Combination

Abstract

The application discloses combination therapies 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

[0001] Any priority application incorporated by reference

[0002] Any and all applications identified in the application data sheet filed together with this application as having foreign or domestic priority claims thereto are hereby expressly incorporated by reference under 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Application No. 63 / 375,809, filed September 15, 2022. Technical Field

[0003] This application relates to the fields of chemistry, biochemistry, and medicine. More specifically, combination therapies are disclosed herein, as well as methods of treating diseases and / or disorders with the combination therapies described herein. Background Art

[0004] Cancer is a family of diseases involving abnormal cell growth and the potential to invade or spread to other parts of the body. Current 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 the cancer is diagnosed. In 2021, approximately 19 million people will be diagnosed with cancer, and it is estimated that 600,000 people in the United States will die from cancer. Accordingly, there remains a need for effective cancer treatments. Summary of the Invention

[0005] Some embodiments described herein relate to combinations of compounds that 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 of any of the foregoing. Other embodiments described herein relate to combinations of compounds that may comprise 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.

[0006] Some embodiments described herein relate to the use of a combination of compounds for treating a disease or disorder, wherein the combination comprises 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 disorder, wherein the combination comprises 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. Yet another other embodiment described herein relates to the use of a combination of compounds in a method for treating a disease or disorder, wherein the combination comprises 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.

[0007] Some embodiments described herein relate to the use of a combination of compounds for treating a disease or disorder, wherein the combination comprises 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 disorder, wherein the combination comprises 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. Yet another other embodiment described herein relates to the use of a combination of compounds in a method for treating a disease or disorder, wherein the combination comprises 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.

[0008] In some embodiments, the disease or disorder can be the cancer described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 Examples of BRAF inhibitors are provided.

[0010] Figure 2 Examples of EGFR inhibitors are provided.

[0011] Figure 3 Representative data obtained from the proliferation assays described herein using the WEE1 inhibitor (ZN-c3), encorafenib, and their dual combination in the HT-29 cell line are shown. The percentage of inhibition is related to the baseline proliferation after treatment with 0.1% DMSO.

[0012] Figure 4 Representative data obtained from the proliferation assays described herein using the WEE1 inhibitor (ZN-c3), encorafenib, and their dual combination in the LS411N cell line are shown. The percentage of inhibition is related to the baseline proliferation after treatment with 0.1% DMSO.

[0013] Figure 5 Representative data obtained from the proliferation assays described herein using the WEE1 inhibitor (ZN-c3), cetuximab, encorafenib, and their combinations (dual and triple) in the HT-29 cell line are shown. The percentage of inhibition is related to the baseline proliferation after treatment with 0.1% DMSO.

[0014] Figure 6Representative data obtained from the proliferation assays described herein using the WEE1 inhibitor (ZN-c3), cetuximab, encorafenib, and their combinations (dual and triple) in the LS411N cell line are shown. Percent inhibition is relative to baseline proliferation after treatment with 0.1% DMSO.

[0015] Figure 7 Representative data obtained from tumor volume measurements conducted during studies of xenografts (CDX) derived from the HT-29 cell line using the WEE1 inhibitor (ZN-c3), encorafenib, cetuximab, and their combinations (dual and triple) in the HT-29 CDX model are shown.

[0016] Figure 8 Representative data obtained from using the WEE1 inhibitor (ZN-c3), encorafenib, cetuximab, and their combinations (dual and triple) from Figure 7 body weight measurements conducted during the HT-29 CDX study are shown.

[0017] Figure 9 Representative data obtained from tumor volume measurements conducted during the LS411N CDX study using the WEE1 inhibitor (ZN-c3), encorafenib, cetuximab, and their combinations (dual and triple) in the LS411N CDX model are shown.

[0018] Figure 10 Representative data obtained from using the WEE1 inhibitor (ZN-c3), encorafenib, cetuximab, and their combinations (dual and triple) from Figure 9 body weight measurements conducted during the LS411N CDX study are shown.

[0019] Figure 11 Representative data obtained from tumor volume measurements conducted during studies of xenografts (PDX) derived from CRC769 patients using the WEE1 inhibitor (ZN-c3), cetuximab, encorafenib, and their combinations (dual and triple) in the CRC769 PDX model are shown.

[0020] Figure 12 Representative data obtained from using the WEE1 inhibitor (ZN-c3), cetuximab, and their combinations (dual and triple) from Figure 11 body weight measurements conducted during the CRC769 PDX study are shown.

[0021] Figure 13Shows representative data obtained from tumor volume measurements taken during the CRC563 PDX study using the WEE1 inhibitor (ZN-c3), cetuximab, encorafenib, and their combinations (dual and triple).

[0022] Figure 14 Shows representative data obtained from body weight measurements taken during the Figure 13 CRC563 PDX study using the WEE1 inhibitor (ZN-c3), cetuximab, and their combinations (dual and triple).

[0023] Figure 15 Shows representative data obtained from tumor volume measurements taken during the CTG-1009 PDX study using the WEE1 inhibitor (ZN-c3), cetuximab, encorafenib, and their combinations (dual and triple).

