitors include afatinib, dacomitinib, erlotinib, gefitinib, osimertinib, cetuximab, necitumumab, nimotuzumab, panitumumab, and N-(5-((4-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-indoline. and (2-(dimethylamino)ethyl)-4-methoxyphenyl)acrylamide (together with pharmaceutically acceptable salts thereof). Figure 2 provides further information regarding EGFR inhibitors.

[0030] Embodiments of combinations of Compound (A) and Compound (B) (including any pharmaceutically acceptable salts thereof), and combinations of Compound (A), Compound (B), and Compound (C) (including any pharmaceutically acceptable salts thereof) are provided in Table 1. In Table 1, "A" indicates Compound (A) (including pharmaceutically acceptable salts thereof), numbers 1A-20A correspond to Compound (B) (including pharmaceutically acceptable salts thereof) provided in Figure 1, and numbers 1B-10B correspond to Compound (C) (including pharmaceutically acceptable salts thereof) provided in Figure 2, including pharmaceutically acceptable salts thereof.

[0031] [Table 1]

[0032] The order of administration of the compounds in the combinations described herein may vary. In embodiments, compound (A) (including a pharmaceutically acceptable salt thereof) can be administered before compound (B) or a pharmaceutically acceptable salt thereof. In other embodiments, compound (A) (including a pharmaceutically acceptable salt thereof) can be administered simultaneously with compound (B) or a pharmaceutically acceptable salt thereof. In still other embodiments, compound (A) (including a pharmaceutically acceptable salt thereof) can be administered after the administration of compound (B) or a pharmaceutically acceptable salt thereof. In some embodiments, compound (C) (including a pharmaceutically acceptable salt thereof) can be administered before both compound (A) and compound (B) (including a pharmaceutically acceptable salt thereof, of any of the foregoing). In other embodiments, compound (C) (including a pharmaceutically acceptable salt thereof) can be administered after both compound (A) and compound (B) (including a pharmaceutically acceptable salt thereof, of any of the foregoing). In still other embodiments, compound (C) (including pharmaceutically acceptable salts thereof) may be administered before one of compounds (A) (including pharmaceutically acceptable salts thereof) and after compound (B) (including pharmaceutically acceptable salts thereof). In still other embodiments, compound (C) (including pharmaceutically acceptable salts thereof) may be administered before one of compounds (B) (including pharmaceutically acceptable salts thereof) and after compound (A) (including pharmaceutically acceptable salts thereof).

[0033] There may be several advantages to using the combinations of compounds described herein, for example, combining compounds that simultaneously attack multiple pathways may be more effective in treating cancers such as those described herein compared to when the combined compounds are used as monotherapies.

[0034] In some embodiments, the combinations described herein (e.g., Compound (A) (including pharmaceutically acceptable salts thereof) and Compound (B) or a pharmaceutically acceptable salt thereof, and Compound (A) (including pharmaceutically acceptable salts thereof), Compound (B) or a pharmaceutically acceptable salt thereof, and Compound (C) or a pharmaceutically acceptable salt thereof) can reduce the number and / or severity of side effects that can be caused by a compound described herein, such as Compound (B), or a pharmaceutically acceptable salt thereof.

[0035] The use of the combinations of compounds described herein can result in additive, synergistic, or strongly synergistic effects. The combinations of compounds described herein can result in effects that are not antagonistic.

