Combination of TEAD inhibitors and HER2 inhibitors for treatment of cancer

Abstract

The present invention relates to a pharmaceutical combination comprising a combination of a TEAD inhibitor and a HER2 inhibitor, and a method of treating cancer using the combination.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical combination comprising a TEAD inhibitor in combination with a HER2 inhibitor, and a method for treating cancer using the combination. Background Art

[0002] The advent of targeted cancer therapies has extended lifespans for patients with various malignancies and has helped to understand the complexity of tumors by enabling insights into mechanisms of drug resistance. Clinical responses to targeted agents are often incomplete and / or transient, a fact that can be broadly divided into two categories: toxicities that prevent optimal drug delivery and thus limit target engagement (Brana and Siu 2012; Chapman, Solit et al. 2014), and the ability of cancer to adapt to perturbations and maintain its proliferative potential (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). Combinations of drugs can address both of these factors by improving overall efficacy and simultaneously targeting tumor robustness and complexity to counteract resistance (Robert, Karaszewska, et al. 2015; Turner, Ro, et al. 2015). It remains unclear how many drugs, and which processes, must be targeted in combination to overcome a particular type of cancer. However, it is almost certain that different pathways or drivers will need to be inhibited, likely requiring two or more drugs (Bozic, Reiter, et al. 2013).

[0003] While a variety of treatment options are available for patients with certain types of cancer, there remains a need for effective and safe combination therapies that can be administered to treat cancer. Summary of the Invention

[0004] The present invention aims to provide an agent to improve the treatment of cancer, in particular by inhibiting cell growth (proliferation) and / or inducing apoptosis (cell death). The present invention also aims to identify novel combination therapies that selectively and synergistically enhance the inhibition of proliferation and / or the induction of apoptosis.

[0005] Surprisingly, it has been found that drug combinations comprising i) a TEAD inhibitor and ii) a HER2 inhibitor can synergistically enhance the inhibition of cancer proliferation and / or the induction of cancer cell apoptosis, as demonstrated in the Examples.

[0006] Thus, according to a first aspect of the present invention, there is hereby provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of a TEAD inhibitor and a HER2 inhibitor.

[0007] According to a second aspect of the present invention, there is provided a TEAD inhibitor for use in the treatment of cancer, wherein the treatment further comprises administering a HER2 inhibitor.

[0008] According to a third aspect of the present invention, there is provided a HER2 inhibitor for use in the treatment of cancer, wherein the treatment further comprises administering a TEAD inhibitor.

[0009] According to a fourth aspect of the present invention, there is provided a combination comprising i) a TEAD inhibitor, ii) a HER2 inhibitor and optionally iii) a SHP2 inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 In vitro viability of the gastric cancer cell line RERF-GC-1B was assessed using CellTiterGlo after 7 days of treatment with (top) the combination of IAG933 and lapatinib, (middle) the combination of IAG933 and TNO155, and (bottom) the combination of IAG933, lapatinib, and 200 nM TNO155. Growth inhibition was normalized to growth on day 0 (drug treatment). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0011] Figure 2 In vitro viability of the gastric cancer cell line SNU-216 was assessed using CellTiterGlo after 7 days of treatment with (top) the combination of IAG933 and lapatinib, (middle) the combination of IAG933 and TNO155, and (bottom) the combination of IAG933, lapatinib, and 200 nM TNO155. Growth inhibition was normalized to growth on day 0 (drug treatment). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0012] Figure 3In vitro viability of the gastric cancer cell line NCI-N87 was assessed using CellTiterGlo after 7 days of treatment with (top) the combination of IAG933 and lapatinib, (middle) the combination of IAG933 and TNO155, and (bottom) the combination of IAG933, lapatinib, and 200 nM TNO155. Growth inhibition was normalized to growth on day 0 (drug treatment). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0013] Figure 4 In vitro viability of the gastric cancer cell line MKN-7 was assessed using CellTiterGlo after 7 days of treatment with (top) the combination of IAG933 and lapatinib, (middle) the combination of IAG933 and TNO155, and (bottom) the combination of IAG933, lapatinib, and 200 nM TNO155. Growth inhibition was normalized to growth on day 0 (drug treatment). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0014] Figure 5 In vitro viability of the non-small cell lung cancer cell line NCI-H2170 was assessed using CellTiterGlo after 7 days of treatment with (top) the combination of IAG933 and lapatinib, (middle) the combination of IAG933 and TNO155, and (bottom) the combination of IAG933, lapatinib, and 200 nM TNO155. Growth inhibition was normalized to growth on day 0 (drug treatment). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0015] Figure 6 In vitro viability of the non-small cell lung cancer cell line CALU-3 was assessed using CellTiterGlo after 7 days of treatment with (top) the combination of IAG933 and lapatinib, (middle) the combination of IAG933 and TNO155, and (bottom) the combination of IAG933, lapatinib, and 200 nM TNO155. Growth inhibition was normalized to growth on day 0 (drug treatment). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0016] Figure 7In vitro viability of the endometrial cell line TEN was assessed using CellTiterGlo after 7 days of treatment with (top) the combination of IAG933 and lapatinib and (bottom) the combination of IAG933, lapatinib, and 200 nM MTNO155. Growth inhibition was normalized to growth on day 0 (drug treatment). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0017] Figure 8 CellTiterGlo was used to assess in vitro viability of the esophageal cell line OE-19 following 7-day treatment with (top) the combination of IAG933 and lapatinib, and (bottom) the combination of IAG933, lapatinib, and 200 nM MTNO155. Growth inhibition was normalized to growth on day 0 (drug treatment). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0018] Figure 9 CellTiterGlo was used to assess in vitro viability of the esophageal cell line TE-4 following 7-day treatment with (top) the combination of IAG933 and lapatinib, and (bottom) the combination of IAG933, lapatinib, and 200 nM MTNO155. Growth inhibition was normalized to growth on day 0 (drug treatment). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0019] Figure 10 Figure 3: Confluence of SNU-216 gastric cancer cells after treatment with the indicated compounds at the indicated concentrations. Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and media was refreshed weekly. Confluence was monitored in real time using the Incucyte® S3 Live Cell Analyzer (Sartorius).

[0020] Figure 11 Figure 3: Confluence of the Calu-3 non-small cell lung cancer cell line after treatment with the indicated compounds at the indicated concentrations. Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and medium was refreshed weekly. Confluence was monitored in real time using the Incucyte® S3 Live Cell Analyzer (Sartorius).

[0021] Figure 12(Top): Images showing cell number and % dead cells (Cytotox dye (Sartorius)) at 96 h in SNU-216 and NCI-N87 gastric cancer cells. Cells were monitored in real time, and cell number and % dead cells were counted using the cell-by-cell module of the Incucyte® S3 Live Cell Analyzer (Sartorius).

[0022] (Bottom): Clonogenicity assays with crystal violet staining in SNU-216 and MKN-7 gastric cancer cells treated with the indicated compounds at the indicated concentrations for 38 days. IAG933 + lapatinib, 600 nM IAG933 and 100 nM lapatinib. IAG(933) + TNO(155) + lapatinib, 600 nM IAG933, 200 nM TNO155, and 100 nM lapatinib.

[0023] Figure 13 Figure 3: Confluence of the NCI-N87 gastric cancer cell line after treatment with the indicated compounds at the indicated concentrations. Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and media was refreshed weekly. Confluence was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius).

[0024] Figure 14 Figure 3: Confluence of MKN-7 gastric cancer cell lines after treatment with the indicated compounds at the indicated concentrations. Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and medium was refreshed weekly. Confluence was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius).

[0025] Figure 15 Figure 3: Confluence of the RERF-GC-1B gastric cancer cell line after treatment with the indicated compounds at the indicated concentrations. Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and media was refreshed weekly. Confluence was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius).

[0026] Figure 16 Figure 3: Confluence of the NCI-H2170 non-small cell lung cancer cell line after treatment with the indicated compounds at the indicated concentrations. Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and media was refreshed weekly. Confluence was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius).

