Combination of TEAD and KRAS G12D inhibitors for treating cancer

Abstract

The present invention relates to pharmaceutical combinations comprising a TEAD inhibitor in combination with a KRAS G12D inhibitor and methods of treating cancer using said combinations.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical combinations comprising a TEAD inhibitor in combination with a KRAS G12D inhibitor and methods of treating cancer using said combinations. [Background technology]

[0002] The advent of targeted cancer therapies has extended patient lifespans for a variety of malignancies and helped us understand tumor complexity through the study of drug resistance mechanisms. The fact that clinical responses to targeted drugs are generally incomplete and / or transient is due to a number of factors that can be broadly categorized into two classes: toxicity, which prevents optimal drug dosing and thus limits target binding (Brana and Siu 2012; Chapman, Solit et al. 2014), and the ability of cancers to adapt and maintain their proliferative potential in response to perturbations (Druker 2008; Chandarlapaty 2012; Doebele, Pilling et al. 2012; Duncan, Whittle et al. 2012; Katayama, Shaw et al. 2012; Lito, Rosen et al. 2013; Sullivan and Flaherty 2013; Solit and Rosen 2014). Drug combinations may address both of these factors by improving overall efficacy and simultaneously targeting tumor robustness and complexity to combat resistance (Robert, Karaszewska et al. 2015; Turner, Ro et al. 2015). It remains unclear how many drugs will be needed and which processes will need to be targeted in combination to overcome a particular type of cancer. However, it will almost certainly be necessary to inhibit different pathways or drivers, likely requiring more than one drug (Bozic, Reiter et al. 2013).

[0003] Despite numerous treatment options for patients with certain types of cancer, there remains a need for effective and safe combination therapies that can be administered for the treatment of cancer.

[0004] Ras proteins are key components of signal transduction pathways that induce cell growth, differentiation, proliferation, and survival. RAS genes are frequently mutated oncogenes in human cancers, and approximately 30% of all human cancers harbor mutations in the KRAS, NRAS, or HRAS genes. Oncogenic Ras is associated with mutations at glycine 12, glycine 13, or glutamine 61 of Ras. These residues are located in the active site of Ras, and mutations result in the aberrant activation of downstream effector pathways (MAPK and PI3K pathways). KRAS is the most frequently mutated RAS gene in cancer, and several tumor types exhibit frequent activating mutations in KRAS, including pancreatic cancer (approximately 90% prevalence), colorectal cancer (approximately 40% prevalence), and non-small cell lung cancer (approximately 30% prevalence). KRAS mutations can be found in other cancer types, including multiple myeloma, uterine cancer, cholangiocarcinoma, gastric cancer, bladder cancer, diffuse large B-cell lymphoma, rhabdomyosarcoma, cutaneous squamous cell carcinoma, cervical cancer, and testicular germ cell cancer.

[0005] KRAS mutations occur in approximately 17.9% of malignant solid tumors. KRAS G12D mutations specifically occur in approximately 4.7% of malignant solid tumors. Cancers in which KRAS G12D mutations are common include pancreatic ductal adenocarcinoma (35%), colorectal cancer (14%), non-small cell lung cancer (4%), gastric cancer (3.7%), and ovarian cancer (3.3%). Summary of the Invention

[0006] The object of the present invention is to provide a medicament for improving the treatment of cancer, specifically by inhibiting cell growth (proliferation) and / or inducing apoptosis (cell death). The object of the present invention is to find a novel combination therapy that selectively synergizes the inhibition of proliferation and / or induction of apoptosis.

[0007] Surprisingly, as demonstrated in the Examples, it has been found that a pharmaceutical combination comprising i) a TEAD inhibitor and ii) a KRAS G12D inhibitor can synergistically inhibit cancer growth and / or induce apoptosis.

[0008] Thus, according to a first aspect of the present invention, there is provided herein a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a TEAD inhibitor in combination with a KRAS G12D inhibitor.

[0009] According to a second aspect of the present invention, there is provided herein a TEAD inhibitor for use in the treatment of cancer, wherein the treatment further comprises administration of a KRAS G12D inhibitor.

[0010] According to a third aspect of the present invention, there is provided herein a KRAS G12D inhibitor for use in the treatment of cancer, wherein the treatment further comprises administration of a TEAD inhibitor.

[0011] According to a fourth aspect of the present invention, there is provided herein a combination comprising i) a TEAD inhibitor, ii) a KRAS G12D inhibitor, and optionally iii) a SHP2 inhibitor. [Brief explanation of the drawings]

