A combination of TEAD and HER2 inhibitors to treat cancer.

Abstract

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 said 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 said combination. [Background technology]

[0002] The emergence of targeted therapies for cancer has extended patient life for various malignancies and has helped to 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 numerous factors that can be broadly classified into two classes: toxicity that interferes with optimal drug dosing and consequently limits target binding (Brana and Siu 2012, Chapman, Solit et al. 2014) and the cancer's ability to adapt and maintain its proliferative capacity 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 can address both 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 are needed and which processes need to be combined and targeted to overcome specific types of cancer. However, it is almost certain that different pathways or facilitators need to be inhibited, and likely that two or more drugs will be required (Bozic, Reiter et al. 2013).

[0003] Despite the numerous treatment options available for patients with specific types of cancer, there is still a need for effective and safe combination therapies that can be administered to treat cancer. [Overview of the project]

[0004] The object of the present invention is to provide a pharmaceutical product for improving the treatment of cancer, specifically, a pharmaceutical product for improving the treatment of cancer 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 synergistically inhibits proliferation and / or induces apoptosis.

[0005] Surprisingly, as demonstrated in the examples, a combination of drugs including i) a TEAD inhibitor and ii) a HER2 inhibitor was found to synergistically inhibit cancer growth and / or induce apoptosis.

[0006] Accordingly, according to a first aspect of the present invention, a method for treating cancer in a subject in need thereof is provided herein, comprising administering a therapeutically effective dose of a TEAD inhibitor to the subject in combination with a HER2 inhibitor.

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

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

[0009] According to a fourth aspect of the present invention, combinations comprising i) a TEAD inhibitor, ii) a HER2 inhibitor, and optionally iii) an SHP2 inhibitor are provided herein. [Brief explanation of the drawing]