[0024] Figure 16 Shows representative data obtained from body weight measurements taken during the Figure 15 CTG-1009 PDX study using the WEE1 inhibitor (ZN-c3), cetuximab, and their combinations (dual and triple). Detailed Description

[0025] Definition

[0026] 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 published documents cited herein are incorporated by reference in their entirety. In the event of multiple definitions of terms herein, the definitions in this section shall control, unless otherwise specified.

[0027] The term "pharmaceutically acceptable salt" refers to salts of a compound that do not cause significant irritation to the organism to which they are administered and do not eliminate 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 the 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 the compound with an organic acid such as an aliphatic or aromatic carboxylic acid or sulfonic acid (e.g., 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-oxoglutaric acid, or naphthalenesulfonic acid). Pharmaceutical salts can also be obtained by reacting the compound with a base to form a salt, such as an ammonium salt, an alkali metal salt (such as a sodium, potassium, or lithium salt), an alkaline earth metal salt (such as a calcium or magnesium salt), a carbonate, a bicarbonate, a salt of an organic base (such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, a C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine), and a salt formed by reaction with an amino acid (such as arginine and lysine). Those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group can associate with a positive charge (e.g., NH2 can become NH3 + ) and this positive charge can be balanced by a negatively charged counterion (such as, Cl - ).

[0028] It should be understood that in any compound described herein having one or more chiral centers, if the absolute stereochemistry is not explicitly indicated, each center can independently be of the R configuration or the S configuration or a mixture thereof. Thus, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic mixtures, or diastereomerically pure, diastereomerically enriched stereoisomeric mixtures. In addition, it should be understood that in any compound described herein having one or more double bonds that can give rise to geometric isomers that can be defined as E or Z, each double bond can independently be E or Z or a mixture thereof. Similarly, it should be understood that in any compound described, all tautomeric forms are also intended to be included.

[0029] It should be understood that in the case where the compounds disclosed herein have unfilled valence valencies, they are filled with hydrogen or its isotopes (e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium)). The compounds described herein can also include all isotopes of the atoms present in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0030] It should be understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium can result in certain therapeutic advantages due to increased metabolic stability, such as, for example, an increased in vivo half-life or a reduced dosage requirement. Each chemical element as represented in the compound structure may contain any isotope of said element. For example, in the compound structure, the presence of a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position where a hydrogen atom may potentially be present in the compound, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Accordingly, unless otherwise explicitly stated in the context, the compounds referred to herein encompass all possible isotopic forms.

[0031] It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of the same elemental composition of the compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated form with a pharmaceutically acceptable solvent such as water, ethanol, etc. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain a stoichiometric or non-stoichiometric amount of the solvent and may form during the crystallization process with a pharmaceutically acceptable solvent such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is an alcohol. Additionally, the compounds provided herein may exist in unsolvated and solvated forms. Generally, the solvated form is considered equivalent to the unsolvated form for the purposes of the compounds and methods provided herein.

[0032] The term "antibody" (Ab) is used herein in the broadest sense and encompasses various antibody structures, including those made by the immune system or synthetic variants thereof, and includes but is 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 a full antibody that contains a portion of the full antibody that binds the antigen to which the full antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab’-SH, F(ab’)2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and single-domain antibodies. Monoclonal antibodies are a class of synthetic antibodies. In cancer treatment, monoclonal antibodies can directly kill cancer cells, they can block the development of tumor blood vessels, and / or they can help the immune system kill cancer cells.

[0033] For the provided range values, it should be understood that the upper and lower limits, and each intermediate value between the upper and lower limits of the range, are encompassed within the embodiments.

[0034] For the terms and phrases used in this application, especially in the appended claims and their variations, unless otherwise expressly stated, they should be understood as open-ended and not restrictive. For the aforementioned examples, the term "including" should be understood as "including but not limited to", "including but not limited to", etc.; as used herein, the term "including" is synonymous with "including", "containing" or "characterized as" and is inclusive or open-ended, and does not exclude additional unlisted elements or method steps; the term "having" should be interpreted as "at least having"; the term "including" should be interpreted as "including but not limited to"; the term "example" is used to provide an illustrative example of the item being discussed, rather than an exhaustive or restrictive list thereof; and the use of terms such as "preferably", "preferred", "desired" and "desired" and words of similar semantics should not be understood to imply that certain features are critical, necessary or even important for structure or function, but are intended only to highlight alternative or additional features that may or may not be used in a specific embodiment. In addition, the term "including" should be interpreted as synonymous with the phrase "at least having" or "at least including". 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.

[0035] For substantially any plural and / or singular terms used herein, a person skilled in the art may convert from the plural to the singular and / or from the singular to the plural, as long as it is appropriate for the context and / or application. For the sake of clarity, various singular / plural permutations may be explicitly stated herein. The indefinite article "a" or "an" does not exclude a plurality. The fact that certain measures are mentioned in mutually different dependent claims does not indicate that a combination of these measures cannot be used to make the advantages more prominent. Any figure marks in the claims should not be understood as limiting their scope.