[0012] [Figure 1] In vitro viability of the KRAS G12D mutant pancreatic ductal adenocarcinoma cancer cell line HPAF-II was assessed using CellTiterGlo after 6 days of treatment with (top) IAG933 in combination with MRTX1133, (middle) TNO155 in combination with MRTX1133, and (bottom) IAG933 in combination with MRTX1133 and 500 nM TNO155. % growth inhibition: 0-99 = growth delay, 100 = growth arrest / stagnation, 101-200 = reduction in cell number / cell death. [Figure 2]In vitro viability of the KRAS G12D mutant pancreatic ductal adenocarcinoma cancer cell line ASPC-I was assessed using CellTiterGlo after 6 days of treatment with (top) IAG933 in combination with MRTX1133, (middle) TNO155 in combination with MRTX1133, and (bottom) IAG933 in combination with MRTX1133 and 500 nM TNO155. % growth inhibition: 0-99 = growth delay, 100 = growth arrest / stagnation, 101-200 = reduction in cell number / cell death. [Figure 3] In vitro viability of the KRAS G12D mutant pancreatic ductal adenocarcinoma cancer cell line SW1990 was assessed using CellTiterGlo after 6 days of treatment with (top) IAG933 in combination with MRTX1133, (middle) TNO155 in combination with MRTX1133, and (bottom) IAG933 in combination with MRTX1133 and 500 nM TNO155. % growth inhibition: 0-99 = growth delay, 100 = growth arrest / stagnation, 101-200 = reduction in cell number / cell death. [Figure 4] Confluency of AsPC KRAS G12D mutant pancreatic ductal adenocarcinoma cell lines after treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with media refreshed once a week. Confluency was monitored using an Incucyte® S3 live cell analyzer (Sartorius). [Figure 5] Confluency of GP2D KRAS G12D colorectal cancer cell line after treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with media refreshed once a week. Confluency was monitored using an Incucyte® S3 live cell analyzer (Sartorius). [Figure 6]Confluency of HPAF-II KRAS G12D mutant pancreatic ductal adenocarcinoma cell lines after treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with media refreshed once a week. Confluency was monitored using an Incucyte® S3 live cell analyzer (Sartorius). DETAILED DESCRIPTION OF THE INVENTION

[0013] As stated above, it is an object of the present invention to find novel combination therapies that selectively synergize in inhibiting proliferation and / or inducing apoptosis.

[0014] Thus, according to a first aspect of the present invention, there is provided herein a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a TEAD inhibitor in combination with a KRAS G12D inhibitor.

[0015] According to a second aspect of the present invention, there is provided herein a TEAD inhibitor for use in the treatment of cancer, wherein the treatment further comprises administration of a KRAS G12D inhibitor.

[0016] According to a third aspect of the present invention, there is provided herein a KRAS G12D inhibitor for use in the treatment of cancer, wherein the treatment further comprises administration of a TEAD inhibitor.

[0017] According to a fourth aspect of the present invention, there is provided herein a combination comprising i) a TEAD inhibitor, ii) a KRAS G12D inhibitor, and optionally iii) a SHP2 inhibitor.

[0018] Surprisingly, as shown in the Examples, the combination of a TEAD inhibitor with a KRAS G12D inhibitor (with or without the further combination of an SHP2 inhibitor) was found to be synergistic in a wide range of cancer models.

[0019] In one embodiment, the TEAD inhibitor is a YAP / TAZ-TEAD protein-protein interaction inhibitor.

[0020] In one embodiment, the TEAD inhibitor is selected from the group consisting of IAG933, 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Compound A), K-975, VT3989, and IK-930.

[0021] In one embodiment, the TEAD inhibitor is IAG933.

[0022] In one embodiment, the KRAS G12D inhibitor is selected from MRTX1133, TAS-0612, ASP-3082, HRS-4642, KRASG12D1, RMC-9805, and siG12D LODER.

[0023] In one embodiment, the KRAS G12D inhibitor is MRTX1133.

[0024] In one embodiment, the TEAD inhibitor is IAG933 and the KRAS G12D inhibitor is MRTX1133.

[0025] In one embodiment, the treatment further comprises administration of an SHP2 inhibitor.

[0026] In one embodiment, the SHP2 inhibitor is selected from the group consisting of bosiprotafib (RMC-4630), ERAS-601, JAB-3312, JAB-3068, HS-10381, ICP-189, ARRY-558 (PF-07284892), ET-0038 (ETS-001), SH-3809, GDC-1971 (RLY-1971 / RO-7517834 / RG-6433), GH-21 (HBI-2376 ), BBP-398 (IACS-13909 / IACS-15509), BPI-442096, I-0436650, PCC-0208023, IACS-15414, RMC-4550, fumosorinone, TYB-1-17, ML-119, GS-493, GS-458, II-B08, PHPS1, 3-Cl-AHPC (MM-002) and TNO155.

[0027] In one embodiment, the SHP2 inhibitor is selected from the group consisting of JAB-3068, bosiprotafib (RMC-4630), RLY1971, and TNO155.

[0028] In one embodiment, the SHP2 inhibitor is TNO155.

[0029] In one embodiment, the TEAD inhibitor is IAG933, the KRAS G12D inhibitor is MRTX1133, and the SHP2 inhibitor, if present, is TNO155.

[0030] In one embodiment, the cancer is a TEAD-dependent cancer.

[0031] In one embodiment, the cancer is a KRAS G12D mutant cancer, for example a KRAS G12D mutant solid tumor.

[0032] In one embodiment, the cancer is selected from pancreatic ductal adenocarcinoma, colorectal cancer, non-small cell lung cancer, gastric cancer, and ovarian cancer.

[0033] In one embodiment, the cancer is KRAS G12D mutant pancreatic ductal adenocarcinoma or KRAS G12D mutant colorectal cancer.

[0034] In one embodiment, the TEAD inhibitor (e.g., IAG933) is administered on each of the first three days of a seven-day treatment cycle, and the treatment consists of at least two treatment cycles.

[0035] In one embodiment, the daily dose of the TEAD inhibitor (e.g., IAG933) on each day of administration is 15 mg to 1500 mg.

[0036] In one embodiment, the daily dose of the TEAD inhibitor (e.g., IAG933) on each day of administration is 100 mg to 1500 mg.

[0037] In one embodiment, the daily dose of the TEAD inhibitor (e.g., IAG933) on each day of administration is 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 375 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 475 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 675 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 80mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg or 1500mg.