[0010] [Figure 1] The in vitro survival rate of the gastric cancer cell line RERF-GC-1B was evaluated using CellTiterGlo after 7 days of treatment with (top) IAG933 in combination with lapatinib, (middle) IAG933 in combination with TNO155, and (bottom) IAG933 in combination with lapatinib and 200 nM TNO155. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = cell count reduction / cell death. [Figure 2] In vitro survival of the gastric cancer cell line SNU-216 was evaluated using CellTiterGlo after 7 days of treatment with (top) IAG933 in combination with lapatinib, (middle) IAG933 in combination with TNO155, and (bottom) IAG933 in combination with lapatinib and 200 nM TNO155. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = cell count reduction / cell death. [Figure 3] In vitro survival of the gastric cancer cell line NCI-N87 was evaluated using CellTiterGlo after 7 days of treatment with (top) IAG933 in combination with lapatinib, (middle) IAG933 in combination with TNO155, and (bottom) IAG933 in combination with lapatinib and 200 nM TNO155. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = cell count reduction / cell death. [Figure 4] In vitro survival of the gastric cancer cell line MKN-7 was evaluated using CellTiterGlo after 7 days of treatment with (top) IAG933 in combination with lapatinib, (middle) IAG933 in combination with TNO155, and (bottom) IAG933 in combination with lapatinib and 200 nM TNO155. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = cell count reduction / cell death. [Figure 5]In vitro survival of the non-small cell lung cancer cell line NCI-H2170 was evaluated using CellTiterGlo after 7 days of treatment with (top) IAG933 in combination with lapatinib, (middle) IAG933 in combination with TNO155, and (bottom) IAG933 in combination with lapatinib and 200 nM TNO155. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = cell count reduction / cell death. [Figure 6] In vitro survival of the non-small cell lung cancer cell line CALU-3 was evaluated using CellTiterGlo after 7 days of treatment with (top) IAG933 in combination with lapatinib, (middle) IAG933 in combination with TNO155, and (bottom) IAG933 in combination with lapatinib and 200 nM TNO155. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = cell count reduction / cell death. [Figure 7] In vitro viability of the endometrial cell line TEN was evaluated using CellTiterGlo after 7 days of treatment with (top) IAG933 in combination with lapatinib, and (bottom) IAG933 in combination with lapatinib and 200 nM TNO155. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = reduced cell number / cell death. [Figure 8] In vitro viability of the esophageal cell line OE-19 was evaluated using CellTiterGlo after 7 days of treatment with (top) IAG933 in combination with lapatinib, and (bottom) IAG933 in combination with lapatinib and 200 nM TNO155. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = cell count reduction / cell death. [Figure 9]In vitro survival of the esophageal cell line TE-4 was evaluated using CellTiterGlo after 7 days of treatment with (top) IAG933 in combination with lapatinib, and (bottom) IAG933 in combination with lapatinib and 200 nM TNO155. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = cell count reduction / cell death. [Figure 10] Confluence of SNU-216 gastric cancer cell lines after treatment with a specified compound at a specified concentration. The compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with the culture medium refreshed once a week. Confluence was monitored in real time using an Incucyte® S3 live cell analyzer (Sartorius). [Figure 11] Confluence of Calu-3 non-small cell lung cancer cell lines after treatment with a specified compound at a specified concentration. The compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with the culture medium refreshed once a week. Confluence was monitored in real time using an Incucyte® S3 live cell analyzer (Sartorius). [Figure 12] (Top): Images showing cell count and % dead cells (Cytotox dye (Saratorius)) at 96 hours in SNU-216 and NCI-N87 gastric cancer cells. Cells were monitored in real time, and cell count and % dead cells were calculated using the cell-by-cell module of the Incucyte® S3 live cell analyzer (Sartorius). (Bottom): Clonality assay, crystal violet staining at 38 days with specified concentrations of specified compounds in SNU-216 and MKN-7 gastric cancer cells. IAG933 + lapatinib: 600 nM IAG933 and 100 nM lapatinib. IAG(933) + TNO(155) + lapatinib: 600 nM IAG933, 200 nM TNO155 and 100 nM lapatinib. [Figure 13] Confluence of NCI-N87 gastric cancer cell lines after treatment with a specified compound at a specified concentration. The compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with the culture medium refreshed once a week. Confluence was monitored using an Incucyte® S3 live cell analyzer (Sartorius). [Figure 14] Confluence of MKN-7 gastric cancer cell lines after treatment with a specified compound at a specified concentration. The compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with the culture medium refreshed once a week. Confluence was monitored using an Incucyte® S3 live cell analyzer (Sartorius). [Figure 15] Confluence of RERF-GC-1B gastric cancer cell lines after treatment with a specified compound at a specified concentration. The compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with the culture medium refreshed once a week. Confluence was monitored using an Incucyte® S3 live cell analyzer (Sartorius). [Figure 16] Confluence of NCI-H2170 non-small cell lung cancer cell lines after treatment with a specified compound at a specified concentration. The compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with the culture medium refreshed once a week. Confluence was monitored using an Incucyte® S3 live cell analyzer (Sartorius). [Figure 17]The in vitro viability of gastric cancer cell line SNU-216 (upper) and non-small cell lung cancer cell line NCI-H2170 (lower) was evaluated using CellTiterGlo after 6 days of treatment with compound A combined with lapatinib. Growth inhibition was normalized to the growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = growth delay, 100 = growth arrest / stagnation, 101-200 = reduction in cell number / cell death. [Figure 18] The in vitro viability of gastric cancer cell line SNU-216 (upper) and non-small cell lung cancer cell line NCI-H2170 (lower) was evaluated using CellTiterGlo after 6 days of treatment with compound B combined with lapatinib. Growth inhibition was normalized to the growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = growth delay, 100 = growth arrest / stagnation, 101-200 = reduction in cell number / cell death. [Figure 19] The in vitro viability of gastric cancer cell line SNU-216 (upper) and non-small cell lung cancer cell line NCI-H2170 (lower) was evaluated using CellTiterGlo after 6 days of treatment with compound C combined with lapatinib. Growth inhibition was normalized to the growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = growth delay, 100 = growth arrest / stagnation, 101-200 = reduction in cell number / cell death. [Figure 20] The in vitro viability of gastric cancer cell line SNU-216 (upper) and non-small cell lung cancer cell line NCI-H2170 (lower) was evaluated using CellTiterGlo after 6 days of treatment with compound D combined with lapatinib. Growth inhibition was normalized to the growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = growth delay, 100 = growth arrest / stagnation, 101-200 = reduction in cell number / cell death. [Figure 21] Confluence of EFM192A breast (HR+ / HER2+) cancer cell line after treatment with the specified compound at the specified concentration. The compound treatment was refreshed every 7 days. The medium was also refreshed once a week. Confluence was monitored using an Incucyte® S3 live cell analysis instrument (Sartorius). [Figure 22]Confluence of OE-19 esophageal cancer cell line after treatment with a specified compound at a specified concentration. The compound treatment was refreshed on day 7 and removed on day 14. The cells were left untreated for the remaining days of the experiment and the medium was refreshed once a week. Confluence was monitored using an Incucyte® S3 live cell analysis instrument (Sartorius). [Figure 23] Confluence of TEN endometrial cancer cell line after treatment with a specified compound at a specified concentration. The compound treatment was refreshed on day 7 and removed on day 14. The cells were left untreated for the remaining days of the experiment and the medium was refreshed once a week. Confluence was monitored using an Incucyte® S3 live cell analysis instrument (Sartorius). [Figure 24] Female nude mice bearing subcutaneous NCI-H2170 HER2-amplified lung cancer xenograft tumors were treated with the single agent or combination of agents shown in the description. IAG933 was administered orally while hIgG1 and trastuzumab were administered intraperitoneally. [Figure 25] SCID mice bearing subcutaneous NCI-N87 HER2-amplified gastric cancer xenograft tumors were treated with the single agent or combination of agents shown in the description. Compound E was administered orally while hIgG1 and trastuzumab were administered intraperitoneally. [Figure 26] Induction of apoptosis-promoting proteins as BIM and BMF (mRNA and protein) could be detected by gene expression analysis (mRNA) and Western blot (protein). ("IAG" in the figure description refers to IAG933 and "LAP" in the figure description refers to lapatinib). [Figure 27]In vitro survival of the breast (HR+ / HER2+) cancer cell line EFM192A was evaluated using CellTiterGlo after 6 days of treatment with (top) IAG933 in combination with lapatinib, (middle) fulvestrant in combination with lapatinib + 600 nM IAG933, and (bottom) IAG933 in combination with lapatinib and 200 nM TNO155. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100 = growth arrest / stagnation, 101-200 = cell count reduction / cell death. [Modes for carrying out the invention]