[0036] In some embodiments, the combinations described herein (e.g., Compound (A) (including a pharmaceutically acceptable salt thereof) and Compound (B) or a pharmaceutically acceptable salt thereof, and Compound (A) (including a pharmaceutically acceptable salt thereof), Compound (B) or a pharmaceutically acceptable salt thereof, and Compound (C) or a pharmaceutically acceptable salt thereof) may provide an additive effect. In some embodiments, the combinations described herein (e.g., Compound (A) (including a pharmaceutically acceptable salt thereof) and Compound (B) or a pharmaceutically acceptable salt thereof, and Compound (A) (including a pharmaceutically acceptable salt thereof), Compound (B) or a pharmaceutically acceptable salt thereof, and Compound (C) or a pharmaceutically acceptable salt thereof) may provide a synergistic effect. In some embodiments, the combinations described herein (e.g., Compound (A) (including a pharmaceutically acceptable salt thereof) and Compound (B) or a pharmaceutically acceptable salt thereof, and Compound (A) (including a pharmaceutically acceptable salt thereof), Compound (B) or a pharmaceutically acceptable salt thereof, and Compound (C) or a pharmaceutically acceptable salt thereof) may produce strong synergistic effects. In some embodiments, the combinations described herein (e.g., Compound (A) (including a pharmaceutically acceptable salt thereof) and Compound (B) or a pharmaceutically acceptable salt thereof, and Compound (A) (including a pharmaceutically acceptable salt thereof), Compound (B) or a pharmaceutically acceptable salt thereof, and Compound (C) or a pharmaceutically acceptable salt thereof) are not antagonistic.

[0037] As used herein, the term "antagonistic" means that the activity of a combination of compounds is less than the sum of the activities of each compound in the combination when the activity of each compound is determined individually (i.e., as a single compound). As used herein, the term "synergistic" means that the activity of a combination of compounds is greater than the sum of the individual activities of each compound in the combination when the activity of each compound is determined individually. As used herein, the term "additive" means that the activity of a combination of compounds is approximately equal to the sum of the individual activities of each compound in the combination when the activity of each compound is determined individually.

[0038] A potential advantage of utilizing the combinations described herein may be that a reduced amount of the compound is required to be effective in treating a disease condition disclosed herein compared to when each compound is administered as a monotherapy. For example, the amount of compound (B) or a pharmaceutically acceptable salt thereof used in the combinations described herein may be less than the amount of compound (B) or a pharmaceutically acceptable salt thereof required to achieve the same reduction in a disease marker (e.g., tumor size) when administered as a monotherapy. Another potential advantage of utilizing the combinations described herein is that the use of two or more compounds with different mechanisms of action may pose a higher barrier to the development of resistance compared to when the compounds are administered as a monotherapy. Additional advantages of utilizing the combinations described herein include little or no cross-resistance between each compound in the combinations described herein, different routes of elimination for each compound in the combinations described herein, and and / or there is little overlapping toxicity between the individual compounds in the combinations described herein.

[0039] Pharmaceutical Composition Compound (A) (including pharmaceutically acceptable salts thereof) may be provided in a pharmaceutical composition. Similarly, Compound (B) and Compound (C) (including pharmaceutically acceptable salts of any of the foregoing) may be provided in a pharmaceutical composition.

[0040] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents, carriers, and / or excipients. Pharmaceutical compositions facilitate administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions are generally tailored to the specific intended route of administration.

[0041] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0042] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no apparent pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. A diluent may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, without limitation, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0043] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelators. is an excipient. In one embodiment, the pharmaceutical composition comprises an antioxidant and / or a metal chelator. A "diluent" is a type of excipient.

[0044] In some embodiments, compound (B) (together with its pharmaceutically acceptable salt) may be provided in a pharmaceutical composition comprising compound (A) (including its pharmaceutically acceptable salt). In other embodiments, compound (B) (together with its pharmaceutically acceptable salt) may be administered in a pharmaceutical composition separate from a pharmaceutical composition comprising compound (A) (including its pharmaceutically acceptable salt). When compound (C) (including its pharmaceutically acceptable salt) is included, compound (C) (including its pharmaceutically acceptable salt) may be provided in a pharmaceutical composition comprising compound (A) (together with its pharmaceutically acceptable salt) and / or compound (B) (together with its pharmaceutically acceptable salt). In another example, compound (C) (including its pharmaceutically acceptable salt) may be provided in a pharmaceutical composition separate from compound (A) (together with its pharmaceutically acceptable salt) and compound (B) (together with its pharmaceutically acceptable salt).