[0038] Thus, in one aspect, the present invention provides the following numbered embodiments: Embodiment 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a TEAD inhibitor in combination with a KRAS G12D inhibitor. Embodiment 2. A TEAD inhibitor for use in the treatment of cancer, wherein the treatment further comprises administration of a KRAS G12D inhibitor. Embodiment 3. A KRAS G12D inhibitor for use in the treatment of cancer, wherein the treatment further comprises administration of a TEAD inhibitor. Embodiment 4. A combination comprising i) a TEAD inhibitor, ii) a KRAS G12D inhibitor, and optionally iii) a SHP2 inhibitor. Embodiment 5. The method according to embodiment 1, the TEAD inhibitor for use according to embodiment 2, the KRAS G12D inhibitor for use according to embodiment 3 or the combination according to embodiment 4, wherein the TEAD inhibitor is a YAP / TAZ-TEAD protein-protein interaction inhibitor. Embodiment 6. The method according to embodiment 1 or embodiment 5, the TEAD inhibitor for use according to embodiment 2 or embodiment 5, the KRAS G12D inhibitor for use according to embodiment 3 or embodiment 5, or the combination according to embodiment 4 or embodiment 5, wherein the TEAD inhibitor is selected from the group consisting of IAG933, 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Compound A), K-975, VT3989, and IK-930. Embodiment 7. The method according to embodiment 6, the TEAD inhibitor for use according to embodiment 6, the KRAS G12D inhibitor for use according to embodiment 6 or the combination according to embodiment 6, wherein the TEAD inhibitor is IAG933. Embodiment 8. The method according to any one of embodiments 1 and 5 to 7, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 7, the KRAS G12D inhibitor for use according to any one of embodiments 3 and 5 to 7, or the combination according to any one of embodiments 4 to 7, wherein the KRAS G12D inhibitor is selected from MRTX1133, TAS-0612, ASP-3082, HRS-4642, KRASG12D1, RMC-9805 and siG12D LODER. Embodiment 9. The method according to embodiment 8, the TEAD inhibitor for use according to embodiment 8, the KRAS G12D inhibitor for use according to embodiment 8 or the combination according to embodiment 8, wherein the KRAS G12D inhibitor is MRTX1133. Embodiment 10. The method according to any one of embodiments 1 and 5 to 9, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 9, or the KRAS G12D inhibitor for use according to any one of embodiments 3 and 5 to 9, wherein the treatment further comprises administration of a SHP2 inhibitor. Embodiment 11. The SHP2 inhibitor is bosiprotafib (RMC-4630), ERAS-601, JAB-3312, JAB-3068, HS-10381, ICP-189, ARRY-558 (PF-07284892), ET-0038 (ETS-001), SH-3809, GDC-1971 (RLY-1971 / RO-7517834 / RG-6433), GH-21 (HBI-2376), BBP-398 (IACS-13909 / IACS-15509), BPI-442096, I-0436650, PC The method according to embodiment 10, the TEAD inhibitor for use according to embodiment 10, the KRAS G12D inhibitor for use according to embodiment 10, or the combination according to any one of embodiments 4 to 9, is selected from the group consisting of C-0208023, IACS-15414, RMC-4550, fumosolinone, TYB-1-17, ML-119, GS-493, GS-458, II-B08, PHPS1, 3-Cl-AHPC (MM-002) and TNO155, preferably selected from the group consisting of JAB-3068, bosiprotafib (RMC-4630), RLY1971 and TNO155. Embodiment 12. The method according to embodiment 11, the TEAD inhibitor for use according to embodiment 11, the KRAS G12D inhibitor for use according to embodiment 11 or the combination according to embodiment 11, wherein the SHP2 inhibitor is TNO155. Embodiment 13. The method according to any one of embodiments 1 and 5 to 12, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 12, or the KRAS G12D inhibitor for use according to any one of embodiments 3 and 5 to 12, wherein the cancer is a TEAD-dependent cancer. Embodiment 14. The method according to any one of embodiments 1 and 5 to 13, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 13, or the KRAS G12D inhibitor for use according to any one of embodiments 3 and 5 to 13, wherein the cancer is a KRAS G12D mutant cancer, such as a KRAS G12D mutant solid tumor. Embodiment 15. The method according to any one of embodiments 1 and 5 to 14, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 14, or the KRAS G12D inhibitor for use according to any one of embodiments 3 and 5 to 14, wherein the cancer is selected from pancreatic ductal adenocarcinoma, colorectal cancer, non-small cell lung cancer, gastric cancer, and ovarian cancer. Embodiment 16. The method according to embodiment 15, the TEAD inhibitor for use according to embodiment 15, or the KRAS G12D inhibitor for use according to embodiment 15, wherein the cancer is KRAS G12D mutant pancreatic ductal adenocarcinoma or KRAS G12D mutant colorectal cancer. Embodiment 17. The method of any one of embodiments 1 and 5 to 16, the TEAD inhibitor for use of any one of embodiments 2 and 5 to 16, or the KRAS inhibitor for use of any one of embodiments 3 and 5 to 16, wherein the TEAD inhibitor (e.g., IAG933) is administered on each of the first three days of a seven-day treatment cycle, and the treatment consists of at least two treatment cycles. Embodiment 18. The method according to any one of embodiments 1 and 5 to 17, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 17, or the KRAS G12D inhibitor for use according to any one of embodiments 3 and 5 to 167, wherein the daily dose of the TEAD inhibitor (e.g., IAG933) on each day of administration is 15 mg to 1500 mg. Embodiment 19. The method, the TEAD inhibitor for use according to embodiment 18, or the KRAS G12D inhibitor for use according to embodiment 18, wherein the daily dose of the TEAD inhibitor (e.g., IAG933) on each day of administration is 100 mg to 1500 mg. Embodiment 20. The daily dose of a TEAD inhibitor (e.g., IAG933) on each day of administration is 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 800 mg, 900 mg, 95 ... 20. The method of embodiment 19, the TEAD inhibitor for use according to embodiment 19, or the KRAS G12D inhibitor for use according to embodiment 19, wherein the dose is 0 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, or 1500 mg.