[0011] As described above, the object of the present invention is to find novel combination therapies that selectively synergistically inhibit proliferation and / or induce apoptosis.

[0012] Accordingly, according to a first aspect of the present invention, a method for treating cancer in a subject in need thereof is provided herein, comprising administering a therapeutically effective dose of a TEAD inhibitor to the subject in combination with a HER2 inhibitor.

[0013] According to a second aspect of the present invention, a TEAD inhibitor for use in the treatment of cancer, wherein the treatment further comprises the administration of a HER2 inhibitor, is provided herein.

[0014] According to a third aspect of the present invention, a HER2 inhibitor for use in the treatment of cancer, wherein the treatment further comprises the administration of a TEAD inhibitor, is provided herein.

[0015] According to a fourth aspect of the present invention, combinations comprising i) a TEAD inhibitor, ii) a HER2 inhibitor, and optionally iii) an SHP2 inhibitor are provided herein.

[0016] Surprisingly, combinations of TEAD inhibitors and HER2 inhibitors (with or without further combinations of SHP2 inhibitors) were found to be synergistic in a wide range of cancer models.

[0017] In one embodiment, the TEAD inhibitor is a YAP / TAZ-TEAD protein-protein interaction inhibitor.

[0018] 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), N-(1-(pyridine-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthoamide (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.

[0019] In one embodiment, the TEAD inhibitor is IAG933.

[0020] In one embodiment, the HER2 inhibitor is an anti-HER2 antibody. In one embodiment, the anti-HER2 antibody is trastuzumab.

[0021] In one embodiment, the HER2 inhibitor is selected from the list consisting of lapatinib, neratinib, tucatinib, trastuzumab, pirotinib, afatinib, pertuzumab, margetuximab, canertinib, dacomitinib, sapitinib, mbritinib, poziotinib, trastuzumab deruxtecan, and adtrastuzumab emtansine.

[0022] In a preferred embodiment, the HER2 inhibitor is lapatinib (e.g., lapatinib ditosylate, e.g., lapatinib ditosylate monohydrate).

[0023] In preferred embodiments, the HER2 inhibitor is lapatinib (e.g., lapatinib ditosylate, e.g., lapatinib ditosylate monohydrate), and the TEAD inhibitor is IAG933.

[0024] In one embodiment, the treatment or combination further includes the administration of an SHP2 inhibitor.

[0025] In one embodiment, 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), and BBP-398 (IACS-13909 / IACS-1550). 9) Selected from the group consisting of 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, bosiprotafib (RMC-4630), RLY1971, and TNO155.

[0026] In one embodiment, the SHP2 inhibitor is TNO155.

[0027] In one embodiment, the SHP2 inhibitor is TNO155, the HER2 inhibitor is lapatinib (e.g., lapatinib ditosylate, e.g., lapatinib ditosylate monohydrate), and the TEAD inhibitor is IAG933.

[0028] In one embodiment, the cancer is TEAD-dependent cancer.

[0029] In one 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., tubular adenocarcinoma), lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma, e.g., gastroesophageal junction cancer), uterine cancer, cervical cancer, bladder cancer, pancreatic cancer, colorectal cancer, ovarian cancer, head and neck cancer, thymoma, and liver cancer.

[0030] In one embodiment, the cancer is breast cancer (for example, HER2+ breast cancer, for example, HER2+ / HR+ breast cancer, for example, HER2+ / ER+ breast cancer, or HER2+ / ER- breast cancer).

[0031] In a preferred embodiment, the cancer is HER2-positive cancer.

[0032] In a preferred embodiment, the cancer is i) HER2-amplified cancer and / or ii) HER2-mutated cancer, and / or iii) the cancer has HER2 protein overexpression.

[0033] In one embodiment, a TEAD inhibitor (e.g., IAG933) is administered on each of the first three days of a 7-day treatment cycle, and the treatment consists of at least two treatment cycles. In an alternative embodiment, a TEAD inhibitor (e.g., IAG933) is administered on the second day (e.g., day 1 and day 4) of a 6-day or 7-day (e.g., day 7) treatment cycle, and the treatment includes at least two treatment cycles.