[0036] Compounds for combination therapy

[0037] Current first-line treatment options for BRAF V600E-mutant metastatic colorectal cancer (mCRC) are limited to chemotherapy with or without bevacizumab. After existing treatments, the BEACON study (ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35) represents the only Phase 3 trial to demonstrate response and survival benefits for patients with BRAF V600E-mutant mCRC who have received existing therapies. Despite the approval of the encorafenib + cetuximab combination therapy in previously treated BRAF V600E-mutant mCRC, second-line and third-line patients still have a highly unmet need. For example, triple combinations have been explored in BRAF-mutant mCRC, but although they have some improved response rates and / or disease control compared to dual combinations, they are associated with higher toxicity. In particular, combinations of dabrafenib + panitumumab, trametinib + panitumumab, and dabrafenib + trametinib + panitumumab have been explored in recent trials, which produce an improved objective response rate (ORR) for triple therapies compared to dual combination regimens, but with an increase in certain adverse events such as grade 3 / 4 diarrhea.

[0038] Combining dual combinations with orthogonal pathway inhibitors may allow for additive or synergistic combinatorial effects with clinically meaningful responses and / or durability of response, without the toxicity observed for other triple combinations (such as those described herein). Inhibiting WEE1 with ZN-c3 (Compound (A)) or its pharmaceutically acceptable is an attractive option because WEE1 targeting is particularly effective in cancer cells with oncogene-driven replication stress, such as those occurring in RAS / RAF mutants or MYC-amplified cells. Consistent with this, some embodiments disclosed herein relate to the use of a compound combination for treating a disease or disorder, wherein the combination may comprise an effective amount of Compound (A) or its pharmaceutically acceptable salt; and an effective amount of Compound (B) or its pharmaceutically acceptable salt; wherein Compound (A) is or its pharmaceutically acceptable; and Compound (B) is a BRAF inhibitor or its pharmaceutically acceptable.

[0039] Some embodiments disclosed herein relate to a compound combination for use in treating a disease or disorder, wherein the combination may comprise an effective amount of Compound (A) or its pharmaceutically acceptable salt; and an effective amount of Compound (B) or its pharmaceutically acceptable salt; wherein Compound (A) is or its pharmaceutically acceptable; and Compound (B) is a BRAF inhibitor or its pharmaceutically acceptable.

[0040] 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 together with its pharmaceutically acceptable salts can be prepared according to the process provided in WO 2019 / 173082. As provided in WO 2019 / 173082, compound (A) (including its pharmaceutically acceptable salts) is active against WEE1.

[0041] Examples of BRAF inhibitors include vemurafenib, dabrafenib, encorafenib, argenafeni, AZ-628, belvarafenib, BMS-908662, CHIR-265, DP-4978, GDC-0879, GW5074, lifirafenib, SB590885, naporafenib, PLX-4720, PLX-8394, ABM-1310, ASN-003, JZP815, and KIN-2787 or pharmaceutically acceptable salts of any of the foregoing. Figure 1 Further information regarding BRAF inhibitors is provided.

[0042] The combinations described herein may further comprise compound (C), including its pharmaceutically acceptable salts, wherein compound (C) may be an EGFR inhibitor or its pharmaceutically acceptable salt. Accordingly, some embodiments disclosed herein relate to the use of a compound combination for treating a disease or disorder, wherein the combination may comprise an effective amount of compound (A) or its pharmaceutically acceptable salt; an effective amount of compound (B) or its pharmaceutically acceptable salt; and an effective amount of compound (C) or its pharmaceutically acceptable salt; wherein compound (A) is or its pharmaceutically acceptable salt; compound (B) is a BRAF inhibitor or its pharmaceutically acceptable salt; and compound (C) is an EGFR inhibitor or its pharmaceutically acceptable salt. Additionally, some embodiments disclosed herein relate to a compound combination for use in treating a disease or disorder, wherein the combination may comprise an effective amount of compound (A) or its pharmaceutically acceptable salt; an effective amount of compound (B) or its pharmaceutically acceptable salt; and an effective amount of compound (C) or its pharmaceutically acceptable salt; wherein compound (A) is or its pharmaceutically acceptable salt; compound (B) is a BRAF inhibitor or its pharmaceutically acceptable salt; and compound (C) is an EGFR inhibitor or its pharmaceutically acceptable salt.

[0043] In some embodiments, the EGFR inhibitor can be a tyrosine kinase inhibitor (TKI). In other embodiments, the EGFR inhibitor can be an antibody, such as but not limited to a 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]pent-1-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (along with its pharmaceutically acceptable salts). Figure 2 Further information regarding the EGFR inhibitor is provided.

[0044] Embodiments of the combination of compound (A) and compound (B) (including pharmaceutically acceptable salts of any of the foregoing) and embodiments of compound (A), compound (B), and compound (C) (including pharmaceutically acceptable salts of any of the foregoing) are provided in Table 1. In Table 1, "A" indicates compound (A) (including its pharmaceutically acceptable salts), numbers 1A-20A correspond to Figure 1 compound (B) (including its pharmaceutically acceptable salts) provided in Figure 2 compound (C) (including its pharmaceutically acceptable salts) provided in

[0045] Table 1

[0046]

[0047]