[0027] Figure 17In vitro viability of the gastric cancer cell line SNU-216 (top) and the non-small cell lung cancer cell line NCI-H2170 (bottom) was assessed using CellTiterGlo after 6 days of treatment with a combination of Compound A and lapatinib. Growth inhibition was normalized to growth on day 0 (drug treatment day). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0028] Figure 18 In vitro viability of the gastric cancer cell line SNU-216 (top) and the non-small cell lung cancer cell line NCI-H2170 (bottom) was assessed using CellTiterGlo after 6 days of treatment with the combination of Compound B and lapatinib. Growth inhibition was normalized to growth on day 0 (drug treatment day). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0029] Figure 19 In vitro viability of the gastric cancer cell line SNU-216 (top) and the non-small cell lung cancer cell line NCI-H2170 (bottom) was assessed using CellTiterGlo after 6 days of treatment with the combination of Compound C and lapatinib. Growth inhibition was normalized to growth on day 0 (drug treatment day). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0030] Figure 20 In vitro viability of the gastric cancer cell line SNU-216 (top) and the non-small cell lung cancer cell line NCI-H2170 (bottom) was assessed using CellTiterGlo after 6 days of treatment with the combination of Compound D and lapatinib. Growth inhibition was normalized to growth on day 0 (drug treatment day). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = decreased cell number / cell death.

[0031] Figure 21 Figure 3: Confluence of the EFM192A breast cancer (HR+ / HER2+) cell line after treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed every 7 days. Culture medium was also refreshed weekly. Confluence was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius).

[0032] Figure 22Figure 3: Confluence of the OE-19 esophageal cancer cell line after treatment with the indicated compounds at the indicated concentrations. Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and media was refreshed weekly. Confluence was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius).

[0033] Figure 23 Figure 3: Confluence of the TEN endometrial cancer cell line after treatment with the indicated compounds at the indicated concentrations. Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and media was refreshed weekly. Confluence was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius).

[0034] Figure 24 Female nude mice bearing subcutaneous NCI-H2170 HER2-amplified lung cancer xenografts were treated with single agents or combinations of agents as indicated in the figure legends. IAG933 was administered orally, while hIgG1 and trastuzumab were administered intraperitoneally.

[0035] Figure 25 Female SCID mice bearing subcutaneous NCI-N87 HER2-amplified gastric cancer xenografts were treated with single agents or combinations of agents as indicated in the figure legends. Compound E was administered orally, while hIgG1 and trastuzumab were administered intraperitoneally.

[0036] Figure 26 : Induction of pro-apoptotic proteins such as BIM and BMF (mRNA and protein) can be detected by gene expression analysis (mRNA) and Western blotting (protein). (“IAG” in the figure legend refers to IAG933, and “LAP” in the figure legend refers to lapatinib.)

[0037] Figure 27 In vitro viability of the breast cancer (HR+ / HER2+) cell line EFM192A was assessed using CellTiterGlo after 6 days of treatment with (top) the combination of IAG933 and lapatinib, (middle) the combination of fulvestrant and lapatinib plus 600 nM IAG933, and (bottom) the combination of IAG933, lapatinib, and 200 nM TNO155. Growth inhibition was normalized to growth on day 0 (drug treatment). % Growth Inhibition: 0-99 = delayed proliferation, 100 = growth arrest / arrest, 101-200 = decreased cell number / cell death. DETAILED DESCRIPTION

[0038] As mentioned above, the object of the present invention is to find new combination therapies that selectively and synergistically enhance the inhibition of proliferation and / or the induction of apoptosis.

[0039] Thus, according to a first aspect of the present invention, there is hereby provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of a TEAD inhibitor and a HER2 inhibitor.

[0040] According to a second aspect of the present invention, there is provided a TEAD inhibitor for use in the treatment of cancer, wherein the treatment further comprises administering a HER2 inhibitor.

[0041] According to a third aspect of the present invention, there is provided a HER2 inhibitor for use in the treatment of cancer, wherein the treatment further comprises administering a TEAD inhibitor.

[0042] According to a fourth aspect of the present invention, there is provided a combination comprising i) a TEAD inhibitor, ii) a HER2 inhibitor and optionally iii) a SHP2 inhibitor.

[0043] Surprisingly, the combination of a TEAD inhibitor and a HER2 inhibitor (and further combinations with or without a SHP2 inhibitor) was found to be synergistic in multiple cancer models.

[0044] In an embodiment, the TEAD inhibitor is a YAP / TAZ-TEAD protein-protein interaction inhibitor.

[0045] In an 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), N-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (Compound B), N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide (Compound C), 3-bromo-5-(3-(4-chlorophenoxy)-4-methylphenyl)-4,5-dihydroisoxazole (Compound D), VT3989 and IK-930.

[0046] In an embodiment, the TEAD inhibitor is IAG933.

[0047] In an embodiment, the HER2 inhibitor is an anti-HER2 antibody. In an embodiment, the anti-HER2 antibody is trastuzumab.

[0048] In an embodiment, the HER2 inhibitor is selected from the list consisting of lapatinib, neratinib, tucatinib, trastuzumab, pyrotinib, afatinib, pertuzumab, magituximab, canertinib, dacomitinib, sabutinib, muritinib, poziotinib, detrastuzumab and ado-enmetrastuzumab.

[0049] In preferred embodiments, the HER2 inhibitor is lapatinib (eg, lapatinib ditosylate, eg, lapatinib ditosylate monohydrate).

[0050] In preferred embodiments, the HER2 inhibitor is lapatinib (eg, lapatinib ditosylate, eg, lapatinib ditosylate monohydrate), and the TEAD inhibitor is IAG933.

[0051] In embodiments, the treatment or combination further comprises administering a SHP2 inhibitor.

[0052] In an embodiment, the SHP2 inhibitor is selected from the group consisting of: Vociprotafib (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, preferably selected from the group consisting of JAB-3068, viciprostafil (RMC-4630), RLY1971 and TNO155.

[0053] In embodiments, the SHP2 inhibitor is TNO155.

[0054] In embodiments, the SHP2 inhibitor is TNO155, the HER2 inhibitor is lapatinib (eg, lapatinib ditosylate, eg, lapatinib ditosylate monohydrate), and the TEAD inhibitor is IAG933.

[0055] In embodiments, the cancer is a TEAD-dependent cancer.

[0056] In an embodiment, the cancer is selected from breast cancer (e.g., HER2+ breast cancer, e.g., HER2+ / HR+ breast cancer, e.g., HER2+ / ER+ breast cancer or HER2+ / ER- breast cancer), gastric cancer (e.g., gastric cancer, e.g., gastric adenocarcinoma, e.g., gastric tubular adenocarcinoma), lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma, e.g., esophagogastric junction cancer), uterine cancer, cervical cancer, bladder cancer, pancreatic cancer, colorectal cancer, ovarian cancer, head and neck cancer, thymoma, and liver cancer.

[0057] In embodiments, the cancer is breast cancer (eg, HER2+ breast cancer, eg, HER2+ / HR+ breast cancer, eg, HER2+ / ER+ breast cancer or HER2+ / ER- breast cancer).

[0058] In preferred embodiments, the cancer is a HER2-positive cancer.

[0059] In preferred embodiments, the cancer is i) a HER2 amplified cancer, and / or ii) a HER2 mutant cancer and / or iii) said cancer has overexpression of HER2 protein.

[0060] In an embodiment, a TEAD inhibitor (e.g., IAG933) is administered on each of the first three days of a seven-day treatment cycle, and wherein the treatment consists of at least two treatment cycles. In an alternative embodiment, a TEAD inhibitor (e.g., IAG933) is administered on two days (e.g., day 1 and day 4) of a six-day or seven-day (e.g., seven-day) treatment cycle, and wherein the treatment comprises at least two treatment cycles.