[0034] In one embodiment, the daily dose of the TEAD inhibitor (e.g., IAG933) on each administration day is 15 mg to 1500 mg. In one embodiment, the daily dose of the TEAD inhibitor (e.g., IAG933) on each administration day is 100 mg to 1500 mg. In one embodiment, 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, 2 The dosages are 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.

[0035] In one embodiment, a HER2 inhibitor (e.g., lapatinib) is administered daily.

[0036] In one embodiment, the daily dose of a HER2 inhibitor (e.g., lapatinib) is 500 to 2000 mg (e.g., 1250 to 1500 mg, e.g., 1250 mg or 1500 mg).

[0037] In one embodiment, the combination is not fixed.

[0038] In one embodiment, the treatment further includes the administration of letrozole.

[0039] Therefore, the present invention provides embodiments numbered as follows: Embodiment 1. A method for treating cancer in a subject requiring such treatment, comprising administering a therapeutically effective dose of a TEAD inhibitor to the subject in combination with a HER2 inhibitor. Embodiment 2. A TEAD inhibitor for use in the treatment of cancer, wherein the treatment further comprises the administration of a HER2 inhibitor. Embodiment 3. A HER2 inhibitor for use in the treatment of cancer, wherein the treatment further comprises the administration of a TEAD inhibitor. Embodiment 4. A combination comprising i) a TEAD inhibitor, ii) a HER2 inhibitor, and optionally iii) an SHP2 inhibitor. Embodiment 5. The TEAD inhibitor is a YAP / TAZ-TEAD protein-protein interaction inhibitor, the method described in Embodiment 1, the TEAD inhibitor for use described in Embodiment 2, the HER2 inhibitor for use described in Embodiment 3, or the combination described in Embodiment 4. Embodiment 6. 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-(pyridine-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthoamide (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, and is the method described in Embodiment 1 or Embodiment 5, the TEAD inhibitor for use described in Embodiment 2 or Embodiment 5, the HER2 inhibitor for use described in Embodiment 3 or Embodiment 5, or the combination described in Embodiment 4 or Embodiment 5. Embodiment 7. The TEAD inhibitor is IAG933, the method according to 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. Embodiment 8. The HER2 inhibitor is an anti-HER2 antibody, the method according to any one of Embodiments 1 and 5-7, the TEAD inhibitor for use according to any one of Embodiments 2 and 5-7, the HER2 inhibitor for use according to any one of Embodiments 3 and 5-7, or any combination according to any one of Embodiments 4-7. Embodiment 9. The anti-HER2 antibody is trastuzumab, as described in Embodiment 8, the TEAD inhibitor for use as described in Embodiment 8, the HER2 inhibitor for use as described in Embodiment 8, or the combination as described in Embodiment 8. Embodiment 10. The HER2 inhibitor is selected from the list consisting of lapatinib, neratinib, tucatinib, trastuzumab, pirotinib, afatinib, pertuzumab, margetuximab, canertinib, dacomitinib, sapitinib, mbritinib, poziotinib, trastuzumab deruxtecan, and adtrastuzumab emtansine, according to the method described in any one of Embodiments 1 and 5-7, a TEAD inhibitor for use as described in any one of Embodiments 2 and 5-7, a HER2 inhibitor for use as described in any one of Embodiments 3 and 5-7, or a combination as described in any one of Embodiments 4-7. Embodiment 11. The HER2 inhibitor is lapatinib (e.g., lapatinib ditosylate, e.g., lapatinib ditosylate monohydrate), the method according to Embodiment 10, the TEAD inhibitor for use as described in Embodiment 10, the HER2 inhibitor for use as described in Embodiment 11, or the combination as described in Embodiment 10. Embodiment 12. The method according to any one of Embodiments 1 and 5-11, further comprising the administration of an SHP2 inhibitor, a TEAD inhibitor for use according to any one of Embodiments 2 and 5-11, or a HER2 inhibitor for use according to any one of Embodiments 3 and 5-11. Embodiment 13. 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, PCC-0208023, IACS- A method according to Embodiment 12, a TEAD inhibitor for use as described in Embodiment 12, a HER2 inhibitor for use as described in Embodiment 12, or any combination according to any one of Embodiments 4 to 11, selected from the group consisting of 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, bosiprotafib (RMC-4630), RLY1971, and TNO155. Embodiment 14. The SHP2 inhibitor is TNO155, the method described in Embodiment 13, the TEAD inhibitor for use as described in Embodiment 13, the HER2 inhibitor for use as described in Embodiment 13, or the combination as described in Embodiment 13. Embodiment 15. The cancer is a TEAD-dependent cancer, and the method is described in any one of Embodiments 1 and 5-14, a TEAD inhibitor for use as described in any one of Embodiments 2 and 5-14, or a HER2 inhibitor for use as described in any one of Embodiments 3 and 5-14. Embodiment 16. 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., tubular adenocarcinoma), lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer (e.g., esophagogastric junction cancer, e.g., squamous cell carcinoma of the esophagus, e.g., gastroesophageal junction cancer), uterine cancer, cervical cancer, bladder cancer, pancreatic cancer, colorectal cancer, ovarian cancer, head and neck cancer, thymoma, and liver cancer, and is a TEAD inhibitor for use as described in Embodiment 1 and any one of 5-15, or a HER2 inhibitor for use as described in Embodiment 3 and any one of 5-15. Embodiment 17. 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), the method according to Embodiment 16, the TEAD inhibitor for use as described in Embodiment 16, or the HER2 inhibitor for use as described in Embodiment 16. Embodiment 18. The cancer is a HER2-positive cancer, and the method is described in any one of Embodiments 1 and 5-17, a TEAD inhibitor for use as described in any one of Embodiments 2 and 5-17, or a HER2 inhibitor for use as described in any one of Embodiments 3 and 5-17. Embodiment 19. The cancer is i) HER2-amplified cancer and / or ii) HER2-mutated cancer and / or iii) the cancer has HER2 protein overexpression, wherein the cancer is a TEAD inhibitor for use as described in any one of Embodiments 1 and 5-18, or a HER2 inhibitor for use as described in any one of Embodiments 2 and 5-18. Embodiment 20. A 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, wherein the treatment is as described in any one of Embodiments 1 and 5-19, a TEAD inhibitor for use as described in any one of Embodiments 2 and 5-19, or a HER2 inhibitor for use as described in any one of Embodiments 3 and 5-19. Embodiment 21. The daily dose of the TEAD inhibitor (e.g., IAG933) for each administration day is 15 mg to 1500 mg, the method according to any one of Embodiments 1 and 5-20, the TEAD inhibitor for use according to any one of Embodiments 2 and 5-20, or the HER2 inhibitor for use according to any one of Embodiments 3 and 5-20. Embodiment 22. The method according to Embodiment 21, the TEAD inhibitor for use as described in Embodiment 21, or the HER2 inhibitor for use as described in Embodiment 21, wherein the daily dose of the TEAD inhibitor (e.g., IAG933) on each administration day is 100 mg to 1500 mg. Embodiment 23. The daily dose of the TEAD inhibitor (e.g., IAG933) for 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. The method according to Embodiment 22, the TEAD inhibitor for use as described in Embodiment 22, or the HER2 inhibitor for use as described in Embodiment 22, wherein the amount is 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. Embodiment 24. A HER2 inhibitor (e.g., lapatinib) administered daily, the method according to any one of Embodiments 1 and 5-23, a TEAD inhibitor for use according to any one of Embodiments 2 and 5-23, or a HER2 inhibitor for use according to any one of Embodiments 3 and 5-23. Embodiment 25. 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), the method according to 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.