[0048] The order of administration of the compounds in the combinations described herein can vary. In some embodiments, compound (A) (including its pharmaceutically acceptable salts) can be administered before compound (B) or its pharmaceutically acceptable salts. In other embodiments, compound (A) (including its pharmaceutically acceptable salts) can be administered concurrently with compound (B) or its pharmaceutically acceptable salts. In yet other embodiments, compound (A) (including its pharmaceutically acceptable salts) can be administered after the administration of compound (B) or its pharmaceutically acceptable salts. In some embodiments, when compound (C) (including its pharmaceutically acceptable salts) can be administered before both compound (A) and compound (B) (including the pharmaceutically acceptable salts of any of the foregoing). In other embodiments, when compound (C) (including its pharmaceutically acceptable salts) can be administered after both compound (A) and compound (B) (including the pharmaceutically acceptable salts of any of the foregoing). In yet other embodiments, when compound (C) (including its pharmaceutically acceptable salts) can be administered before one of compound (A) (including its pharmaceutically acceptable salts) and after compound (B) (including its pharmaceutically acceptable salts). In yet other embodiments, when compound (C) (including its pharmaceutically acceptable salts) can be administered before one of compound (B) (including its pharmaceutically acceptable salts) and after compound (A) (including its pharmaceutically acceptable salts).

[0049] There can be several advantages to using the combinations of compounds described herein. For example, combining compounds that attack multiple pathways simultaneously may be more effective in treating cancers (such as those described herein) compared to when the compounds of the combination are used as monotherapies.

[0050] In some embodiments, combinations as described herein (such as compound (A) (including its pharmaceutically acceptable salts) and compound (B) or its pharmaceutically acceptable salts and compound (A) (including its pharmaceutically acceptable salts), compound (B) or its pharmaceutically acceptable salts and compound (C) or its pharmaceutically acceptable salts) can reduce the number and / or severity of side effects attributable to the compounds described herein (such as compound (B)) or its pharmaceutically acceptable salts.

[0051] Use of the combinations of compounds described herein can produce additive, synergistic or strongly synergistic effects. The combinations of compounds described herein can produce non-antagonistic effects.

[0052] In some embodiments, combinations as described herein (such as compound (A) (including its pharmaceutically acceptable salts) and compound (B) or its pharmaceutically acceptable salts, and compound (A) (including its pharmaceutically acceptable salts), compound (B) or its pharmaceutically acceptable salts, and compound (C) or its pharmaceutically acceptable salts) may produce an additive effect. In some embodiments, combinations as described herein (e.g., compound (A) (including its pharmaceutically acceptable salts) and compound (B) or its pharmaceutically acceptable salts, and compound (A) (including its pharmaceutically acceptable salts), compound (B) or its pharmaceutically acceptable salts, and compound (C) or its pharmaceutically acceptable salts) may produce a synergistic effect. In some embodiments, combinations as described herein (e.g., compound (A) (including its pharmaceutically acceptable salts) and compound (B) or its pharmaceutically acceptable salts, and compound (A) (including its pharmaceutically acceptable salts), compound (B) or its pharmaceutically acceptable salts, and compound (C) or its pharmaceutically acceptable salts) may produce a strong synergistic effect. In some embodiments, combinations as described herein (such as compound (A) (including its pharmaceutically acceptable salts) and compound (B) or its pharmaceutically acceptable salts, and compound (A) (including its pharmaceutically acceptable salts), compound (B) or its pharmaceutically acceptable salts, and compound (C) or its pharmaceutically acceptable salts) are non-antagonistic.

[0053] As used herein, the term "antagonistic" means that when the activity of each compound is determined individually (i.e., as a single compound), the activity of the compound combination is less than the sum of the activities of the compounds in the combination. As used herein, the term "synergistic" means that when the activity of each compound is determined individually, the activity of the compound combination is greater than the sum of the individual activities of the compounds in the combination. As used herein, the term "additive effect" means that when the activity of each compound is determined individually, the activity of the compound combination is approximately equal to the sum of the individual activities of the compounds in the combination.

[0054] The potential advantages of using combinations as described herein may include that the amount of the compounds required to effectively treat the disease conditions disclosed herein is reduced compared to when each compound is administered as a single therapy. 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 single therapy. Another potential advantage of using combinations as described herein is that using two or more compounds with different mechanisms of action may pose a higher barrier to the development of drug resistance compared to when a compound is administered as a single therapy. Additional advantages of using combinations as described herein may include: little or no cross-resistance between the compounds of the combinations described herein; different elimination pathways for the compounds of the combinations described herein; and / or little or no overlapping toxicity between the compounds of the combinations described herein.

[0055] Pharmaceutical composition

[0056] Compound (A) (including its pharmaceutically acceptable salts) may be provided in a pharmaceutical composition. Similarly, compound (B) and compound (C) may be provided in a pharmaceutical composition, including the pharmaceutically acceptable salts of any of the foregoing.

[0057] 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 the administration of compounds to an organism. Pharmaceutical compositions may also be obtained by reacting the 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 will generally be formulated according to the particular intended route of administration.

[0058] As used herein, a "carrier" is a compound that facilitates the binding of a compound to a cell or tissue. For example but not limited to, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into the cells or tissues of a subject.

[0059] As used herein, a "diluent" is a component of a pharmaceutical composition that has no significant drug activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the volume of a potent drug that is too small in mass to be manufactured and / or administered. It 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, but not limited to, phosphate buffered saline that mimics the pH and isotonicity of human blood.