[0061] In an embodiment, the daily dose of the TEAD inhibitor (eg, IAG933) is 15 mg to 1500 mg per administration day. In an embodiment, the daily dose of the TEAD inhibitor (eg, IAG933) is 100 mg to 1500 mg per administration day. In an embodiment, the daily dose of a TEAD inhibitor (e.g., IAG933) on each administration day 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg. mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg or 1500 mg.

[0062] In embodiments, the HER2 inhibitor (eg, lapatinib) is administered daily.

[0063] In embodiments, the daily dose of the HER2 inhibitor (eg, lapatinib) is 500 to 2000 mg (eg, 1250 to 1500 mg, eg, 1250 mg or 1500 mg).

[0064] In an embodiment, the combination is not fixed.

[0065] In embodiments, the treatment further comprises administration of letrozole.

[0066] Therefore, the present invention provides the following numbered embodiments:

[0067] Example 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a TEAD inhibitor and a HER2 inhibitor.

[0068] Example 2. A TEAD inhibitor for use in the treatment of cancer, wherein the treatment further comprises administering a HER2 inhibitor.

[0069] Example 3. A HER2 inhibitor for use in the treatment of cancer, wherein the treatment further comprises administering a TEAD inhibitor.

[0070] Example 4. A combination comprising i) a TEAD inhibitor, ii) a HER2 inhibitor and optionally iii) a SHP2 inhibitor.

[0071] Example 5. The method of Example 1, the TEAD inhibitor for use according to Example 2, the HER2 inhibitor for use according to Example 3, or the combination according to Example 4, wherein the TEAD inhibitor is a YAP / TAZ-TEAD protein-protein interaction inhibitor.

[0072] Embodiment 6. The method of embodiment 1 or embodiment 5, the TEAD inhibitor for use according to embodiment 2 or embodiment 5, the HER2 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), N-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (Compound B), N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide (Compound C), 3-bromo-5-(3-(4-chlorophenoxy)-4-methylphenyl)-4,5-dihydroisoxazole (Compound D), VT3989 and IK-930.

[0073] Embodiment 7. The method of embodiment 6, the TEAD inhibitor for use according to embodiment 6, the HER2 inhibitor for use according to embodiment 6, or the combination according to embodiment 6, wherein the TEAD inhibitor is IAG933.

[0074] Embodiment 8. The method of 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 HER2 inhibitor for use according to any one of embodiments 3 and 5 to 7, or the combination of any one of embodiments 4 to 7, wherein the HER2 inhibitor is an anti-HER2 antibody.

[0075] Example 9. The method of Example 8, the TEAD inhibitor for use according to Example 8, the HER2 inhibitor for use according to Example 8, or the combination according to Example 8, wherein the anti-HER2 antibody is trastuzumab.

[0076] Embodiment 10. The method of 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 HER2 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 HER2 inhibitor is selected from the list consisting of lapatinib, neratinib, tucatinib, trastuzumab, pyrotinib, afatinib, pertuzumab, magituximab, canertinib, dacomitinib, sabutinib, mulitinib, poziotinib, detrastuzumab and ado-enmetrastuzumab.

[0077] Embodiment 11. The method of embodiment 10, the TEAD inhibitor for use according to embodiment 10, the HER2 inhibitor for use according to embodiment 11, or the combination according to embodiment 10, wherein the HER2 inhibitor is lapatinib (e.g., lapatinib ditosylate, e.g., lapatinib ditosylate monohydrate).

[0078] Embodiment 12. The method of any one of embodiments 1 and 5 to 11, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 11, or the HER2 inhibitor for use according to any one of embodiments 3 and 5 to 11, wherein the treatment further comprises administering a SHP2 inhibitor.

[0079] Embodiment 13. The method of embodiment 12, the TEAD inhibitor for use according to embodiment 12, the HER2 inhibitor for use according to embodiment 12, or the combination according to any one of embodiments 4 to 11, wherein the SHP2 inhibitor is selected from the group consisting of: viciprostafil (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, fumosolidone, 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, viciprostafil (RMC-4630), RLY1971 and TNO155.

[0080] Embodiment 14. The method of embodiment 13, the TEAD inhibitor for use according to embodiment 13, the HER2 inhibitor for use according to embodiment 13, or the combination according to embodiment 13, wherein the SHP2 inhibitor is TNO155.

[0081] Embodiment 15. The method of 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 HER2 inhibitor for use according to any one of embodiments 3 and 5 to 14, wherein the cancer is a TEAD-dependent cancer.

[0082] Embodiment 16. The method of any one of embodiments 1 and 5 to 15, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 15, or the HER2 inhibitor for use according to any one of embodiments 3 and 5 to 15, wherein the cancer is selected from breast cancer (e.g., HER2+ breast cancer, e.g., HER2+ / HR+ breast cancer, e.g., HER2+ / ER+ breast cancer or HER2+ / ER- breast cancer), gastric cancer (e.g., gastric cancer, e.g., gastric adenocarcinoma, e.g., gastric tubular adenocarcinoma), lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma, e.g., esophagogastric junction cancer), uterine cancer, cervical cancer, bladder cancer, pancreatic cancer, colorectal cancer, ovarian cancer, head and neck cancer, thymoma, and liver cancer.

[0083] Example 17. The method of Example 16, the TEAD inhibitor for use according to Example 16, or the HER2 inhibitor for use according to Example 16, wherein the cancer is breast cancer (e.g., HER2+ breast cancer, e.g., HER2+ / HR+ breast cancer, e.g., HER2+ / ER+ breast cancer or HER2+ / ER- breast cancer).

[0084] Embodiment 18. The method of 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 HER2 inhibitor for use according to any one of embodiments 3 and 5 to 17, wherein the cancer is a HER2-positive cancer.

[0085] Embodiment 19. The method of any one of embodiments 1 and 5 to 18, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 18, or the HER2 inhibitor for use according to any one of embodiments 3 and 5 to 18, wherein the cancer is i) a HER2 amplified cancer, and / or ii) a HER2 mutant cancer and / or iii) the cancer has overexpression of HER2 protein.

[0086] Embodiment 20. The method of any one of embodiments 1 and 5 to 19, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 19, or the HER2 inhibitor for use according to any one of embodiments 3 and 5 to 19, wherein the TEAD inhibitor (eg, IAG933) is administered on each of the first 3 days of a 7-day treatment cycle, and wherein the treatment consists of at least two treatment cycles.

[0087] Embodiment 21. The method of any one of embodiments 1 and 5 to 20, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 20, or the HER2 inhibitor for use according to any one of embodiments 3 and 5 to 20, wherein the daily dose of the TEAD inhibitor (e.g., IAG933) on each administration day is 15 mg to 1500 mg.

[0088] Embodiment 22. The method according to embodiment 21, the TEAD inhibitor for use according to embodiment 21, or the HER2 inhibitor for use according to embodiment 21, wherein the daily dose of the TEAD inhibitor (eg, IAG933) on each administration day is 100 mg to 1500 mg.

[0089] Embodiment 23. The method of embodiment 22, the TEAD inhibitor for use according to embodiment 22, or the HER2 inhibitor for use according to embodiment 22, wherein the daily dose of the TEAD inhibitor (e.g., IAG933) on each administration day 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, 900 mg, 950 mg. mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg or 1500 mg.

[0090] Embodiment 24. The method of any one of embodiments 1 and 5 to 23, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 23, or the HER2 inhibitor for use according to any one of embodiments 3 and 5 to 23, wherein the HER2 inhibitor (e.g., lapatinib) is administered daily.

[0091] Embodiment 25. The method of any one of embodiments 1 and 5 to 24, the TEAD inhibitor for use according to any one of embodiments 2 and 5 to 24, or the HER2 inhibitor for use according to any one of embodiments 3 and 5 to 24, wherein the daily dose of the HER2 inhibitor (e.g., lapatinib) is 500 to 2000 mg (e.g., 1250 to 1500 mg, e.g., 1250 mg or 1500 mg).