[0045] The pharmaceutical compositions described herein can be administered to human patients either by themselves or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or with carriers, diluents, excipients, or combinations thereof. The appropriate formulation depends on the selected route of administration. Techniques for formulating and administering the compounds described herein are known to those skilled in the art.

[0046] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping, or tabletting processes. In addition, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0047] Multiple techniques for administering compounds, salts, and / or compositions exist in the art, including, but not limited to, oral, rectal, intrapulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection. In some embodiments, compound (A) (including its pharmaceutically acceptable salts) can be administered orally. In some embodiments, compound (A) (including its pharmaceutically acceptable salts) can be provided to a subject by the same route of administration as compound (B) (together with its pharmaceutically acceptable salts) and / or compound (C) (together with its pharmaceutically acceptable salts). In other embodiments, compound (A) (including its pharmaceutically acceptable salts) can be provided to a subject by a different route of administration than compound (B) (together with its pharmaceutically acceptable salts) and / or compound (C) (together with its pharmaceutically acceptable salts).

[0048] The compounds, salts, and / or compositions may also be administered in a local rather than systemic manner, for example, by injecting or implanting the compound directly into the affected area, often as a depot or sustained-release formulation. Additionally, the compounds can be administered in targeted drug delivery systems, for example, in liposomes coated with tissue-specific antibodies. The liposomes will be targeted to and selectively taken up by the organ. For example, intranasal or intrapulmonary delivery may be desirable to target respiratory diseases or conditions.

[0049] The composition may be provided in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient, if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also have a notice associated with the container in a format prescribed by government agencies regulating the manufacture, use, or sale of pharmaceuticals. The notice may be accompanied by a label that reflects approval by an agency of the drug form for human or animal administration. Such notice may be, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions that may include the compounds and / or salts described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0050] Uses and Treatment Methods As provided herein, in some embodiments, a disease or condition can be treated using a compound combination comprising an effective amount of Compound (A) (including a pharmaceutically acceptable salt thereof) and an effective amount of Compound (B) or a pharmaceutically acceptable salt thereof. Accordingly, some embodiments disclosed herein relate to a method of treating a disease or condition, comprising administering to a subject a compound combination, wherein the combination can comprise an effective amount of Compound (A) or a pharmaceutically acceptable salt thereof and an effective amount of Compound (B) or a pharmaceutically acceptable salt thereof, where Compound (A) and Compound (B) are as defined herein. In some embodiments, a disease or condition can be treated using a compound combination comprising an effective amount of Compound (A) (including a pharmaceutically acceptable salt thereof), an effective amount of Compound (B) (including a pharmaceutically acceptable salt thereof), and an effective amount of Compound (C) (including a pharmaceutically acceptable salt thereof). Accordingly, some embodiments disclosed herein relate to a method of treating a disease or condition, comprising administering to a subject a combination of compounds, wherein the combination can include an effective amount of Compound (A), or a pharmaceutically acceptable salt thereof; an effective amount of Compound (B), or a pharmaceutically acceptable salt thereof; and an effective amount of Compound (C), or a pharmaceutically acceptable salt thereof, wherein Compound (A), Compound (B), and Compound (C) are as defined herein.

[0051] In some embodiments, the disease or condition may be colorectal cancer. In one embodiment, the disease or condition may be advanced colorectal cancer. In one embodiment, the disease or condition may be metastatic colorectal cancer. In one embodiment, the disease or condition may be advanced and / or metastatic colorectal cancer that has progressed after one or two prior treatment regimens, such as those described herein. BRAF mutations (i.e., mutations in the BRAF gene) may occur in colorectal cancer. For example, the BRAF mutations may be activating mutations. In one embodiment, at least one of the BRAF mutations may be a BRAF mutation occurring at the V600 codon. In some embodiments, the BRAF mutation may be V600E, which has a valine to glutamic acid substitution at the codon. In one embodiment, the disease or condition may be BRAF V600E mutant metastatic colorectal cancer.