[0060] As used herein, "excipient" refers to a substantially inert substance that is added to a pharmaceutical composition to provide, but not limited to, volume, consistency, stability, binding ability, lubrication, disintegration ability, etc. to the composition. For example, stabilizers such as antioxidants and metal chelating agents are excipients. In one embodiment, the pharmaceutical composition comprises an antioxidant and / or a metal chelating agent. "Diluent" is a type of excipient.

[0061] In some embodiments, compound (B) and its pharmaceutically acceptable salts may be provided in a pharmaceutical composition that comprises compound (A) (including its pharmaceutically acceptable salts). In other embodiments, compound (B) and its pharmaceutically acceptable salts may be administered to a pharmaceutical composition that is separate from a pharmaceutical composition that comprises compound (A) (including its pharmaceutically acceptable salts). When compound (C) (including its pharmaceutically acceptable salts) is included, compound (C) (including its pharmaceutically acceptable salts) may be disposed in a pharmaceutical composition that comprises compound (A) together with its pharmaceutically acceptable salts and / or compound (B) together with its pharmaceutically acceptable salts. In other instances, compound (C) (including its pharmaceutically acceptable salts) may be disposed in a pharmaceutical composition that is separate from compound (A) (together with pharmaceutically acceptable salts) and compound (B) (together with pharmaceutically acceptable salts).

[0062] The pharmaceutical compositions described herein may be administered to a human patient per se, or incorporated into a composition in which the pharmaceutical composition is mixed with other active ingredients (such as in combination therapy), or with a carrier, diluent, excipient, or a combination thereof. The correct formulation depends on the chosen route of administration. Techniques for formulating and administering the compounds described herein are known to those of skill in the art.

[0063] The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example, by means of conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, entrapping, or tabletting processes. Additionally, they contain the active ingredient in an amount effective to achieve its intended use. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0064] There are a variety of techniques for administering compounds, salts and / or compositions in the art, including but not limited to oral, rectal, pulmonary, 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 salt) can be administered orally. In some embodiments, compound (A) (including its pharmaceutically acceptable salt) can be provided to the subject by the same route of administration as compound (B) together with its pharmaceutically acceptable salt and / or compound (C) together with its pharmaceutically acceptable salt. In other embodiments, compound (A) (including its pharmaceutically acceptable salt) can be provided to the subject by a different route of administration than compound (B) together with its pharmaceutically acceptable salt and / or compound (C) together with its pharmaceutically acceptable salt.

[0065] Compounds, salts and / or compositions may also be administered in a local rather than a systemic manner, for example, by direct injection or implantation of the compound into the affected area in the form of a reservoir or sustained release formulation. In addition, the compound may be administered in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposome will be targeted to and selectively taken up by an organ. For example, intranasal or pulmonary delivery to target respiratory diseases or conditions may be desirable.

[0066] The composition may (if desired) be present in a package or dispenser device, which may include one or more unit dosage forms containing the active ingredient. The package may, for example, include metal or plastic foil, such as a blister package. The package or dispenser device may be accompanied by instructions for use. The package or dispenser may also be accompanied by a notice associated with the container form as specified by a government agency regulating the manufacture, use or sale of the drug, which reflects the agency's approval of the form of the drug for human or veterinary administration. For example, such notices may be labels approved by the U.S. Food and Drug Administration for prescription drugs or approved product inserts. Compositions that may include compounds and / or salts formulated in a compatible pharmaceutical carrier as described herein may also be prepared, placed, and labeled for treatment of the indicated disorder in an appropriate container.

[0067] Use and treatment method

[0068] As provided herein, in some embodiments, a compound combination comprising an effective amount of compound (A) (including its pharmaceutically acceptable salts) and an effective amount of compound (B) or its pharmaceutically acceptable salts can be used for treating a disease or disorder. Accordingly, some embodiments disclosed herein relate to methods of treating a disease or disorder, the methods comprising administering to a subject a compound combination; wherein the combination can comprise an effective amount of compound (A) or its pharmaceutically acceptable salts; and an effective amount of compound (B) or its pharmaceutically acceptable salts; wherein compound (A) and compound (B) are as defined herein. In some embodiments, a compound combination comprising an effective amount of compound (A) (including its pharmaceutically acceptable salts), an effective amount of compound (B) (including its pharmaceutically acceptable salts), and an effective amount of compound (C) (including its pharmaceutically acceptable salts) can be used for treating a disease or disorder. Accordingly, some embodiments disclosed herein relate to methods of treating a disease or disorder, the methods comprising administering to a subject a compound combination; wherein the combination can comprise an effective amount of compound (A) or its pharmaceutically acceptable salts; an effective amount of compound (B) or its pharmaceutically acceptable salts; and an effective amount of compound (C) or its pharmaceutically acceptable salts; wherein compound (A), compound (B), and compound (C) are as defined herein.

[0069] In some embodiments, the disease or disorder can be colorectal cancer. In one embodiment, the disease or disorder can be advanced colorectal cancer. In one embodiment, the disease or disorder can be metastatic colorectal cancer. In one embodiment, the disease or disorder can be advanced and / or metastatic colorectal cancer that has progressed following one or two existing treatment regimens (such as those described herein). BRAF mutations (i.e., mutations at the BRAF gene) can occur in colorectal cancer. For example, the BRAF mutation can be an activating mutation. In one embodiment, at least one of the BRAF mutations can be a BRAF mutation that occurs at codon V600. In some embodiments, the BRAF mutation can be V600E, a substitution from valine to glutamate at the codon. In one embodiment, the disease or disorder can be BRAF V600E-mutant metastatic colorectal cancer.