[0092] definition

[0093] IAG933 is a YAP / TAZ-TEAD protein-protein interaction inhibitor that can be used to treat diseases or conditions mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interactions, such as cancer, particularly cancers with: (i) one or more YAP / TAZ fusions; (ii) one or more NF2 / LATS1 / 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.

[0094] IAG933 has the following chemical structure: , its chemical name is 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.

[0095] Lapatinib has the following chemical structure: Lapatinib is chemically known as N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulfonyl)ethyl]amino}methyl)-2-furyl]-quinazolinamine. It is marketed as Tykerb or Tyverb in its xylenesulfonic acid monohydrate form, N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methanesulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine bis(4-methylbenzenesulfonate) monohydrate. Lapatinib is also known as LAP016 and GW-572016.

[0096] As used herein, the term "Compound A" refers to , 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide, which is Example 144 of WO 2021 / 186324, is a close analog of IAG933.

[0097] As used herein, the term "Compound B" refers to , N-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide. Compound B is also known as VT-104, and its synthesis is described in the art. It is also commercially available.

[0098] As used herein, the term "Compound C" refers to , N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide. Compound C is also known as K-975 and is commercially available.

[0099] As used herein, the term "Compound D" refers to , 3-bromo-5-(3-(4-chlorophenoxy)-4-methylphenyl)-4,5-dihydroisoxazole. The synthesis of compound D is described in WO 2020 / 243423.

[0100] As used herein, the term "Compound E" refers to , a close analog of IAG933. The synthesis of compound E is described in WO 2021 / 186324.

[0101] Unless otherwise indicated herein or clearly contradicted by context, in the context of describing the present invention (especially in the context of the claims below), the terms "a" and "an" and "the" and similar referents are to be construed to include both the singular and the plural. When the plural form is used for compounds, patients, cancers, etc., this is intended to refer to a single compound, patient, etc.

[0102] References in this specification to "the present invention" are intended to reflect the several inventive embodiments disclosed herein and should not be construed as unnecessary limitations on the claimed subject matter.

[0103] As used herein, the term "synergistic effect" refers to the effect of two or three therapeutic agents that produce an effect, such as slowing the progression of a proliferative disease (particularly cancer or its symptoms), that is greater than the simple sum of the effects of each agent administered on its own. Synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, NHG and Scheiner, LB, Clin. Pharmacokinet. [Clinical Pharmacokinet.] 6: 429-453 (1981)), the Loewe additivity equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. [Archives of Experimental Pathology and Pharmacology] 114: 313-326 (1926)), and the median effect equation (Chou, TC and Talalay, P., Adv. Enzyme Regul. [Progress in Enzyme Regulation Research] 22: 27-55 (1984)). Each of the equations mentioned above can be applied to experimental data to generate corresponding graphs to help evaluate the effects of drug combinations. The corresponding graphs associated with the equations mentioned above are concentration-effect curves, isobolograms, and combination index curves.

[0104] The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound and which are typically not biologically or otherwise undesirable. Due to the presence of amino groups, the compounds may be capable of forming acid addition salts.

[0105] Unless otherwise stated or clearly indicated by the context, references to therapeutic agents useful in the pharmaceutical combinations of the present invention include the free base of the compound and all pharmaceutically acceptable salts of the compound.

[0106] The term "combination" or "pharmaceutical combination" is defined herein to mean a fixed combination in the form of one dosage unit, a non-fixed combination for combined administration, or a kit of parts, wherein the therapeutic agents can be administered together simultaneously, independently or separately within time intervals, which preferably allows the combination partners to exhibit a cooperative, e.g., synergistic, effect. Thus, the individual compounds of the pharmaceutical combination of the present invention can be administered simultaneously or sequentially.

[0107] Furthermore, the pharmaceutical combination of the present invention may be in the form of a fixed combination or in the form of a non-fixed combination.

[0108] The term "fixed combination" means that the therapeutic agents, eg the individual compounds of the combination, are in the form of a single entity or dosage form.

[0109] The term "non-fixed combination" means that the therapeutic agents (e.g., the individual compounds of the combination) are administered to a patient as separate entities or dosage forms either simultaneously or sequentially without specific time limits, wherein preferably, such administration provides therapeutically effective levels of both therapeutic agents in the body of a subject, e.g., a mammal or human in need thereof.

[0110] The pharmaceutical combination may further comprise at least one pharmaceutically acceptable carrier. Therefore, the present invention relates to a pharmaceutical composition comprising the pharmaceutical combination of the present invention and at least one pharmaceutically acceptable carrier.

[0111] As used herein, the term "carrier" or "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and the like, and combinations thereof, as would be appreciated by one skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). Except in the case where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

[0112] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0113] Generally, the term "pharmaceutical composition" is defined herein to mean a mixture or solution containing at least one therapeutic agent to be administered to a subject (e.g., a mammal or human). The pharmaceutical combinations of the present invention can be formulated as pharmaceutical compositions suitable for enteral or parenteral administration, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules, suppositories, or ampoules. Unless otherwise indicated, these are prepared in a manner known per se, for example, by various conventional mixing, comminution, direct compression, granulation, sugar coating, dissolution, lyophilization methods, or manufacturing techniques readily apparent to those skilled in the art. It should be understood that the unit content of the combination partner contained in an individual dose of each dosage form does not necessarily constitute an effective amount in itself, as the necessary effective amount can be achieved by administering multiple dosage units. The pharmaceutical composition may contain from about 0.1% to about 99.9%, preferably from about 1% to about 60%, of one or more therapeutic agents. One of ordinary skill in the art can select one or more of the aforementioned carriers by routine experimentation without undue burden regarding the specific desired properties of the dosage form. The amount of each carrier used may vary within conventional ranges in the art. The following references disclose techniques and excipients for formulating oral dosage forms. See The Handbook of Pharmaceutical Excipients, 4th ed., Rowe et al., eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th ed., Gennaro, ed., Lippincott Williams & Wilkins (2003). These optional additional conventional carriers can be incorporated into the oral dosage form by incorporating one or more conventional carriers into the initial mixture before or during granulation, or by combining one or more conventional carriers with granules comprising the combination of agents in the oral dosage form or the individual agents of the combination of agents. In the latter embodiment, the combined mixture can be further blended, for example, by a V-blender, and then compressed or molded into tablets (e.g., monolithic tablets), encapsulated in capsules, or filled into sachets. Obviously, the pharmaceutical combination of the present invention may be used in the manufacture of a medicament.

[0114] The present invention relates to such pharmaceutical combinations or compositions, in particular for use as medicaments.

[0115] In particular, the combinations or compositions of the present invention may be applied in the treatment of cancer.

[0116] The present invention also relates to the use of the pharmaceutical combination or pharmaceutical composition of the present invention for preparing a medicament for treating cancer, and to a method for treating cancer in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of the pharmaceutical combination or pharmaceutical composition according to the present invention.

[0117] As used herein, the term "treat" includes treatment that alleviates, relieves, or alleviates at least one symptom in a subject, increases progression-free survival, overall survival, prolongs the duration of response, or delays disease progression. For example, treatment can be the reduction of one or more symptoms of a disorder or the complete eradication of a disorder (e.g., cancer). Within the meaning of the present invention, the term "treat" also means preventing or delaying the onset of a disease (i.e., the period prior to clinical manifestation of the disease) and / or reducing the risk of disease development or worsening in a patient (e.g., a mammal, particularly a human patient). As used herein, the term "treat" includes inhibition of tumor growth, including direct inhibition of primary tumor growth and / or systemic inhibition of metastatic cancer cells.

[0118] "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, mice, apes, humans, farm animals, sport animals, and pets.

[0119] As used herein, a subject is "in need of" or "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0120] The term "comprising" encompasses "including" as well as "consisting of;" for example, a composition comprising X may consist only of X, or may include additional, eg, X and Y.

[0121] The term "therapeutically effective amount" of a compound of the invention (e.g., a chemical entity or biologic) refers to an amount of the compound of the invention that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In one embodiment, the in vivo therapeutically effective amount can be in the range of about 0.1-500 mg / kg, or about 1-100 mg / kg, depending on the route of administration.