[0039] definition IAG933 is a YAP / TAZ-TEAD protein-protein interaction inhibitor useful for treating diseases or conditions mediated by YAP overexpression, YAP amplification, and / or YAP / TAZ-TEAD interaction, such as cancers, particularly those with (i) one or more YAP / TAZ fusions, (ii) one or more NF2, LATS1, or LATS2 truncating mutations or deletions, or (iii) one or more functional YAP / TAZ fusions. The synthesis of IAG933 is described in WO 2021 / 186324 (Example 155), which is incorporated by reference.

[0040] IAG933 has the following chemical structure: [ka] and has the chemical name 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide.

[0041] In describing the invention (particularly in the claims below), the terms "a," "an," and "the," and similar references shall be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The plural, when used with respect to compounds, patients, cancers, and the like, shall also refer to a single compound, patient, or the like.

[0042] References herein to the "present invention" are intended to reflect some of the inventive embodiments disclosed herein and should not be construed as unnecessarily limiting the claimed subject matter.

[0043] The term "synergistic effect," as used herein, refers to the action of two or three therapeutic agents that produces a greater effect (e.g., delaying the progression of a proliferative disease, particularly cancer, or its symptoms) than the simple sum of the effects of each drug when administered alone. Synergistic effect can be calculated using suitable methods, such as the Sigmoid-Emax equation (Holford, N.H.G. and Scheiner, L.B., Clin. Pharmacokinet. 6:429-453 (1981)), the Loewe additivity equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114:313-326 (1926)), and the median effect equation (Chou, T.C. and Talalay, P., Adv. Enzyme Regul. 22:27-55 (1984)). Each of the above-mentioned equations can be applied to experimental data to generate corresponding graphs to assist in evaluating the effect of drug combinations. The corresponding graphs associated with the above-referenced equations are the concentration-effect curve, the isobologram curve and the combination index curve, respectively.

[0044] The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds and that are typically not biologically or otherwise undesirable. The compounds may be capable of forming acid addition salts by virtue of the presence of an amino group.

[0045] Unless otherwise indicated or expressly indicated in context, references to therapeutic agents useful in the pharmaceutical combinations of the present invention include both the free base of the compound and all pharmaceutically acceptable salts of the compound.

[0046] A "combination" or "pharmaceutical combination" is defined herein to refer to a fixed combination, a non-fixed combination, or a kit of parts in one unit dosage form for combined administration in which the therapeutic agents can be administered independently and simultaneously, or preferably together separately within a time interval that allows the combination partners to exert a cooperative (e.g., synergistic) effect. Thus, the single compounds of the pharmaceutical combination of the present invention can be administered simultaneously or sequentially.

[0047] Furthermore, the pharmaceutical combination of the present invention may be in the form of a fixed combination or a non-fixed combination.

[0048] The term "fixed combination" means that the therapeutic agents (eg, single compounds of the combination) are in the form of a single entity or dosage form.

[0049] The term "non-fixed combination" means that the therapeutic agents (e.g., single compounds of the combination) are administered to a patient as separate entities or dosage forms either simultaneously or sequentially with no specific time constraints, preferably such administration providing therapeutically effective levels of the two therapeutic agents in the body of a subject (e.g., a mammal or human) in need thereof.

[0050] The pharmaceutical combination may further comprise at least one pharmaceutically acceptable carrier. Thus, the present invention relates to a pharmaceutical composition comprising the pharmaceutical combination of the present invention and at least one pharmaceutically acceptable carrier.

[0051] As used herein, the term "carrier" or "pharmaceutically acceptable carrier" includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, that would be known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0052] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0053] Generally, a "pharmaceutical composition" is defined herein to refer to a mixture or solution containing at least one therapeutic agent administered to a subject (e.g., a mammal or human). The pharmaceutical combination may be formulated in a pharmaceutical composition suitable for enteral or parenteral administration, e.g., in unit dosage forms such as sugar-coated tablets, tablets, capsules, or suppositories, or ampoules. Unless otherwise specified, these are prepared by methods known per se, e.g., by various conventional mixing, milling, direct compression, granulation, sugar-coating, dissolving, lyophilization processes, or manufacturing techniques readily apparent to those skilled in the art. It will be understood that the unit content of a combination partner contained in an individual dose of each dosage form need not necessarily constitute an effective amount, since the required effective amount may be achieved by administration of multiple dosage units. Pharmaceutical compositions may contain from about 0.1% to about 99.9%, preferably from about 1% to about 60%, of a therapeutic agent. Those skilled in the art may select one or more of the aforementioned carriers for the specific desired properties of the dosage form by routine experimentation without any undue burden. The amount of each carrier used may vary within conventional ranges in the art. The following references disclose techniques and excipients used to formulate oral dosage forms: The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003) and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003). These optional additional conventional carriers may be incorporated into the oral dosage form by incorporating one or more conventional carriers into the initial mixture before or during granulation, or by combining one or more conventional carriers with granules containing the drug combination or individual drugs of the drug combination in the oral dosage form.In the latter embodiment, the combined mixture may be further blended, for example, in a V-blender, and then compressed or molded into a tablet (e.g., monolithic tablet), encapsulated in a capsule, or filled into a sachet. Obviously, the pharmaceutical combination of the present invention may be used to manufacture a pharmaceutical product.