[0070] In some cases, following cancer treatment, a subject may experience recurrence or reoccurrence of cancer. As used herein, the terms “recurrence” and “reoccurrence” are used in their ordinary meaning as understood by one of ordinary skill in the art. Accordingly, the cancer can be recurrent cancer.

[0071] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles, and especially mammals. "Mammal" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates (such as monkeys, chimpanzees, and apes), and especially humans. In some embodiments, the subject can be a human. In some embodiments, the subject can be a child and / or an infant. In other embodiments, the subject can be an adult. In one embodiment, the subject can be a human suffering from advanced colorectal cancer. In one embodiment, the subject can be a human suffering from metastatic colorectal cancer. In one embodiment, the subject can be a human suffering from advanced and / or metastatic colorectal cancer, the disease having progressed after one or two existing treatment regimens.

[0072] As used herein, the terms "treatment" and "therapy" do not necessarily mean a complete cure or elimination of a disease or disorder. Any degree of alleviation of any undesired sign or symptom of a disease or disorder can be considered a treatment and / or therapy. In addition, treatment can include actions that can worsen the overall health perception or appearance of the subject.

[0073] The term "effective amount" is used to indicate the amount of an active compound or agent that causes the indicated biological or pharmacological response. For example, an effective amount of a compound, salt, or composition can be the amount required to prevent, alleviate, or improve the symptoms of a disease or disorder, or to extend the survival rate of the treated subject. The response can occur in a tissue, system, animal, or human, and includes alleviating the signs or symptoms of the treated disease or disorder. The determination of an effective amount is well within the capabilities of those skilled in the art based on the disclosure provided herein. The effective amount required as a dose of the compounds disclosed herein will depend on the route of administration, the type of animal (including human) being treated, and the physical characteristics of the particular animal under consideration. The dose can be modulated to achieve the desired effect, but the dose will depend on factors such as body weight, diet, concurrent drug therapy, and other factors that will be recognized by those skilled in the medical arts.

[0074] For example, an effective amount of a compound or radiation is the amount that results in: (a) a reduction, alleviation, or disappearance of one or more symptoms caused by cancer, (b) a reduction in tumor size, (c) the elimination of the tumor, and / or (d) long-term disease stabilization (growth arrest) of the tumor.

[0075] The amount of the compound, salt and / or composition required for use in therapy will vary not only with the particular compound or salt selected, but also with the route of administration, the nature and / or symptoms of the disease or disorder being treated, and the age and condition of the patient, and will ultimately be determined by the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated on the basis of the free base. As will be understood by those skilled in the art, in some cases it may be necessary to administer the compounds disclosed herein in amounts that exceed or even far exceed the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive diseases or disorders.

[0076] As will be apparent to those skilled in the art, the available in vivo dosage to be administered and the specific mode of administration will vary depending on the age, weight, severity of the affliction, species of mammal being treated, the particular compound employed, and the specific use for which these compounds are being used. The determination of the effective dosage level (which is the dosage level necessary to achieve the desired result) can be accomplished by those skilled in the art using conventional methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, the available dosage of compound (A), (B), and / or (C) or a pharmaceutically acceptable salt of any of the foregoing can be determined by comparing their in vitro activity and in vivo activity in an animal model. Such comparisons can be accomplished by comparison with established drugs such as cisplatin and / or gemcitabine.

[0077] The dosage and interval can be adjusted individually to provide plasma levels of the active moiety sufficient to maintain the modulating effect or the minimum effective concentration (MEC). The MEC will vary for each compound, but can be estimated on the basis of in vivo data and / or in vitro data. The dosage necessary to achieve the MEC will depend on the individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. The MEC value can also be used to determine the dosage interval. The composition should be administered using a regimen that maintains plasma levels for a time that is 10% to 90% higher than the MEC, preferably between 30% and 90%, most preferably between 50% and 90%. In the case of topical administration or selective uptake, the effective local concentration of the pharmaceutical need not be related to the plasma concentration.

[0078] It should be noted that in the event of toxicity or organ dysfunction, the attending physician will know how and when to terminate, interrupt, or adjust the administration. Conversely, in the event of an insufficient clinical response (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The magnitude of the dose administered in the management of the disorder of interest will vary according to the severity of the disease or condition to be treated and the route of administration. For example, the severity of a disease or condition can be evaluated in part by standard prognostic assessment methods. In addition, the dose and possible dose frequency will also vary according to age, body weight, and the response of the individual patient. Procedures comparable to those discussed above can be used in veterinary medicine.