[0122] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to reducing or suppressing a given condition, symptom, disorder, or disease, or significantly reducing the baseline activity of a biological activity or process.

[0123] The optimal dosage of each combination partner for treating cancer can be determined empirically for each individual using known methods and will depend on a variety of factors, including but not limited to: the extent of the disease; the age, weight, general health, sex, and diet of the individual; the time and route of administration; and other medications the individual is taking. The optimal dosage can be determined using routine tests and procedures well known in the art. The amount of each combination partner that can be combined with the carrier material to produce a single dosage form will vary depending on the individual being treated and the particular mode of administration. In some embodiments, a unit dosage form containing a combination of agents as described herein will contain each agent in the combination in an amount typically administered when the agents are administered alone.

[0124] The frequency of dosage can vary depending on the compound used and the specific condition to be treated or prevented. Generally, it is preferred to use the minimum dose sufficient to provide effective therapy. Patients can generally be monitored for therapeutic effectiveness using assays appropriate for the condition being treated or prevented, which assays will be familiar to those of ordinary skill in the art.

[0125] 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 and include, but are not limited to, colorectal cancer, gastric cancer, endometrial cancer, prostate cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, ovarian cancer, and the like.

[0126] The terms "tumor" and "cancer" are used interchangeably herein, e.g., both terms include solid tumors and liquid tumors, such as diffuse or circulating tumors. As used herein, the terms "cancer" or "tumor" include pre-malignant as well as malignant cancers and tumors.

[0127] 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 relevant, for example, in cancers in which the Hippo pathway is genetically altered.

[0128] In embodiments, the HER2 inhibitor is also an EGFR inhibitor.

[0129] As used herein, the term "HER2-positive cancer" refers to any cancer in which the cancer is a HER2-amplified cancer and / or a HER2-mutated cancer and / or in which the cancer has overexpression of HER2 protein.

[0130] In embodiments, the HER2 inhibitor is an anti-HER2 antibody (e.g., trastuzumab). However, in preferred embodiments, the HER2 inhibitor is a small molecule HER2 inhibitor (e.g., a HER2 inhibitor and an EGFR inhibitor, such as lapatinib). In embodiments, the HER2 inhibitor is a tyrosine kinase inhibitor, e.g., a tyrosine kinase inhibitor that inhibits HER2 and EGFR, such as lapatinib. It should be understood that the effects of trastuzumab are generally considered to be underestimated in vitro compared to in vivo. Without limitation, this may be due to the additional immunomodulatory effects of NK cells, which lead to a more enhanced effect in vivo, especially when the model is not immunosuppressed.

[0131] 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 an example, in a biochemical assay described in WO 2021 / 186324, and / or in a reporter gene cell assay described in WO 2021 / 186324, and / or in a proliferation cell assay described in WO 2021 / 186324, IC 50 [µM] is <10, such as <5, such as <2, such as <1, such as <0.5, such as <0.2, such as <0.1. WO 2021 / 186324 is hereby incorporated by reference.

[0132] The YAP / TAZ-TEAD protein-protein interaction inhibitors described herein are TEAD inhibitors that inhibit TEAD activity by inhibiting the interaction between the YAP / TAZ complex and TEAD. Hyperactivation of YAP / TAZ, leading 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.

[0133] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2021 / 087008.

[0134] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2021 / 102204.

[0135] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2020 / 214734.

[0136] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2020 / 097389.

[0137] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2019 / 222431.

[0138] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2019 / 113236.

[0139] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2019 / 040380.

[0140] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2018 / 204532.

[0141] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2017 / 058716.

[0142] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2022 / 159986.

[0143] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2022 / 120354.

[0144] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2022 / 120355.

[0145] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2022 / 120353.

[0146] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2020 / 243423.

[0147] In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO 2020 / 243415.

[0148] In an embodiment, the TEAD inhibitor is IAG933, ie, 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 An alternative 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.

[0149] In an embodiment, the TEAD inhibitor is Compound A, ie, 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 An alternative 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.

[0150] The synthesis and characterization of IAG933 (Example 155) and Compound A (Example 144) are described in WO 2021 / 186324 (which is hereby incorporated by reference).

[0151] In embodiments where TNO155 is present as part of a method or combination, TNO155 is administered orally at a dose of about 1.5 mg / day, or 3 mg / day, or 6 mg / day, or 10 mg / day, or 20 mg / day, or 30 mg / day, or 40 mg / day, or 50 mg / day, or 60 mg / day, or 70 mg / day, or 80 mg / day, or 90 mg / day, or 100 mg / day.

[0152] In embodiments where TNO155 is present as part of a method or combination, the daily dose of TNO155 is administered in a 21 day cycle of 2 weeks on followed by 1 week off.

[0153] In embodiments where TNO155 is present as part of a method or combination, the daily dose of TNO155 is 20 mg.

[0154] In embodiments where TNO155 is present as part of a method or combination, the dosing schedule of TNO155 is once daily (QD) or twice daily (BID).

[0155] In embodiments where TNO155 is present as part of a method or combination, TNO155 is administered orally.

[0156] 'Zwitterion' or 'zwitterionic form' means a compound that contains both positively and negatively charged functional groups.

[0157] Unless defined otherwise, 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.

[0158] Although methods and materials similar or equivalent to those described herein can be used for practice or test 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.In addition, materials, methods and examples are only illustrative and not intended to be limiting.All methods described herein can be carried out in any suitable order, unless otherwise indicated herein or otherwise clearly contradictory with context.The use of any and all examples or exemplary language (e.g., "such as") provided herein is only intended to better illustrate the present invention, and is not intended to limit the scope of the invention claimed in addition.

[0159] Isomers

[0160] Any asymmetric atom (e.g., carbon, etc.) useful in one or more compounds of the present invention may be present in a racemic or enantiomerically enriched form, e.g., in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms with unsaturated double bonds may, where possible, be present in cis-(Z)- or trans-(E)-form.

[0161] Accordingly, as used herein, the compounds useful in the present invention may be 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.

[0162] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0163] Any resulting racemate of a compound or intermediate useful in the present invention can be resolved into its optical antipodes by known methods, for example, by separating its diastereomeric salts obtained with an optically active acid or base and releasing the optically active acidic or basic compound. In particular, the basic moiety can be used to resolve the compound useful in the present invention into its optical antipodes, for example, by fractional crystallization of salts formed with an optically active acid such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic compounds or racemic intermediates useful in the present invention can also be resolved by chiral chromatography (e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent).

[0164] Compounds useful in the present invention, i.e., compounds of formula (I) containing groups capable of acting as hydrogen bond donors and / or acceptors, are capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting the compound of formula (I) with the co-crystal former in solution under crystallization conditions and isolating the co-crystals thus formed. Suitable co-crystal formers include those described in WO 2004 / 078163.

[0165] In addition, the compounds useful in the present invention (including their salts) may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including 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 those commonly used in the pharmaceutical art and are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0166] Dosage form

[0167] The combination of the invention may be in unit dosage form having about 1-2000 mg of each active ingredient, for example for a subject of about 50-70 kg.

[0168] 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 and not administered on the following 4 days of the 7-day treatment cycle.

[0169] Preferably, at least two treatment cycles are consecutive, i.e. the second treatment cycle follows immediately after the first treatment cycle. For example, the present invention thus includes the following:

[0170] Days 1-3: TEAD inhibitor administered daily;

[0171] Days 4-7: no TEAD inhibitor administration;

[0172] Days 8-10: daily administration of the TEAD inhibitor; and

[0173] Days 11-14: No TEAD inhibitor was administered.

[0174] In this example, days 1-3 and days 8-10 are administration days. Thus, an "administration day" refers to any day on which a TEAD inhibitor is administered to a patient.