[0054] The present invention relates to such pharmaceutical combinations or compositions which are particularly useful as medicaments.

[0055] In particular, the combination or composition of the present invention may be applied in the treatment of cancer.

[0056] The present invention also relates to the use of the pharmaceutical combination or the pharmaceutical composition of the present invention for the preparation of a medicament for the treatment of cancer and to a method of treating cancer in a subject in need thereof, which method comprises administering to the subject a therapeutically effective amount of the pharmaceutical combination according to the present invention or the pharmaceutical composition according to the present invention.

[0057] The term "treatment," as used herein, includes treatment that relieves, reduces, or alleviates at least one symptom of a subject, treatment that prolongs progression-free survival, treatment that prolongs overall survival, treatment that prolongs the duration of response, or treatment that delays progression of a disease. For example, treatment can be the alleviation of one or several symptoms of a disorder or the complete eradication of a disorder, such as cancer. Within the meaning of the present invention, the term "treatment" also refers to arresting, delaying the onset (i.e., the period before clinical symptoms of the disease) and / or reducing the risk of developing or worsening a disease in a patient, e.g., a mammal; in particular, the patient is a human. The term "treatment," as used herein, includes direct inhibition of primary tumor growth and / or inhibition of tumor growth incorporating systemic inhibition of metastatic cancer cells.

[0058] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets.

[0059] As used herein, a subject is "in need of" or "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0060] The term "comprising" encompasses "including" and "consisting of," e.g., a composition comprising X can be exclusive of X or can include additional items (e.g., X and Y).

[0061] The term "therapeutically effective amount" of a compound of the invention (e.g., a chemical entity or biological agent) refers to the amount of a compound of the invention that elicits a biological or medical response in a subject, such as eliciting a reduction or inhibition of enzyme or protein activity, or ameliorating a symptom, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease. In one embodiment, a therapeutically effective amount in vivo can range from about 0.1 to 500 mg / kg or from about 1 to 100 mg / kg, depending on the route of administration.

[0062] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0063] The optimal dosage of each combination partner for treating cancer can be empirically determined for each individual using known methods and will depend on various factors, including, but not limited to, the extent of disease progression, the individual's age, weight, general health, sex, and diet, the time and route of administration, and other medications the individual is taking. Optimal dosages can be established using routine testing and procedures known in the art. The amount of each combination partner that can be combined with a carrier material to produce a single dosage form will vary depending on the individual being treated and the specific mode of administration. In some embodiments, a unit dosage form containing the drug combinations described herein will contain the amount of each drug of the combination that would typically be administered if the drug were administered alone.

[0064] The frequency of dosing can vary depending on the compound used and the particular condition being treated or prevented. Generally, use of the minimum dosage sufficient to provide effective therapy is preferred. Patients can generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those skilled in the art.

[0065] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or to other parts of the body through the bloodstream and lymphatic system. Examples of various cancers are described herein, including, but not limited to, colorectal cancer, gastric cancer, endometrial cancer, prostate cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, ovarian cancer, etc.

[0066] The terms "tumor" and "cancer" are used interchangeably herein, e.g., both terms encompass solid and liquid tumors, e.g., diffuse or circulating tumors. As used herein, the term "cancer" or "tumor" includes pre-cancerous and malignant cancers and tumors.

[0067] As used herein, the term "TEAD-dependent cancer" refers to any cancer in which TEAD (i.e., TEAD1, TEAD2, TEAD3 and / or TEAD4) or mutants or variants thereof are known to be implicated, for example, in cancers in which the Hippo pathway is genetically altered.

[0068] As used herein, the term "TEAD inhibitor" refers to a compound that has activity as an inhibitor of TEAD (i.e., TEAD1, TEAD2, TEAD3, and / or TEAD4) or a mutant or variant thereof, which can be assayed in vitro, in vivo, or in a cell line. In one example, an IC50 inhibitor is detected in the biochemical assay described in WO 2021 / 186324, and / or the reporter gene cell assay described in WO 2021 / 186324, and / or the proliferation cell assay described in WO 2021 / 186324. 50 [μM] is <10, for example <5, for example <2, for example <1, for example <0.5, for example <0.2, for example <0.1. WO 2021 / 186324 is incorporated herein by reference.

[0069] The YAP / TAZ-TEAD protein-protein interaction inhibitor described herein refers to a TEAD inhibitor that inhibits TEAD activity by inhibiting the interaction between the YAP / TAZ complex and TEAD. Overactivation of YAP / TAZ, which leads to TEAD activation, has been reported in many cancers, such as malignant pleural mesothelioma. Therefore, inhibiting the interaction between YAP / TAZ and TEAD is a promising mechanism for inhibiting TEAD activity.

[0070] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2021 / 087008.

[0071] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2021 / 102204.

[0072] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2020 / 214734.

[0073] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2020 / 097389.

[0074] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2019 / 222431.

[0075] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2019 / 113236.

[0076] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2019 / 040380.

[0077] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2018 / 204532.

[0078] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2017 / 058716.

[0079] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2022 / 159986.

[0080] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2022 / 120354.

[0081] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2022 / 120355.

[0082] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2022 / 120353.

[0083] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2020 / 243423.

[0084] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2020 / 243415.

[0085] In one embodiment, the TEAD inhibitor is IAG933, i.e., 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide. IAG933 has the following structure: [ka] Another chemical name for IAG933 is (4P)-4-{(2S)-5-chloro-6-fluoro-2-phenyl-2-[(2S)-pyrrolidin-2-yl]-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy)-N-methylpyridine-3-carboxamide.