[0079] Known methods can be used to evaluate the efficacy and toxicity of the compounds, salts, and compositions disclosed herein. For example, the toxicology of a particular compound or a subset of the compound (sharing certain chemical moieties) can be established by determining its in vitro toxicity to cell lines such as mammalian and preferably human cell lines. The results of such studies generally predict toxicity in animals such as mammals or more specifically humans. Alternatively, known methods can be used to determine the toxicity of a particular compound in animal models such as mice, rats, rabbits, dogs, or monkeys. Several well-recognized methods such as in vitro methods, animal models, or human clinical trials can be used to establish the efficacy of a particular compound. When selecting a model to determine efficacy, one of ordinary skill in the art can follow the prior art to select an appropriate model, dose, route of administration, and / or protocol.

[0080] Example

[0081] Additional embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0082] Example 1: In vitro tumor cell proliferation assay

[0083] will contain 1.5x 10 in 100 μL of medium 3A cell suspension of the total cells was deposited in each well of an ultra-low attachment 96-well plate. The plate was incubated at 37 °C with 95% oxygen and 5% CO2 for 72 hours to allow spheroid formation. After 72 hours, 10 μL of medium with or without cetuximab was deposited into each well to bring the final volume to 110 μL. The ZN-c3 and / or encorafenib compounds were deposited into the plate in DMSO at the indicated concentrations using an automated drug dispenser. The total DMSO content was normalized to 0.1% of the total volume in all assay conditions. The plate was sealed with a breathable membrane to reduce evaporation and incubated at 37 °C with 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 3DCTG reagent (Promega, catalog number G9683) was added to each well. The plate was stirred at 520 revolutions per minute (rpm) for 5 minutes, allowed to stabilize for 30 minutes in the dark, and then luminescence was measured on an M5e microplate reader (SpectraMax). The percentage viability was calculated as the percentage of cell viability relative to a vehicle control containing only DMSO.

[0084] Tables 2 and 3 and the attached Figure 3 to the attached Figure 6 detail the compounds used and their concentrations in the cell proliferation assays and the percentage inhibition of tumor cells. The percentage inhibition values indicate that for both HT-29 and LS411N cells, any dual-agent treatment containing 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-agent treatments. For example, ZN-c3 + encorafenib inhibited tumor cell proliferation better than encorafenib alone, and ZN-c3 + cetuximab inhibited tumor cell proliferation better than cetuximab alone. In HT-29, dual-agent treatment with ZN-c3 + encorafenib and triple-agent treatment with ZN-c3 + encorafenib + cetuximab achieved similar tumor cell inhibition to dual-agent treatment with encorafenib + cetuximab (see Figure 5 ). In LS411N, dual-agent treatment with ZN-c3 + encorafenib achieved similar tumor cell inhibition to dual-agent treatment with encorafenib + cetuximab, but triple-agent treatment with ZN-c3 + encorafenib + cetuximab achieved higher tumor cell inhibition than dual-agent treatment with encorafenib + cetuximab (see Figure 6 ).

[0085] Table 2

[0086]

[0087] Table 3

[0088]

[0089]

[0090] In vivo preclinical studies on cell line-derived xenografts (CDX) and patient-derived xenograft models Research

[0091] CDX model: 95% viable tumor cells (5×10 6 ) in a single cell suspension in 100 μL of serum-free RPMI 1640 (COLO205), 95% viable tumor cells (2×10 6 ) in a single cell suspension in 100 μL of serum-free modified McCoy’s 5a medium (HT-29), or 95% viable tumor cells (2×10 6 ) in a single cell suspension in a 100 μL mixture of serum-free RPMI 1640 and Matrigel (1:1 ratio) (LS411N) were subcutaneously inoculated into the right lower abdomen of BALB / c nude mice at 6 to 8 weeks of age.

[0092] PDX model: Tumor fragments (CRC769, CRC563, CTG-1009) were removed from cryopreservation and implanted into female athymic nude Foxnlnu mice. The fragments were allowed to grow and then excised once they reached an appropriate volume. Tumor slurry was made from 50% freshly harvested tumor cut into small tumor fragments in PBS and 50% Matrigel. The tumor slurry was subcutaneously injected into the flanks of female athymic nude Foxnlnu mice at 6 to 8 weeks of age.

[0093] Grouping and treatment were started when the average tumor volume reached approximately 220 mm 3 (a single tumor was between 200 mm 3 and 240 mm 3(within the range). Carrier animals were treated daily with 10 mL / kg HP-β-CD p.o. (gavage). Encorafenib was prepared weekly in 0.5% carboxymethylcellulose∶0.5% Tween 80∶99% deionized water and administered daily (QD) at the indicated oral dose (p.o.) (doses are shown in Tables 4 and 5). ZN-c3 was prepared daily in 20% HP-β-CD and administered daily at the indicated dose p.o. (doses are shown in Tables 4 and 5). Cetuximab was diluted in PBS buffer pH 7.0 at the time of administration and administered intraperitoneally (i.p.) at the indicated dose every two weeks (BIW). (Doses are shown in Tables 4 and 5). Body weights and tumor volumes of all animals were measured twice weekly throughout the study for a duration of 21 days or 22 days or 3 weeks (for CDX models HT-29 and LS411N) or for a duration of 28 days or 4 weeks (for PDX models CRC769, CRC563, and CTG-1009). Tumor size measurements were performed using calipers, and the formula: TV = a × b2 / 2 was used throughout the study to estimate tumor volume (mm 3 ), where "a" and "b" are the long and short diameters of the tumor, respectively. Animals were euthanized when the individual tumor burden exceeded 2000 mm 3 or were in a condition of continuous deterioration or near lethargy.