[0052] In some cases, following cancer treatment, a subject may experience a return or recurrence of cancer. As used herein, the terms "relapse" and "recurrence" are used in their ordinary sense as understood by those skilled in the art. Thus, the cancer may be a recurrent cancer.

[0053] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include cold- and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and particularly mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and particularly humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant. In other embodiments, the subject may be an adult. In one embodiment, the subject may be a human with advanced colorectal cancer. In one embodiment, the subject may be a human with metastatic colorectal cancer. In one embodiment, the subject may be a human with one or more diseases. The subject may be a human with advanced and / or metastatic colorectal cancer that has progressed after two prior treatment regimens.

[0054] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean a complete cure or elimination of a disease or condition. Any alleviation of any undesirable signs or symptoms of a disease or condition, to any degree, can be considered treatment and / or therapy. Furthermore, treatment can include actions that may worsen a subject's overall feeling of health or appearance.

[0055] The term "effective amount" is used to refer to the amount of an active compound or agent that elicits the indicated biological or pharmaceutical response. For example, an effective amount of a compound, salt, or composition may be the amount necessary to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or to prolong the survival of the subject being treated. This response may occur in a tissue, system, animal, or human, and includes alleviation of signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosages can be adjusted to achieve the desired effect and will depend on factors such as body weight, diet, concomitant medications, and other factors that one skilled in the medical field would recognize.

[0056] For example, an effective amount of a compound or radiation is an amount that results in (a) reduction, alleviation, or elimination of one or more symptoms caused by cancer, (b) reduction in tumor size, (c) elimination of the tumor, and / or (d) long-term disease stabilization (growth arrest) of the tumor.

[0057] The amount of compound, salt, and / or composition required for use in treatment will vary depending not only on the particular compound or salt selected, but also on the route of administration, the nature and / or symptoms of the disease or condition being treated, and the age and condition of the patient, and is ultimately at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated as the free base. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges set forth herein to effectively and aggressively treat, particularly, progressive diseases or conditions.

[0058] As will be readily apparent to those skilled in the art, useful in vivo dosages and specific methods of administration will vary depending on the age, weight, severity of the affliction, the mammalian species being treated, the specific compound used, and the specific application for which these compounds are being used. Determination of effective dosage levels, i.e., the dosage levels necessary to achieve the desired results, can be accomplished by those skilled in the art using routine methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages of compounds (A), (B), and / or (C), or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparisons can be made with established drugs such as cisplatin and / or gemcitabine.

[0059] Dosage amount and interval are adjusted individually to provide plasma levels of the active moiety sufficient to maintain a modulating effect or minimal effective concentration (MEC). The MEC may be determined by the MEC value. The MEC varies for each compound but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compositions maintain plasma levels above the MEC for 10-90% of the time, preferably 30-90% of the time, and most preferably 50-90% of the time. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0060] It should be noted that the attending physician would know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The magnitude of the dose administered in the management of the disease of interest will vary with the severity of the disease or condition to be treated and the route of administration. The severity of the disease or condition can, for example, be assessed, in part, by standard prognostic evaluation methods. Furthermore, the dose, and perhaps dose frequency, will also vary with the age, weight, and response of the individual patient. Programs equivalent to those discussed above can be used in veterinary medicine.

[0061] The compounds, salts, and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing a particular chemical moiety can be established by determining in vitro toxicity in cell lines, such as mammalian cell lines, preferably human cell lines. The results of such studies often predict toxicity in animals, such as mammals, or particularly humans. Alternatively, the toxicity of a particular compound in an animal model, such as a mouse, rat, rabbit, dog, or monkey, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model for determining efficacy, those skilled in the art can rely on the state of the art to guide them in selecting the appropriate model, dose, route of administration, and / or regimen. [Example]

[0062] Further embodiments, which are not intended to limit the scope of the claims in any way, are disclosed in more detail in the examples below.