[0040] definition IAG933 is a YAP / TAZ-TEAD protein-protein interaction inhibitor useful for treating diseases or conditions mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interactions, particularly cancers having (i) one or more YAP / TAZ fusions, (ii) one or more NF2, LATS1, LATS2 cleavage mutations or deletions, or (iii) one or more functional YAP / TAZ fusions. The synthesis of IAG933 is described in International Publication No. 2021 / 186324 (Example 155), which is incorporated by reference.

[0041] IAG933 has the following chemical structure: [ka] It also has the chemical name 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide. Lapatinib has the following chemical structure [ka] It also has the chemical name N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulfonyl)ethyl]amino}methyl)-2-furyl]-quinazolinamine. This is commercially available as Tykerb or Tyverb in the form of a ditosylate monohydrate, N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis(4-methylbenzenesulfonate) monohydrate. Lapatinib is also known as LAP016 and GW-572016.

[0042] As used herein, the term "compound A" means [ka] This 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 described in Example 144 of International Publication No. 2021 / 186324 and is a close relative of IAG933.

[0043] As used herein, the term "compound B" means [ka] This refers to N-(1-(pyridine-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthoamide. Compound B is also known as VT-104, and its synthesis has been described in the Art. It is also available for commercial purchase.

[0044] As used herein, the term "compound C" is used [ka] This refers to N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide. Compound C is also known as K-975 and is commercially available.

[0045] As used herein, the term "compound D" means [ka] This refers to 3-bromo-5-(3-(4-chlorophenoxy)-4-methylphenyl)-4,5-dihydroisoxazole. The synthesis of compound D is described in International Publication No. 2020 / 243423.

[0046] As used herein, the term "compound E" means [ka] This refers to a close relative of IAG933. The synthesis of compound E is described in International Publication No. 2021 / 186324.

[0047] In the descriptions of the present invention (especially in the following claims), the terms “one (a),” “one (an),” and “it,” and similar terms, shall be construed to include both singular and plural forms unless otherwise specifically indicated herein or unless the context clearly contradicts this. The plural form, when used for compounds, patients, cancer, and the like, shall also mean a single compound, patient, or the like.