[0086] In one embodiment, the TEAD inhibitor is Compound A, i.e., 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide. Compound A has the following structure: [ka] Another chemical name for Compound A is (2P)-2-{(2S,3S)-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-methoxybenzamide.

[0087] The synthesis and characterization of IAG933 (Example 155) and Compound A (Example 144) are described in WO 2021 / 186324, which is incorporated herein by reference.

[0088] In one embodiment where TNO155 is present as part of a method or combination, TNO155 is administered orally at a dose of about 1.5 mg per day, or 3 mg per day, or 6 mg per day, or 10 mg per day, or 20 mg per day, or 30 mg per day, or 40 mg per day, or 50 mg per day, or 60 mg per day, or 70 mg per day, or 80 mg per day, or 90 mg per day, or 100 mg per day.

[0089] In one embodiment where TNO155 is present as part of the method or combination, the daily dose of TNO155 is in a 21 day cycle of two weeks on medication followed by one week off medication.

[0090] In one embodiment where TNO155 is present as part of the method or combination, the daily dose of TNO155 is 20 mg.

[0091] In one embodiment where TNO155 is present as part of the method or combination, the dosing schedule for TNO155 is once daily (QD) or twice daily (BID).

[0092] In one embodiment where TNO155 is present as part of a method or combination, TNO155 is administered orally.

[0093] In one embodiment where MRTX1133 is present as part of a method or combination, MRTX1133 is administered orally. In an alternative embodiment, MRTX1133 is administered intravenously.

[0094] "Zwitterion" or "zwitterionic form" refers to a compound that contains both positively charged and negatively charged functional groups.

[0095] 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 to which this invention belongs.

[0096] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention and does not limit the scope of the invention as otherwise claimed.

[0097] Isomers Any asymmetric atom (e.g., carbon or the like) of the compound that can be used in the present invention can be present in a racemic form or enriched in one enantiomer, for example, in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in the (R)- or (S)-configuration. Substituents on atoms with unsaturated double bonds can be present in cis-(Z)- or trans-(E)-form, if possible.

[0098] Thus, as used herein, the compounds that may be used in the present invention may exist in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0099] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization on the basis of the physical chemical differences of the constituent components.

[0100] Any resulting racemic forms of the compounds or intermediates that can be used in the present invention can be resolved into their optical antipodes by known methods, for example, by separating their diastereomeric salts obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. In particular, compounds that can be used in the present invention can be resolved into their optical antipodes by, for example, fractional crystallization of salts formed with optically active acids (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid) using such basic moieties. Racemic compounds or racemic intermediates that can be used in the present invention can also be resolved by chiral chromatography (e.g., high-pressure liquid chromatography (HPLC) using a chiral adsorbent).

[0101] The compounds that can be used in the present invention (i.e., compounds of formula (I) that contain groups that can act as donors and / or acceptors for hydrogen bonds) may be capable of forming co-crystals with a suitable co-crystal former. The co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting a compound of formula (I) in solution with a co-crystal former under crystallization conditions and isolating the co-crystal thereby formed. Suitable co-crystal formers include those described in WO 2004 / 078163.

[0102] Furthermore, the compounds (including their salts) that can be used in the present invention can also be obtained in the form of their hydrates, or can include other solvents used in their crystallization. The compounds of the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (e.g., water). The term "solvate" refers to a molecular complex of a compound (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are commonly used in the pharmaceutical field and are known to be harmless to recipients, such as water, ethanol, and the like. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0103] Dosage form The combination of the present invention may be, for example, a unit dosage of about 1 to 2000 mg of each active ingredient for a subject of about 50 to 70 kg.

[0104] It should be understood that "administered on each of the first 3 days of a 7-day treatment cycle" means that the TEAD inhibitor or a pharmaceutically acceptable salt thereof is administered on each of the first 3 days of a 7-day treatment cycle, but not on the subsequent 4 days of the 7-day treatment cycle.

[0105] Preferably, at least two treatment cycles are consecutive, i.e., the second treatment cycle immediately follows the first treatment cycle. Thus, for example, the present invention includes: Days 1-3: TEAD inhibitors administered daily; Days 4-7: No TEAD inhibitor administered, Days 8-10: TEAD inhibitor administered daily, and Days 11-14: No TEAD inhibitor administered.

[0106] In this example, days 1-3 and days 8-10 are administration days. Thus, "administration day" refers to any day on which a TEAD inhibitor is administered to a patient.

[0107] If present, the third (fourth, etc.) treatment cycle preferably follows immediately after the previous treatment cycle. Thus, in one embodiment where there are three treatment cycles, the present invention includes: Days 1-3: TEAD inhibitors administered daily; Days 4-7: No TEAD inhibitor administered, Days 8-10: TEAD inhibitor administered daily; Days 11-14: No TEAD inhibitor administered, Days 15-17: TEAD inhibitors administered daily, and Days 18-21: No TEAD inhibitor administered.

[0108] In one embodiment, there are three or more treatment cycles, such as four or more treatment cycles, for example five or more treatment cycles, such as six or more treatment cycles, for example eight or more treatment cycles, such as ten or more treatment cycles.

[0109] In alternative embodiments, the TEAD inhibitor is administered on day 2 of a 6-day or 7-day treatment cycle, and the treatment comprises at least two treatment cycles, e.g., i) days 1 and 4 of a 6-day schedule, or ii) days 1 and 4 of a 7-day schedule, e.g., days 1 and 4 of a 7-day schedule.

[0110] As used herein, the term "daily dose" (e.g., of a TEAD inhibitor) refers to the total dose (e.g., of a TEAD inhibitor) administered to an individual in one 24-hour period.