[0063] Example 1: In vitro tumor cell proliferation assay 1.5 x 10 cells in 100 µL of culture medium 3A cell suspension containing 100 total cells was placed into each well of an ultra-low attachment 96-well plate. The plate was incubated at 37°C under 95% oxygen and 5% CO2 for 72 hours to allow spheroid formation. After 72 hours, 10 μL of culture medium with or without cetuximab was added to each well to a final volume of 110 μL. ZN-c3 and / or encorafenib compounds in DMSO were added to the plate at the indicated concentrations using an automated drug dispenser. Total DMSO content was normalized to 0.1% of the total volume under all assay conditions. The plate was sealed with breathable film to reduce evaporation and incubated at 37°C under 95% oxygen and 5% CO2 for 192 hours. After 192 hours, the plate was removed from the incubator and allowed to reach room temperature. 100 μL of room-temperature 3D CTG reagent (Promega, catalog number G9683) was added to each well. Plates were agitated at 520 revolutions per minute (rpm) for 5 minutes, allowed to stabilize for 30 minutes protected from light, and then luminescence was measured on an M5e plate reader (SpectraMax). Percent survival was calculated as a percentage of cell survival relative to the DMSO-only vehicle control.

[0064] Tables 2 and 3 and accompanying Figures 3-6 detail the compounds and their concentrations used in the cell proliferation assays, as well as the percent inhibition of tumor cells. The percent inhibition values ​​indicate that in both HT-29 and LS411N cells, any dual drug treatment that included ZN-c3 (i.e., ZN-c3 + encorafenib or ZN-c3 + cetuximab) was able to inhibit tumor cell proliferation better than either of their respective single drug treatments, e.g., ZN-c3 + encorafenib inhibited tumor cell proliferation better than encorafenib alone. These results indicate that ZN-c3 plus cetuximab inhibited tumor cell growth better than cetuximab alone. In HT-29, dual-drug treatment with ZN-c3 plus encorafenib and triple-drug treatment with ZN-c3 plus encorafenib and cetuximab achieved similar tumor cell inhibition as dual-drug treatment with encorafenib and cetuximab (see Figure 5). In LS411N, dual-drug treatment with ZN-c3 plus encorafenib achieved similar tumor cell inhibition as dual-drug treatment with encorafenib and cetuximab, but triple-drug treatment with ZN-c3 plus encorafenib and cetuximab achieved greater tumor cell inhibition than dual-drug treatment with encorafenib and cetuximab (see Figure 6).

[0065] [Table 2]

[0066] [Table 3]

[0067] In vivo preclinical studies on cell line-derived xenograft (CDX) and patient-derived xenograft models CDX model: Inject 95% viable tumor cells (5 × 10) in 100 µL of serum-free RPMI 1640 into the right flank of 6-8 week-old BALB / c nude mice. 6 ) (COLO205), 95% viable tumor cells (2 × 10 ) in 100 μL of serum-free McCoy's 5a modified medium. 6 ) (HT-29), or 95% viable tumor cells (2 × 10 ) in 100 μL of serum-free RPMI 1640 and Matrigel mixture (1:1 ratio). 6 ) (LS411N) single cell suspension was inoculated subcutaneously.

[0068] PDX model: Tumor fragments (CRC769, CRC563, CTG-1009) were retrieved from cryopreservation and implanted into female athymic nude Foxnlnu mice. The fragments were allowed to grow and then excised when they reached the appropriate volume. Tumor slurry was made from 50% freshly harvested tumors minced into small tumor fragments in PBS and 50% Matrigel. The tumor slurry was injected subcutaneously into the flanks of 6-8 week-old female athymic nude Foxnlnu mice.