[0048] References to “the present invention” in this specification are intended to reflect some embodiments of the invention disclosed herein and should not be construed as unnecessarily limiting the subject matter claimed.

[0049] As used herein, the term "synergistic effect" refers to the combined action of two or three therapeutic agents that produce a greater effect (e.g., an effect of delaying the progression of proliferative disorders, particularly cancer or its symptoms) compared to the simple sum of the effects of each drug administered individually. Synergistic effects can be calculated using preferred methods such as the Sigmoid-Emax equation (Holford, NHG and Scheiner, LB, 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, TC and Talalay, P., Adv. Enzyme Regul. 22:27-55 (1984)). Applying each of the equations mentioned above to experimental data to create corresponding graphs may help evaluate the effects of drug combinations. The corresponding graphs associated with the equations mentioned above are the concentration-effect curve, the isobologram curve, and the combined exponential curve, respectively.

[0050] The term "pharmaceutically acceptable salt" refers to a salt of a compound that retains its biological efficacy and properties and is not typically biologically or otherwise undesirable. This compound may be capable of forming an acid addition salt in the presence of an amino group.

[0051] Unless otherwise indicated or expressly indicated herein, 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.

[0052] "Combination" or "pharmaceutical combination" is defined herein as referring to a fixed combination, non-fixed combination, or kit of parts in a single unit dosage form for combination administration, in which therapeutic agents can be administered independently and simultaneously, or separately together within a time interval that allows the combination partners to exert a cooperative (e.g., synergistic) effect. Thus, single compounds of the pharmaceutical combination of the present invention may be administered simultaneously or sequentially.

[0053] Furthermore, the pharmaceutical combinations of the present invention may be in the form of fixed combinations or non-fixed combinations.

[0054] The term "fixed combination" means that the therapeutic agent (e.g., the single compound in the combination) is in the form of a single entity or dosage form.

[0055] The term "non-fixed combination" means that the therapeutic agents (e.g., a single compound of the combination) are administered to the patient simultaneously or sequentially as separate entities or dosage forms without specific time constraints, preferably such administration provides therapeutically effective levels of the two therapeutic agents in the body of the target subject (e.g., mammal or human).

[0056] The pharmaceutical combination may further include 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.

[0057] As used herein, the terms “carrier” or “pharmaceutically acceptable carrier” include all solvents, dispersions, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption retarders, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, colorants, and the like, as well as combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th Ed., Mack Printing Company, 1990, pp. 1289–1329). Unless any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is intended.

[0058] The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problems or complications, within the bounds of good medical judgment, and that is commensurate with a reasonable benefit-risk ratio.

[0059] Generally, “pharmaceutical composition” is defined herein as a mixture or solution comprising at least one therapeutic agent to be administered to a subject (e.g., a mammal or a human). These pharmaceutical combinations may be formulated as pharmaceutical compositions suitable for enteral or parenteral administration, in unit dosage forms such as sugar-coated tablets, tablets, capsules, suppositories, or ampoules. Unless otherwise indicated, these are prepared by methods known to themselves, such as various conventional mixing, grinding, direct compression, granulation, sugar coating, dissolution, lyophilization processes, or manufacturing techniques readily apparent to those skilled in the art. Since the required effective amount can be achieved by administering multiple dosage units, it will be understood that the unit content of the combination partner contained in individual doses of each dosage form does not need to constitute an effective amount in itself. Pharmaceutical compositions may contain about 0.1% to about 99.9%, preferably about 1% to about 60% of the therapeutic agent. Those skilled in the art can, without any undue burden, select one or more of the aforementioned carriers for specific desired properties of the dosage form by routine experimentation. The amount of each carrier used may vary within the conventional range in the art. The following reference discloses the techniques and excipients used to formulate oral dosage forms: The Handbook of Pharmaceutical Excipients, 4 th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003) and Remington: the Science and Practice of Pharmacy, 20 thSee 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 a combination of drugs in the oral dosage form or with granules containing the individual drugs of the drug combination. In the latter embodiment, the combined mixture may be further blended, for example, by a V-blender, and then compressed or molded into a tablet (e.g., a single tablet), which may be encapsulated in a capsule or filled into a pouch. Clearly, the pharmaceutical combinations of the present invention may be used to manufacture pharmaceuticals.

[0060] The present invention relates to such pharmaceutical combinations or pharmaceutical compositions that are particularly useful as pharmaceuticals.

[0061] Specifically, the combination or composition of the present invention may be applied to the treatment of cancer.

[0062] The present invention also relates to the use of the pharmaceutical combination or pharmaceutical composition of the present invention for the preparation of pharmaceuticals for the treatment of cancer, and to a method for treating cancer in a subject in need thereof, which includes administering a therapeutically effective amount of the pharmaceutical combination or pharmaceutical composition according to the present invention to the subject.