[0175] When present, the third (fourth, etc.) treatment cycle preferably follows immediately after the previous treatment cycle. Thus, in an embodiment having three treatment cycles, the present invention includes the following:

[0176] Days 1-3: TEAD inhibitor administered daily;

[0177] Days 4-7: no TEAD inhibitor administration;

[0178] Days 8-10: TEAD inhibitor administered daily;

[0179] Days 11-14: no TEAD inhibitor administration;

[0180] Days 15-17: daily administration of the TEAD inhibitor; and

[0181] Days 18-21: No TEAD inhibitor was administered.

[0182] In an embodiment, there are three or more treatment cycles, such as four or more treatment cycles, such as five or more treatment cycles, such as six or more treatment cycles, such as eight or more treatment cycles, such as ten or more treatment cycles.

[0183] In alternative embodiments, the TEAD inhibitor is administered on two days of a 6-day or 7-day treatment cycle, and wherein the treatment comprises at least two treatment cycles, e.g., on i) day 1 and day 4 of a 6-day schedule or ii) day 1 and day 4 of a 7-day schedule, e.g., day 1 and day 4 of a 7-day schedule.

[0184] As used herein, the term "daily dose" (eg, daily dose of a TEAD inhibitor) refers to the total dose (eg, total dose of a TEAD inhibitor) administered to a subject within 24 hours of a day.

[0185] When a dosage (e.g., a dosage of a TEAD inhibitor) is referred to herein, e.g., expressed in mg (milligrams), it refers to the amount (e.g., an equivalent amount of TEAD inhibitor) in free form (i.e., excluding, e.g., salts or co-crystal partners and any solvent present).

[0186] The TEAD inhibitor is preferably 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.

[0187] Preferably, take the TEAD inhibitor with a glass of water without chewing the capsule or tablet.

[0188] If a patient is assigned to a dose level that requires taking multiple capsules / tablets of a TEAD inhibitor, the TEAD inhibitor capsules / tablets should be taken consecutively within as short an interval as possible (e.g., within 5 minutes).

[0189] Preferably, the TEAD inhibitor is administered at approximately the same time on each administration day. Preferably, the TEAD inhibitor is administered once a day on each administration day. More preferably, the TEAD inhibitor is administered in the morning.

[0190] Preferably, the TEAD inhibitor is administered in the fasting state, ie, at least 1 hour before or 2 hours after a meal.

[0191] combination

[0192] "Combination" refers to a fixed combination in the form of one dosage unit, or combined administration, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof and a combination partner (e.g., another drug, also referred to as "therapeutic agent" or "co-agent") as explained below can be administered independently at the same time or separately within time intervals, especially where these time intervals allow the combination partners to exhibit a synergistic (e.g., synergistic) effect. The individual components can be packaged in one kit or packaged separately. One or both components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration. As used herein, the terms "co-administration" or "combined administration" and the like are intended to encompass the administration of the 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. As used herein, the term "pharmaceutical combination" means a product resulting from the mixing or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents (e.g., a combination partner of the invention) are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the therapeutic agents (e.g., a combination partner of the invention) are administered to a patient as separate entities simultaneously, concurrently, or sequentially (without specific time limits), wherein such administration provides therapeutically effective levels of the two compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more therapeutic agents.

[0193] 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 be administered together to form the combination therapy: (i) prior to issuing the combination product to a physician (e.g., in the case of a kit comprising the therapeutic agents); (ii) by the physician themselves (or under the physician's direction) shortly before administration; or (iii) in the patient themselves, e.g., during sequential administration of the therapeutic agents.

[0194] Examples

[0195] Example 1

[0196] The in vitro viability of the gastric cancer cell line REFR-GC-1B was assessed using CellTiterGlo after 7 days of treatment with a combination of IAG933 and lapatinib (± TNO155). The growth of REFR-GC-1B cells was inhibited by IAG933 alone, but not by lapatinib alone. In addition, the combination of IAG933 and lapatinib showed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of lapatinib ( Figure 1 ).

[0197] Example 2

[0198] The in vitro viability of the gastric cancer cell line SNU-216 was assessed using CellTiterGlo after 7 days of treatment with a combination of IAG933 and lapatinib (± TNO155). The growth of SNU-216 cells was inhibited by both IAG933 alone and lapatinib alone (maximal effect of lapatinib alone: ​​arrest). Furthermore, the combination of IAG933 and lapatinib demonstrated synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of lapatinib ( Figure 2 ).

[0199] Example 3

[0200] The in vitro viability of the gastric cancer cell line NCI-N87 was assessed using CellTiterGlo after 7 days of treatment with a combination of IAG933 and lapatinib (± TNO155). The growth of NCI-N87 cells was inhibited by both IAG933 alone (maximum effect: arrest) and lapatinib alone. In addition, the combination of IAG933 and lapatinib showed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of lapatinib ( Figure 3 ).

[0201] Example 4

[0202] The in vitro viability of the gastric cancer cell line MKN-7 was assessed using CellTiterGlo after 7 days of treatment with a combination of IAG933 and lapatinib (± TNO155). The growth of MKN-7 cells was inhibited by both IAG933 alone (maximum effect: arrest) and lapatinib alone (maximum effect below arrest). Furthermore, the combination of IAG933 and lapatinib demonstrated synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of IAG933. Further combination with TNO155 was beneficial at lower concentrations of lapatinib (± TNO155). Figure 4 ).

[0203] Example 5

[0204] The in vitro viability of the non-small cell lung cancer cell line NCI-H2170 was assessed using CellTiterGlo after 7 days of treatment with a combination of IAG933 and lapatinib (± TNO155). The growth of NCI-H2170 cells was inhibited by lapatinib alone, but not by IAG933 alone. In addition, the combination of IAG933 and lapatinib showed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of lapatinib ( Figure 5 ).

[0205] Example 6

[0206] The in vitro viability of the non-small cell lung cancer cell line CALU-3 was assessed using CellTiterGlo after 7 days of treatment with a combination of IAG933 and lapatinib (± TNO155). The growth of CALU-3 cells was inhibited by both IAG933 alone (maximum effect: arrest) and lapatinib alone. In addition, the combination of IAG933 and lapatinib showed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of lapatinib ( Figure 6 ).

[0207] Example 7

[0208] The in vitro viability of the endometrial cancer cell line TEN was assessed using CellTiterGlo after 7 days of treatment with a combination of IAG933 and lapatinib (± TNO155). The growth of TEN cells was inhibited by both IAG933 alone and lapatinib alone (maximal effect below stasis). In addition, the combination of IAG933 and lapatinib showed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of lapatinib ( Figure 7 ).

[0209] Example 8

[0210] CellTiterGlo was used to assess the in vitro viability of the esophageal cancer cell line OE-19 after 7 days of treatment with a combination of IAG933 and lapatinib (± TNO155). The growth of OE-19 cells was inhibited by both IAG933 alone (maximum effect below stasis) and lapatinib alone. In addition, the combination of IAG933 and lapatinib demonstrated synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of lapatinib ( Figure 8 ).

[0211] Example 9

[0212] The in vitro viability of the esophageal cancer cell line TE-4 was assessed using CellTiterGlo after 7 days of treatment with a combination of IAG933 and lapatinib (± TNO155). TE-4 cell growth was inhibited by lapatinib alone, but not by IAG933 alone. Furthermore, the combination of IAG933 and lapatinib demonstrated synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of lapatinib ( Figure 9 ).

[0213] Example 10

[0214] In the SNU-216 gastric cancer model, IAG933 alone and IAG933 combined with lapatinib ( Figure 10 - on) or trastuzumab ( Figure 10 The combination of IAG933 (lower) and TNO155 (lower) impeded cell growth during treatment and delayed growth after compound washout. The dual combination delayed cell growth beyond that of IAG933 alone, while the triple combination with TNO155 completely blocked growth. Growth was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius). Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and culture medium was refreshed weekly.

[0215] Example 11

[0216] In the Calu-3 non-small cell lung cancer model, the combination of IAG933 and lapatinib ( Figure 11 - top) blocked cell growth during treatment and delayed growth after compound washout. Addition of TNO155 further delayed cell growth. IAG933 and trastuzumab ( Figure 11 – Bottom) Cell growth during delayed treatment. Growth was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius). Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and culture medium was refreshed weekly.