[0069] The average tumor volume was approximately 220 mm 3 (Individual tumors are 200-240 mm 3 When the serotonin concentration reached 1000 mg / kg, grouping and treatment were initiated. Vehicle animals were treated with 10 mL / kg of HP-β-CD Encorafenib was prepared weekly in 0.5% carboxymethylcellulose:0.5% Tween 80:99% deionized water and administered orally (po) once daily (QD) at the indicated dose (see Tables 4 and 5 for dosage). ZN-c3 was prepared daily in 20% HP-β-CD and administered po at the indicated dose (see Tables 4 and 5 for dosage). Cetuximab was diluted in PBS buffer pH 7.0 at the time of administration and administered intraperitoneally (ip) biweekly (BIW) at the indicated dose (see Tables 4 and 5 for dosage). All Animal body weights and tumor volumes were measured twice weekly throughout the study, which was 21 or 22 days or 3 weeks in duration (for CDX models HT-29 and LS411N) or 28 days or 4 weeks in duration (for PDX models CRC769, CRC563, and CTG-1009). Tumor size measurements were performed using calipers and tumor volume (mm 3 ) was estimated throughout the study using the formula: TV = a × b / 2, where "a" and "b" are the long and short diameters of the tumor, respectively. 3 Animals were euthanized when the body temperature exceeded 100°C, or when their condition continued to deteriorate or they became near comatose.

[0070] Tumor volume measurements (six measurements total over the 21 or 22 day study) for the CDX model are shown in Figure 7 (BRAF mt HT-29 CRC) and Figure 9 (also BRAF mt Based on tumor volume measurements, tumor growth inhibition (TGI) values ​​were calculated and are provided in Table 4. In this model, triple therapy with ZN-c3 plus encorafenib and cetuximab induced tumor regression that was superior to the current standard-of-care double therapy of encorafenib and cetuximab for metastatic colorectal cancer (TGI values ​​were 100.9 (ZN-c3 + encorafenib + cetuximab) compared with 88.2 (encorafenib + cetuximab) in HT-29, and significantly 107.6 (ZN-c3 + encorafenib + cetuximab) compared with 63.4 (encorafenib + cetuximab) in LS411N. Furthermore, in LS411N, the double therapy with ZN-c3 plus encorafenib induced superior tumor inhibition compared with the standard-of-care therapy (TGI value was 101.7). As shown in Figure 8 for HT-29 and Figure 10 for LS411N, as well as Table 4 for both models, body weight measurements for the CDX models (six measurements taken throughout the 21-day or 22-day study) showed minimal weight change throughout the study of the exemplary combination therapies, i.e., ZN-c3 + encorafenib + cetuximab triple therapy and encorafenib + cetuximab dual therapy. Typically, a weight loss of more than 15% indicates that the treatment regimen is not well tolerated.

[0071] Tumor volume measurements of PDX models (8 measurements total over the 28-day study) were performed as shown in Figure 11 (BRAF mt CRC769), Figure 13 (similarly BRAF mt CRC563), and Figure 15 (also BRAF mtBased on tumor volume measurements, tumor growth inhibition (TGI) values ​​were calculated and are provided in Table 5. In all three PDX models, the triple therapy of ZN-c3 + encorafenib + cetuximab induced tumor regression, which was superior to the current standard of care double therapy of encorafenib + cetuximab for metastatic colorectal cancer. The TGI values ​​were significantly higher than those of CRC (CTG-1009). 86.8 (ZN-c3 + encorafenib + cetuximab) compared with 65.0 (encorafenib + cetuximab) in 769, 79.6 (ZN-c3 + encorafenib + cetuximab) compared with 48.7 (encorafenib + cetuximab) in CRC563, and 97.9 (ZN-c3 + encorafenib + cetuximab) compared with 86.9 (encorafenib + cetuximab) in CTG-1009. Furthermore, in all three PDX models, ZN-c3 + encorafenib dual therapy resulted in higher TGI values ​​than standard of care encorafenib + cetuximab dual therapy, with TGI values ​​of 82.3 (CRC769), 57.2 (CRC563), and 103.44 (CTG-1009) compared to 65.0 (CRC769), 48.7 (CRC563), and 86.9 (CTG-1009). As shown in Figure 12 (CRC769), Figure 14 (CRC563), and Figure 16 (CTG-1009) and Table 5, weight measurements of PDX models (8 measurements total throughout the 28-day study) showed minimal weight change throughout the study of the exemplary combination therapies, i.e., ZN-c3 + encorafenib + cetuximab triple therapy and encorafenib + cetuximab dual therapy.