[0063] As used herein, the term “treatment” includes treatments that reduce, alleviate or mitigate at least one symptom of the subject, treatments that extend progression-free survival, treatments that extend overall survival, treatments that extend the duration of response, or treatments that delay the progression of the disease. For example, a treatment could be the alleviation of one or more symptoms of a disorder or the complete eradication of a disorder such as cancer. Within the scope of the present invention, the term “treatment” also means preventing or delaying the onset (i.e., the period before the clinical symptoms of the disease) and / or reducing the risk of developing or worsening the disease in a patient, e.g., a mammal, and in particular, the patient is a human. As used herein, the term “treatment” includes inhibition of tumor growth incorporating direct inhibition of primary tumor growth and / or systemic inhibition of metastatic cancer cells.

[0064] In this specification, “subject,” “individual,” or “patient” are used synonymously and refer to vertebrates, preferably mammals, and more preferably humans. Examples of mammals include, but are not limited to, mice, monkeys, humans, livestock, sport animals, and pets.

[0065] As used herein, an object "needs" or "requires" a treatment if such object would benefit from such treatment biologically, medically, or in terms of quality of life.

[0066] The term "includes" is similar to "contains" in that it includes "consist of," for example, a composition containing X may contain something that is exclusive to X or additional to it (e.g., X and Y).

[0067] The term "therapeutic dose" of the compound of the present invention (e.g., a chemical entity or a biological agent) refers to the amount of the compound of the present invention that induces a target biological or medical response, for example, by inducing a reduction or inhibition of enzyme or protein activity, or by improving symptoms, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease. In one embodiment, the in vivo therapeutic dose may range from about 0.1 to 500 mg / kg or from about 1 to 100 mg / kg, depending on the route of administration.

[0068] As used herein, the terms “inhibit,” “inhibit,” or “to inhibit” refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0069] The optimal dose of each combination partner for cancer treatment can be empirically determined for each individual using known methods and will depend on a variety of factors, including, but not limited to, the stage of disease progression, the individual's age, weight, overall health, sex and diet, time and route of administration, and other medications the individual is taking. The optimal dose can be established using routine tests 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 in the combination that would typically be administered if the drugs were administered alone.

[0070] The frequency of medication may vary depending on the compound used and the specific condition being treated or prevented. Generally, it is preferable to use the minimum dose sufficient to provide effective treatment. Patients may generally be monitored for therapeutic efficacy using assays suitable for the condition being treated or prevented, which will be well known to those skilled in the art.

[0071] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Various examples of cancer are described herein, including, 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, and ovarian cancer.

[0072] The terms “tumor” and “cancer” are used herein as synonymous, and for example, both terms encompass solid and liquid tumors, such as diffuse or circulating tumors. As used herein, the terms “cancer” or “tumor” include precancerous and malignant cancers and tumors.

[0073] As used herein, the term “TEAD-dependent cancer” means any cancer in which TEAD (i.e., TEAD1, TEAD2, TEAD3 and / or TEAD4) or its variants or variants are known to be associated, for example, with genetically altered Hippo pathways.

[0074] In one embodiment, the HER2 inhibitor is also an EGFR inhibitor.

[0075] As used herein, the term “HER2-positive cancer” means any cancer in which the cancer is HER2-amplified and / or HER2-mutated and / or has HER2 protein overexpression.

[0076] In one embodiment, the HER2 inhibitor is an anti-HER2 antibody (e.g., trastuzumab). However, in a preferred embodiment, the HER2 inhibitor is a small molecule HER2 inhibitor (e.g., a HER2 inhibitor and an EGFR inhibitor, e.g., lapatinib). In one embodiment, the HER2 inhibitor is a tyrosine kinase inhibitor, e.g., a tyrosine kinase inhibitor that inhibits both HER2 and EGFR, e.g., lapatinib. It should be understood that the effects of trastuzumab are generally considered to be underestimated in vitro compared to in vivo. This may be due to additional immunomodulatory effects by NK cells that result in a more enhanced effect in vivo, particularly when the model is not immunosuppressed.

[0077] As used herein, the term “TEAD inhibitor” refers to a compound having the activity of an inhibitor of TEAD (i.e., TEAD1, TEAD2, TEAD3, and / or TEAD4) or a variant or variant thereof, which can be assayed in vitro, in vivo, or in cell lines. For example, in the biochemical assay described in International Publication No. 2021 / 186324, and / or the reporter gene cell assay described in International Publication No. 2021 / 186324, and / or the proliferation cell assay described in International Publication No. 2021 / 186324, IC 50 [μM] is <10, e.g., <5, e.g., <2, e.g., <1, e.g., <0.5, e.g., <0.2, e.g., <0.1. International Publication No. 2021 / 186324 is incorporated herein by reference.