[0217] Example 12

[0218] In cell death assays ( Figure 12In the figure (top), IAG933 combined with lapatinib or trastuzumab resulted in a decrease in cell number and an increase in the percentage of dead cells in NCI-N87 and SNU-216 gastric cancer cells. Addition of TNO155 augmented these effects. Clonogenicity assays after crystal violet staining were performed after 38 days ( Figure 12 – Bottom) Middle: Cell death and clonogenicity were observed in SNU-216 and MKN-7 gastric cancer cells with the combination of IAG933 and lapatinib ± TNO155. SNU-216 and, to a lesser extent, MKN-7 cells were sensitive to IAG933 alone during long-term treatment.

[0219] IAG933 + Lapatinib, 600 nM IAG933 and 100 nM lapatinib. IAG(933) + TNO(155) + Lapatinib, 600 nM IAG933, 200 nM TNO155, and 100 nM lapatinib.

[0220] Example 13

[0221] In the NCI-N87 gastric cancer model, IAG933 and lapatinib ( Figure 13 – above) or trastuzumab ( Figure 13 The combination (below) prevented cell growth during treatment and resulted in a growth delay after compound washout. For IAG933 and trastuzumab, the further inclusion of TNO155 resulted in an additional growth delay, while for IAG933 and lapatinib, this completely prevented cell growth even after compound washout. Growth was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius). Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated again for the remainder of the experiment, and culture medium was refreshed weekly.

[0222] Example 14

[0223] In the MKN-7 gastric cancer model, IAG933 and lapatinib ( Figure 14 – above) or trastuzumab ( Figure 14 The combination (bottom) blocked cell growth during treatment and resulted in a growth delay after compound washout. For IAG933 and trastuzumab, the further inclusion of TNO155 led to an additional growth delay, while for IAG933 and lapatinib, this completely blocked cell growth even after compound washout. Growth was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius). Compound treatment was renewed on day 7 and removed on day 14. For the remainder of the experiment, cells were not treated, and culture medium was refreshed weekly.

[0224] Example 15

[0225] In the RERF-GC-1B gastric cancer model, IAG933 alone and IAG933 plus lapatinib ( Figure 15 – above) or trastuzumab ( Figure 15 The combination (bottom) blocked cell growth during treatment and delayed growth after compound washout, with the combined effect being more pronounced. When TNO155 was further included, both combination regimens completely blocked cell growth even after compound washout. Growth was monitored using an Incucyte® S3 live cell analyzer (Sartorius). Compound treatment was renewed on day 7 and removed on day 14. For the remainder of the experiment, cells were not treated, and culture medium was refreshed weekly.

[0226] Example 16

[0227] In the NCI-H2170 non-small cell lung cancer model, IAG933 and lapatinib with or without TNO155 ( Figure 16 – Top) Complete abrogation of cell growth with no viable cells as revealed by the absence of proliferation after compound washout. IAG933 and trastuzumab ( Figure 16 The combination of TNO155 (lower panel) and TNO155 (lower panel) inhibited cell proliferation, and the addition of TNO155 resulted in more pronounced cell killing, as revealed by compound washout followed by resumption of growth with only a small number of viable cells. Cell proliferation was monitored using an Incucyte® S3 live cell analyzer (Sartorius). Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remaining experimental days.

[0228] Example 17

[0229] After six days of treatment with a combination of Compound A and lapatinib, the in vitro viability of the gastric cancer cell line SNU-216 and the non-small cell lung cancer cell line NCI-H2170 was assessed using CellTiterGlo. The growth of both SNU-216 and NCI-H2170 cells was inhibited by both Compound A and lapatinib alone. Furthermore, in both cell lines, the combination of Compound A and lapatinib demonstrated synergistic growth inhibition compared to either treatment alone.

[0230] Example 18

[0231] The in vitro viability of the gastric cancer cell line SNU-216 and the non-small cell lung cancer cell line NCI-H2170 was assessed using CellTiterGlo after 6 days of treatment with a combination of Compound B and lapatinib. The growth of both SNU-216 and NCI-H2170 cells was inhibited by lapatinib alone, but not by Compound B alone. In both cell lines, the combination of Compound B and lapatinib showed synergistic growth inhibition compared to either treatment alone.

[0232] Example 19

[0233] CellTiterGlo was used to assess the in vitro viability of the gastric cancer cell line SNU-216 and the non-small cell lung cancer cell line NCI-H2170 after 6 days of treatment with a combination of Compound C and lapatinib. The growth of both SNU-216 and NCI-H2170 cells was inhibited by lapatinib alone, but not by Compound C alone (at least outside of very high concentrations of Compound C). In both cell lines, the combination of Compound C and lapatinib demonstrated synergistic growth inhibition compared to either treatment alone.

[0234] Example 20

[0235] CellTiterGlo was used to assess the in vitro viability of the gastric cancer cell line SNU-216 and the non-small cell lung cancer cell line NCI-H2170 after 6 days of treatment with a combination of Compound D and lapatinib. The growth of both SNU-216 and NCI-H2170 cells was inhibited by lapatinib alone, but not by Compound D alone (at least outside of very high concentrations of Compound D). In both cell lines, the combination of Compound D and lapatinib demonstrated synergistic growth inhibition compared to either treatment alone.

[0236] Example 21

[0237] In the EFM192A breast cancer (HR+ / HER2+) model, IAG933 and lapatinib ( Figure 21 The combination (+ / - fulvestrant) resulted in enhanced growth control over either IAG933 or lapatinib alone. Growth was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius). Compound treatments were updated weekly / every 7 days.

[0238] Example 22

[0239] In the OE-19 esophageal cancer model, IAG933 and lapatinib ( Figure 22The combination of IAG933 and lapatinib resulted in enhanced growth control compared to either IAG933 or lapatinib alone. The inclusion of TNO155 further enhanced growth control. Growth was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius). Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and culture medium was refreshed weekly.

[0240] Example 23

[0241] In the TEN endometrial cancer model, IAG933 and lapatinib ( Figure 23 The combination of IAG933 and lapatinib resulted in enhanced growth control compared to either IAG933 or lapatinib alone. The inclusion of TNO155 further enhanced growth control. Growth was monitored using the Incucyte® S3 Live Cell Analyzer (Sartorius). Compound treatment was renewed on day 7 and removed on day 14. Cells were not treated for the remainder of the experiment, and culture medium was refreshed weekly.

[0242] Example 24

[0243] The NCI-H2170 HER2-amplified lung cancer xenograft model was used for pharmacology studies in mice. Two control groups (vehicle and hIgG1 kappa LC) as well as the IAG933-treated group showed rapid tumor growth, with average tumor size reaching 1000 mm within 9-20 days. 3 Trastuzumab therapy resulted in a modest reduction in tumor growth, with a mean tumor volume of 649 mm on day 22. 3 The combination of trastuzumab and IAG933 stabilized tumor growth and achieved 414 mm on day 28 after the first dose. 3 The average value of .

[0244] Example 25

[0245] The NCI-N87 HER2-amplified gastric cancer xenograft model was used for pharmacological studies in mice. Tumors treated with control therapy, vehicle, and hIgG1 κ LC reached 931 and 664 mm in 26 days. 3 Trastuzumab and Compound E therapy resulted in tumor stasis, with mean tumor volumes of 194 and 279 mm, respectively, at day 26. 3 The combination of trastuzumab and compound E triggered near-complete tumor regression, with a mean of 17 mm obtained on day 26 after the first dose. 3For the latter group, treatment was stopped on day 28, and tumors were further monitored until day 98. A sustained antitumor effect was observed on day 98, with a mean tumor size of 160 mm 3 , which is still lower than the size at randomization.