[0072] Based on statistical analysis between standard of care doublet therapy (encorafenib + cetuximab) and triplet therapy (ZN-c3 + encorafenib + cetuximab), in vivo studies were summarized. All CDX and PDX models had statistically significant improvements with triplet therapy over doublet therapy without tolerability issues. Analysis between standard of care doublet therapy (encorafenib + cetuximab) and ZN-c3 encorafenib doublet therapy showed that all models, except HT-29, had statistically significant improvements with the latter over the former without tolerability issues.

[0073] [Table 4]

[0074] [Table 5]

[0075] Moreover, the foregoing has been described in some detail by way of illustration and example, for purposes of clarity and understanding. However, it will be understood by those skilled in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. It is therefore to be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all changes and alternative forms consistent with the true scope and spirit of the present disclosure.

Claims

1. 1. Use of a combination of compounds for treating a disease or condition, said combination comprising an effective amount of compound (A) or a pharmaceutically acceptable salt thereof, and an effective amount of compound (B) or a pharmaceutically acceptable salt thereof, wherein compound (A) is 【Chemical 1】 or a pharmaceutically acceptable salt thereof, and compound (B) is a BRAF inhibitor or a pharmaceutically acceptable salt thereof.

2. 2. The use of claim 1, wherein the BRAF inhibitor is selected from the group consisting of vemurafenib, dabrafenib, encorafenib, agerafenib, AZ-628, belbalafenib, BMS-908662, CHIR-265, DP-4978, GDC-0879, GW5074, lifirafenib, SB590885, naporafenib, PLX-4720, PLX-8394, ABM-1310, ASN-003, JZP815 KIN-2787, and a pharmaceutically acceptable salt of any of the foregoing.

3. The use according to claim 2, wherein the BRAF inhibitor is vemurafenib or a pharmaceutically acceptable salt thereof.

4. The use according to claim 2, wherein the BRAF inhibitor is dabrafenib or a pharmaceutically acceptable salt thereof.

5. The use according to claim 2, wherein the BRAF inhibitor is encorafenib or a pharmaceutically acceptable salt thereof.

6. The use according to any one of claims 1 to 5, wherein the combination further comprises an effective amount of compound (C) or a pharmaceutically acceptable salt thereof, wherein compound (C) is an EGFR inhibitor or a pharmaceutically acceptable salt thereof.

7. The use according to claim 6, wherein the EGFR inhibitor is a tyrosine kinase inhibitor.

8. The use according to claim 6, wherein the EGFR inhibitor is a monoclonal antibody or an antigen-binding fragment thereof.

9. 6. The method of claim 5, wherein the EGFR inhibitor is selected from the group consisting of afatinib, dacomitinib, erlotinib, gefitinib, osimertinib, cetuximab, necitumumab, nimotuzumab, panitumumab, and N-(5-((4-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, and pharmaceutically acceptable salts or antigen-binding fragments of any of the foregoing. Use as described in.

10. The use according to any one of claims 1 to 9, wherein the disease or condition is colorectal cancer.

11. The use according to claim 10, wherein the colorectal cancer is advanced colorectal cancer.

12. The use according to claim 10, wherein the colorectal cancer is metastatic colorectal cancer.

13. 13. The use according to claim 11 or 12, wherein the advanced colorectal cancer and / or the metastatic colorectal cancer has progressed after one or two prior treatment regimens.

14. The use according to any one of claims 10 to 13, wherein the colorectal cancer has a BRAF mutation.

15. The use according to any one of claims 10 to 14, wherein the BRAF mutation is an activating mutation.

16. 15. The use according to claim 14, wherein the BRAF mutation occurs at the V600 codon.

17. 17. The use of claim 16, wherein the BRAF mutation is V600E.

18. The use according to any one of claims 1 to 17, wherein the disease or condition is BRAF V600E mutated metastatic colorectal cancer.

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