[0094] In Figure 7 (HT-29, which is BRAF mt CRC) and Figure 9 (LS411N, which is also BRAF mt CRC), tumor volume measurements for the CDX models are provided (a total of 6 measurements throughout the 21-day or 22-day study). Based on the tumor volume measurements, tumor growth inhibition (TGI) values were calculated and are provided in Table 4. In both CDX models, the triple therapy of ZN-c3 + encorafenib + cetuximab induced tumor regression, which was superior to the current standard-of-care dual therapy of encorafenib + cetuximab for metastatic colorectal cancer, with a TGI value of 100.9 (ZN-c3 + encorafenib + cetuximab) compared to 88.2 (encorafenib + cetuximab) in HT-29, and significantly 107.6 (ZN-c3 + encorafenib + cetuximab) compared to 63.4 (encorafenib + cetuximab) in LS411N. Additionally, in LS411N, the dual therapy of ZN-c3 + encorafenib induced tumor inhibition superior to the standard of care, with a TGI value of 101.7. As in Figure 8 of HT-29 and Figure 10As shown in Table 4 for both models, the body weight measurement results of the CDX model (a total of 6 measurements over the entire 21 - or 22 - day study) indicate minimal body weight changes during the study of the exemplary combination therapies (i.e., the triple therapy of ZN - c3 + encorafenib + cetuximab and the dual therapy of encorafenib + cetuximab). Generally, a body weight loss greater than 15% indicates that the treatment regimen is not well - tolerated.

[0095] In Figure 11 (CRC769, which is BRAF mt CRC), Figure 13 (CRC563, which is also BRAF mt CRC) and Figure 15 (CTG - 1009, which is also BRAF mt CRC), the tumor volume measurement results of the PDX model (a total of 8 measurements over the entire 28 - day study) are provided. Based on the tumor volume measurement results, the tumor growth inhibition (TGI) values are calculated and provided in Table 5. In all three PDX models, the triple therapy of ZN - c3 + encorafenib + cetuximab induces tumor regression, which is superior to the current standard dual therapy of encorafenib + cetuximab for metastatic colorectal cancer. Compared with 65.0 (encorafenib + cetuximab) in CRC769, the TGI value is 86.8 (ZN - c3 + encorafenib + cetuximab); compared with 48.7 (encorafenib + cetuximab) in CRC563, it is 79.6 (ZN - c3 + encorafenib + cetuximab); and compared with 86.9 in CTG - 1009, it is 97.9 (ZN - c3 + encorafenib + cetuximab). Additionally, in all three PDX models, the dual therapy of ZN - c3 + encorafenib results in higher TGI values than the standard dual therapy of encorafenib + cetuximab. Compared with 65.0 (CRC769), 48.7 (CRC563), and 86.9 (CTG - 1009), the TGI values are 82.3 (CRC769), 57.2 (CRC563), and 103.44 (CTG - 1009). As Figure 12 (CRC769), Figure 14 (CRC563) and Figure 16 (CTG - 1009) and as shown in Table 5, the body weight measurement results of the PDX model (a total of 8 measurement results over the entire 28 - day study) indicate minimal body weight changes during the study of the exemplary combination therapies (i.e., the triple therapy of ZN - c3 + encorafenib + cetuximab and the dual therapy of encorafenib + cetuximab).

[0096] In summary, in vivo studies based on statistical analysis between the standard-of-care dual therapy (encorafenib + cetuximab) and triple therapy (ZN-c3 + encorafenib + cetuximab) showed that all CDX models and PDX models had statistically significant improvements with triple therapy compared to dual therapy, without tolerance issues. Analysis between the standard-of-care dual therapy (encorafenib + cetuximab) and ZN-c3 encorafenib dual therapy showed that all models except HT-29 had statistically significant improvements with the latter compared to the former, without tolerance issues.

[0097]

[0098]

[0099] In addition, although some detailed descriptions have been made above by way of illustration and example for clarity and understanding, those skilled in the art will understand that many and various modifications can be made without departing from the essence of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are merely illustrative and are not intended to limit the scope of the present disclosure, but also cover all modifications and alternatives that conform to the true scope and essence of the present disclosure.

Claims

1. Use of a combination of compounds for the treatment of a disease or disorder, wherein said combination comprises 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 or a pharmaceutically acceptable salt thereof; and compound (B) is a BRAF inhibitor or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein the BRAF inhibitor is selected from the group consisting of vemurafenib, dabrafenib, encorafenib, argenafeni, AZ-628, bevacafenib, BMS-908662, CHIR-265, DP-4978, GDC-0879, GW5074, lifirafenib, SB590885, nabrafenib, PLX-4720, PLX-8394, ABM-1310, ASN-003, JZP815, KIN-2787, and pharmaceutically acceptable salts 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. The use according to claim 6, 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]pent-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.

10. The use according to any one of claims 1 to 9, wherein the disease or disorder 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. The use according to claim 11 or claim 12, wherein the advanced colorectal cancer and / or metastatic colorectal cancer has progressed after one or two existing 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. The use according to claim 14, wherein the BRAF mutation occurs at codon V600.

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

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

Images