[0111] As used herein, reference to a dose (e.g., of a TEAD inhibitor) in mg (milligrams) means an (equivalent) amount (e.g., TEAD inhibitor) in free form (i.e., excluding, for example, a salt or co-crystal partner, as well as any solvent present).

[0112] Preferably, the TEAD inhibitor is provided in the form of an oral dosage form, more preferably in the form of a solid oral dosage form, such as a capsule or tablet.

[0113] Preferably, the TEAD inhibitor is taken with a glass of water without chewing the capsule or tablet.

[0114] If a patient is assigned to a dose level in which multiple capsules / tablets of a TEAD inhibitor are taken, the TEAD inhibitor capsules / tablets should be taken consecutively within as short a time interval as possible, e.g., within 5 minutes.

[0115] Preferably, the TEAD inhibitor is administered at approximately the same time on each administration day. Preferably, the TEAD inhibitor is administered once daily on each administration day. More preferably, the TEAD inhibitor is administered in the morning.

[0116] Preferably, the TEAD inhibitor is administered in the fasted state, ie, at least 1 hour before or 2 hours after a meal.

[0117] combination "Combination" refers to a fixed combination in one unit dosage form or to combined administration in which a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a combination partner (e.g., another drug, as described below, also referred to as a "therapeutic agent" or "adjuvant") are administered simultaneously and independently or separately within a time interval (particularly, these time intervals allow the combination partners to exhibit a cooperative effect, e.g., a synergistic effect). The single components may be packaged in a kit or individually. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose before administration. The terms "co-administration" or "administration in combination," or the like, as used herein, are meant to encompass the administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination," as used herein, refers to a product resulting from the mixing or combining of multiple therapeutic agents, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that both therapeutic agents (e.g., combination partners of the present invention) are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that both therapeutic agents (e.g., combination partners of the present invention) are administered to a patient as separate entities simultaneously, in parallel, or sequentially with no specific time limit, such administration resulting in therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy (e.g., administration of three or more therapeutic agents).

[0118] In the combination therapies of the present invention, the therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the therapeutic agents may (i) be combined into a combination therapy prior to delivery of the combination product to the physician (e.g., in the case of a kit containing the therapeutic agents), (ii) be combined into a combination therapy by the physician (or under the physician's supervision) immediately prior to administration, or (iii) be combined into a combination therapy by the patient themselves, e.g., during sequential administration of the therapeutic agents. [Example]

[0119] Example 1 In vitro viability of the KRAS G12D mutant pancreatic ductal adenocarcinoma cell line HPAF-II was assessed using CellTiterGlo after 6 days of treatment with IAG933 in combination with MRTX1133 (±TNO155). Growth of HPAF-II cells was inhibited by IAG933 alone and MRTX1133 alone. Furthermore, the combination of IAG933 and MRTX1133 demonstrated synergistic growth inhibition compared with either treatment alone. Further combination with TNO155 provided additional combinatorial benefit (Figure 1).

[0120] Example 2 In vitro viability of the KRAS G12D mutant pancreatic ductal adenocarcinoma cell line ASPC-1 was assessed using CellTiterGlo after 6 days of treatment with IAG933 in combination with MRTX1133 (±TNO155). ASPC-1 cell proliferation was inhibited by IAG933 alone and MRTX1133 alone. Furthermore, the combination of IAG933 and MRTX1133 demonstrated synergistic growth inhibition compared with either treatment alone. Further combination with TNO155 provided additional combination benefit (Figure 2).

[0121] Example 3 In vitro viability of the KRAS G12D mutant pancreatic ductal adenocarcinoma cell line SW1990 was assessed using CellTiterGlo after 6 days of treatment with IAG933 in combination with MRTX1133 (±TNO155). Growth of SW1990 cells was inhibited by IAG933 alone and MRTX1133 alone. Furthermore, the combination of IAG933 and MRTX1133 demonstrated synergistic growth inhibition compared with either treatment alone. Further combination with TNO155 provided additional combination benefit (Figure 3).

[0122] Example 4 The combination of IAG933 and MRTX1133 (Figure 4) results in enhanced growth control compared to IAG933 alone in an ASPC-1 KRAS G12D mutant pancreatic ductal adenocarcinoma model. The addition of TNO155 (triple combination) further reduces cell growth upon compound washout in both combinations. Growth was monitored using an Incucyte® S3 live cell analyzer (Sartorius). Compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with media refreshed once a week.

[0123] Example 5 The combination of IAG933 and MRTX1133 (Figure 5) results in enhanced growth control over IAG933 alone in the GP2D KRAS G12D colorectal cancer model. The additional inclusion of TNO155 further reduces cell growth upon compound washout in both combinations. Growth was monitored using an Incucyte® S3 live cell analyzer (Sartorius). Compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with media refreshed once a week.

[0124] Example 6 The combination of IAG933 and MRTX1133 (Figure 6) resulted in enhanced growth control compared to IAG933 alone in an HPAF-II KRAS G12D mutant pancreatic ductal adenocarcinoma model. The additional inclusion of TNO155 completely abolished cell growth upon compound washout in both combinations. Growth was monitored using an Incucyte® S3 live cell analyzer (Sartorius). Compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with media refreshed once a week.

Claims

1. 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a TEAD inhibitor in combination with a KRAS G12D inhibitor.

2. 1. A TEAD inhibitor for use in the treatment of cancer, wherein said treatment further comprises administration of a KRAS G12D inhibitor.

3. 1. A KRAS G12D inhibitor for use in the treatment of cancer, wherein said treatment further comprises administration of a TEAD inhibitor.