[0246] Example 26

[0247] They found that HER2 inhibition led to downregulation of the MAPK pathway, which increased Bim expression and activation, while YAP-TEAD inhibition led to an increase in BMF. Bim and BMF are pro-apoptotic proteins. Therefore, their higher expression leads to a higher degree of apoptosis and cell death.

[0248] Example 27

[0249] The in vitro viability of the breast cancer (HR+ / HER2+) cell line EFM192A was assessed using CellTiterGlo after 6 days of treatment with either the combination of IAG933 and lapatinib (±TNO155) or the combination of fulvestrant and lapatinib + IAG933. The growth of EFM192A cells was inhibited by lapatinib alone, to a lesser extent by IAG933 alone (below stagnation), and no inhibition was achieved by fulvestrant alone. In addition, the combination of IAG933 and lapatinib showed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of lapatinib. In addition, the combination of fulvestrant with lapatinib + IAG933 did not show additional synergistic growth inhibition compared to IAG933 + lapatinib (±TNO155). Figure 27 ).

Claims

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a TEAD inhibitor and a HER2 inhibitor.

2. A TEAD inhibitor for use in the treatment of cancer, wherein the treatment further comprises administering a HER2 inhibitor.

3. A HER2 inhibitor for use in the treatment of cancer, wherein the treatment further comprises administering a TEAD inhibitor.

4. A combination comprising i) a TEAD inhibitor, ii) a HER2 inhibitor and optionally iii) a SHP2 inhibitor.

5. The method of claim 1, the TEAD inhibitor for use according to claim 2, the HER2 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 claim 5, the TEAD inhibitor for use according to claim 2 or claim 5, the HER2 inhibitor for use according to claim 3 or claim 5, or the combination according to claim 4 or claim 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), N-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (Compound B), N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide (Compound C), 3-bromo-5-(3-(4-chlorophenoxy)-4-methylphenyl)-4,5-dihydroisoxazole (Compound D), VT3989, and IK-930.

7. The method of claim 6, the TEAD inhibitor for use according to claim 6, the HER2 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 and 5 to 7, the TEAD inhibitor for use according to any one of claims 2 and 5 to 7, the HER2 inhibitor for use according to any one of claims 3 and 5 to 7, or the combination according to any one of claims 4 to 7, wherein the HER2 inhibitor is an anti-HER2 antibody.

9. The method of claim 8, the TEAD inhibitor for use according to claim 8, the HER2 inhibitor for use according to claim 8, or the combination according to claim 8, wherein the anti-HER2 antibody is trastuzumab.

10. The method of any one of claims 1 and 5 to 7, the TEAD inhibitor for use according to any one of claims 2 and 5 to 7, the HER2 inhibitor for use according to any one of claims 3 and 5 to 7, or the combination according to any one of claims 4 to 7, wherein the HER2 inhibitor is selected from the list consisting of lapatinib, neratinib, tucatinib, trastuzumab, pyrotinib, afatinib, pertuzumab, magituximab, canertinib, dacomitinib, sabutinib, mulitinib, poziotinib, detrastuzumab and ado-enmetrastuzumab.

11. The method of claim 10, the TEAD inhibitor for use according to claim 10, the HER2 inhibitor for use according to claim 10, or the combination according to claim 10, wherein the HER2 inhibitor is lapatinib (e.g., lapatinib ditosylate, e.g., lapatinib ditosylate monohydrate).

12. The method according to any one of claims 1 and 5 to 11, the TEAD inhibitor for use according to any one of claims 2 and 5 to 11 or the HER2 inhibitor for use according to any one of claims 3 and 5 to 11, wherein the treatment further comprises administering a SHP2 inhibitor.

13. The method according to claim 12, the TEAD inhibitor for use according to claim 12, the HER2 inhibitor for use according to claim 12, or the combination according to any one of claims 4 to 11, wherein the SHP2 inhibitor is selected from the group consisting of: viciprostafil (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, fumosolidone, 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, viciprostafil (RMC-4630), RLY1971 and TNO155.

14. The method of claim 13, the TEAD inhibitor for use according to claim 13, the HER2 inhibitor for use according to claim 13, or the combination according to claim 13, wherein the SHP2 inhibitor is TNO155.

15. The method according to any one of claims 1 and 5 to 14, the TEAD inhibitor for use according to any one of claims 2 and 5 to 14 or the HER2 inhibitor for use according to any one of claims 3 and 5 to 14, wherein the cancer is a TEAD-dependent cancer.

16. The method according to any one of claims 1 and 5 to 15, the TEAD inhibitor for use according to any one of claims 2 and 5 to 15 or the HER2 inhibitor for use according to any one of claims 3 and 5 to 15, wherein the cancer is selected from breast cancer (e.g., HER2+ breast cancer, e.g., HER2+ / HR+ breast cancer, e.g., HER2+ / ER+ breast cancer or HER2+ / ER- breast cancer), gastric cancer (e.g., gastric cancer, e.g., gastric adenocarcinoma, e.g., gastric tubular adenocarcinoma), lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma, e.g., esophagogastric junction cancer), uterine cancer, cervical cancer, bladder cancer, pancreatic cancer, colorectal cancer, ovarian cancer, head and neck cancer, thymoma, and liver cancer.

17. The method of claim 16, the TEAD inhibitor for use according to claim 16, or the HER2 inhibitor for use according to claim 16, wherein the cancer is breast cancer (e.g., HER2+ breast cancer, e.g., HER2+ / HR+ breast cancer, e.g., HER2+ / ER+ breast cancer or HER2+ / ER- breast cancer).

18. The method of any one of claims 1 and 5 to 17, the TEAD inhibitor for use according to any one of claims 2 and 5 to 17, or the HER2 inhibitor for use according to any one of claims 3 and 5 to 17, wherein the cancer is a HER2-positive cancer.

19. The method of any one of claims 1 and 5 to 18, the TEAD inhibitor for use according to any one of claims 2 and 5 to 18, or the HER2 inhibitor for use according to any one of claims 3 and 5 to 18, wherein the cancer is i) a HER2 amplified cancer, and / or ii) a HER2 mutant cancer and / or iii) the cancer has overexpression of HER2 protein.

20. The method according to any one of claims 1 and 5 to 19, the TEAD inhibitor for use according to any one of claims 2 and 5 to 19 or the HER2 inhibitor for use according to any one of claims 3 and 5 to 19, wherein the TEAD inhibitor (e.g. IAG933) is administered on each of the first 3 days of a 7-day treatment cycle, and wherein the treatment consists of at least two treatment cycles.

21. The method according to any one of claims 1 and 5 to 20, the TEAD inhibitor for use according to any one of claims 2 and 5 to 20 or the HER2 inhibitor for use according to any one of claims 3 and 5 to 20, wherein the daily dose of the TEAD inhibitor (e.g. IAG933) on each administration day is 15 mg to 1500 mg.

22. The method according to claim 21, the TEAD inhibitor for use according to claim 21 or the HER2 inhibitor for use according to claim 21, wherein the daily dose of the TEAD inhibitor (eg, IAG933) is 100 mg to 1500 mg per administration day.

23. The method of claim 22, the TEAD inhibitor for use according to claim 22 or the HER2 inhibitor for use according to claim 22, wherein the daily dose of the TEAD inhibitor (e.g., IAG933) on each administration day 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, 900 mg, 950 mg, 1000 mg, mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg or 1500 mg.

24. The method of any one of claims 1 and 5 to 23, the TEAD inhibitor for use according to any one of claims 2 and 5 to 23, or the HER2 inhibitor for use according to any one of claims 3 and 5 to 23, wherein the HER2 inhibitor (e.g., lapatinib) is administered daily.

25. The method according to any one of claims 1 and 5 to 24, the TEAD inhibitor for use according to any one of claims 2 and 5 to 24, or the HER2 inhibitor for use according to any one of claims 3 and 5 to 24, wherein the daily dose of the HER2 inhibitor (e.g., lapatinib) is 500 to 2000 mg (e.g., 1250 to 1500 mg, e.g., 1250 mg or 1500 mg).

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