4. A combination comprising i) a TEAD inhibitor, ii) a KRAS G12D inhibitor, and optionally iii) a SHP2 inhibitor.

5. The method of claim 1, the TEAD inhibitor for use according to claim 2, the KRAS G12D inhibitor for use according to claim 3, or the combination according to claim 4, wherein the TEAD inhibitor is a YAP / TAZ-TEAD protein-protein interaction inhibitor.

6. The method of claim 1 or 5, the TEAD inhibitor for use according to claim 2 or 5, the KRAS G12D inhibitor for use according to claim 3 or 5, or the combination according to claim 4 or 5, wherein the TEAD inhibitor is selected from the group consisting of IAG933, (2P)-2-{(2S,3S)-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-methoxybenzamide (Compound A), K-975, VT3989, and IK-930.

7. 7. The method according to claim 6, the TEAD inhibitor for use according to claim 6, the KRAS G12D inhibitor for use according to claim 6 or the combination according to claim 6, wherein the TEAD inhibitor is IAG933.

8. The method of any one of claims 1 or 5 to 7, the TEAD inhibitor for use of any one of claims 2 or 5 to 7, the KRAS G12D inhibitor for use of any one of claims 3 or 5 to 7, or the combination of any one of claims 4 to 7, wherein the KRAS G12D inhibitor is selected from MRTX1133, TAS-0612, ASP-3082, HRS-4642, KRASG12D1, RMC-9805 and siG12D LODER.

9. 9. The method of claim 8, the TEAD inhibitor for use according to claim 8, the KRAS G12D inhibitor for use according to claim 8 or the combination according to claim 8, wherein the KRAS G12D inhibitor is MRTX1133.

10. The method of any one of claims 1 or 5 to 9, the TEAD inhibitor for use of any one of claims 2 or 5 to 9, or the KRAS G12D inhibitor for use of any one of claims 3 or 5 to 9, wherein the treatment further comprises administration of an SHP2 inhibitor.

11. The SHP2 inhibitors include bosiprotafib (RMC-4630), ERAS-601, JAB-3312, JAB-3068, HS-10381, ICP-189, ARRY-558 (PF-07284892), ET-0038 (ETS-001), SH-3809, GDC-1971 (RLY-1971 / RO-7517834 / RG-6433), GH-21 (HBI-2376), BBP-398 (IACS-13909 / IACS-15509), BPI-442096, I-0436650, and PCC 11. The method of claim 10, the TEAD inhibitor for use according to claim 10, the KRAS G12D inhibitor for use according to claim 10 or the combination according to any one of claims 4 to 9, wherein the inhibitor is selected from the group consisting of: IACS-0208023, IACS-15414, RMC-4550, fumosolinone, TYB-1-17, ML-119, GS-493, GS-458, II-B08, PHPS1, 3-Cl-AHPC (MM-002) and TNO155, and preferably selected from the group consisting of JAB-3068, bosiprotafib (RMC-4630), RLY1971 and TNO155.

12. 12. The method of claim 11, the TEAD inhibitor for use according to claim 11, the KRAS G12D inhibitor for use according to claim 11 or the combination according to claim 11, wherein the SHP2 inhibitor is TNO155.

13. The method according to any one of claims 1 or 5 to 12, the TEAD inhibitor for use according to any one of claims 2 or 5 to 12, or the KRAS G12D inhibitor for use according to any one of claims 3 or 5 to 12, wherein the cancer is a TEAD-dependent cancer.

14. The method of any one of claims 1 or 5 to 13, the TEAD inhibitor for use of any one of claims 2 or 5 to 13, or the KRAS G12D inhibitor for use of any one of claims 3 or 5 to 13, wherein the cancer is a KRAS G12D mutant cancer, such as a KRAS G12D mutant solid tumor.

15. The method of any one of claims 1 or 5 to 14, the TEAD inhibitor for use of any one of claims 2 or 5 to 14, or the KRAS G12D inhibitor for use of any one of claims 3 or 5 to 14, wherein the cancer is selected from pancreatic ductal adenocarcinoma, colorectal cancer, non-small cell lung cancer, gastric cancer, and ovarian cancer.

16. 16. The method according to claim 15, the TEAD inhibitor for use according to claim 15, or the KRAS G12D inhibitor for use according to claim 15, wherein the cancer is KRAS G12D mutant pancreatic ductal adenocarcinoma or KRAS G12D mutant colorectal cancer.

17. The method of any one of claims 1 or 5-16, the TEAD inhibitor for use of any one of claims 2 or 5-16, or the KRAS inhibitor for use of any one of claims 3 or 5-16, wherein the TEAD inhibitor (e.g., IAG933) is administered on each of the first three days of a seven-day treatment cycle, and the treatment consists of at least two treatment cycles.

18. 16. The method of any one of claims 1 or 5 to 17, the TEAD inhibitor for use of any one of claims 2 or 5 to 17, or the KRAS G12D inhibitor for use of any one of claims 3 or 5 to 167, wherein the daily dose of the TEAD inhibitor (e.g., IAG933) on each day of administration is 15 mg to 1500 mg.

19. 19. The method of claim 18, the TEAD inhibitor for use according to claim 18, or the KRAS G12D inhibitor for use according to claim 18, wherein the daily dose of the TEAD inhibitor (e.g., IAG933) on each day of administration is 100 mg to 1500 mg.

20. The daily dose of the TEAD inhibitor (e.g., IAG933) on each administration day may be 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 105 ...

20. The method of claim 19, the TEAD inhibitor for use according to claim 19, or the KRAS G12D inhibitor for use according to claim 19, wherein the dose is 0 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, or 1500 mg.

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