[0078] The YAP / TAZ-TEAD protein-protein interaction inhibitors described herein refer to TEAD inhibitors that inhibit TEAD activity by inhibiting the interaction between the YAP / TAZ complex and TEAD. Overactivation 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.

[0079] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2021 / 087008.

[0080] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2021 / 102204.

[0081] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2020 / 214734.

[0082] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2020 / 097389.

[0083] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2019 / 222431.

[0084] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2019 / 113236.

[0085] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2019 / 040380.

[0086] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2018 / 204532.

[0087] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2017 / 058716.

[0088] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2022 / 159986.

[0089] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2022 / 120354.

[0090] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2022 / 120355.

[0091] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2022 / 120353.

[0092] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2020 / 243423.

[0093] In one embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in International Publication No. 2020 / 243415.

[0094] In one embodiment, the TEAD inhibitor is IAG933, namely 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide. IAG933 has the following structure [ka] It has. Another chemical name for IAG933 is (4P)-4-{(2S)-5-chloro-6-fluoro-2-phenyl-2-[(2S)-pyrrolidine-2-yl]-2,3-dihydro-1-benzofuran-4-yl}5-fluoro-6-(2-hydroxyethoxy)-N-methylpyridine-3-carboxamide.

[0095] In one embodiment, the TEAD inhibitor is compound A, namely 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] It has the following chemical name: (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.

[0096] The synthesis and characterization of IAG933 (Example 155) and compound A (Example 144) are described in International Publication No. 2021 / 186324, which is incorporated herein by reference.

[0097] In one embodiment in which TNO155 is present as part of a method or combination, TNO155 is administered orally in doses of approximately 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.

[0098] In one embodiment in which TNO155 is present as part of a method or combination, the daily dose of TNO155 is a 21-day cycle consisting of two weeks of administration followed by one week of rest.

[0099] In one embodiment in which TNO155 is present as part of a method or combination, the daily dose of TNO155 is 20 mg.

[0100] In one embodiment in which TNO155 is present as part of a method or combination, the administration schedule for TNO155 is once daily (QD) or twice daily (BID).

[0101] In one embodiment in which TNO155 is present as part of a method or combination, TNO155 is administered orally.

[0102] "Amphoteric" or "amphoteric form" refers to a compound that contains both a positively charged functional group and a negatively charged functional group.

[0103] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention pertains.

[0104] Methods and materials similar to or equivalent to those described herein may be used in carrying out or testing the present invention, but preferred methods and materials are described below. All publications, patent applications, patents and other references referenced herein are incorporated in their entirety by reference. Furthermore, materials, methods and examples are illustrative and not intended to limit. Unless otherwise indicated herein or unless explicitly stated otherwise, all methods described herein may be carried out in any preferred order. The use of any examples or exemplary words provided herein (e.g., "etc.") is intended solely to further illustrate the invention and not to limit the scope of the invention as otherwise claimed.

[0105] isomer Any chiral atom (e.g., carbon or similar) of the compounds that can be used in the present invention may exist in a racemic state or may be rich in one enantiomer, for example, in (R)-, (S)-, or (R,S)- configurations. In certain embodiments, each chiral atom has an enantiomer 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 having unsaturated double bonds may, where possible, exist in cis-(Z)- or trans-(E)- form.

[0106] Therefore, as used herein, the compounds that can be used in the present invention may exist in one form of possible stereoisomers, rotational isomers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antagonistics), racemates, or mixtures thereof.

[0107] Any mixture from which stereoisomers are obtained can be separated, for example, by chromatography and / or fractional recrystallization, based on the physicochemical differences of the constituent components, into pure or substantially pure geometric or optical isomers, diastereomers, or racemates.

[0108] Any racemic mixture from which compounds or intermediates that can be used in the present invention are obtained can be divided into optical counterparts by known methods, for example, by separating the diastereomer salts obtained with an optically active acid or base and liberating the optically active acidic or basic compound. In particular, compounds that can be used in the present invention can be divided into their optical counterparts by fractional crystallization of salts formed with an optically active acid (e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-thuloyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid) using the basic moiety. Racemic compounds or racemic intermediates that can be used in the present invention can also be divided by chiral chromatography (e.g., high-pressure liquid chromatography (HPLC) using a chiral adsorbent).

[0109] Compounds that can be used in the present invention (i.e., compounds of formula (I) containing groups capable of acting as donors and / or acceptors for hydrogen bonding) may be able to form cocrystals with suitable cocrystal-forming agents. These cocrystals can be prepared from compounds of formula (I) by known cocrystal-forming procedures. Such procedures include grinding, heating, co-sublimation, eu-melting, or contacting the compound of formula (I) in solution with a cocrystal-forming agent under crystallization conditions, and then isolating the resulting cocrystal. Suitable cocrystal-forming agents are those described in International Publication No. 2004 / 078163.

[0110] Furthermore, the compounds (including salts thereof) that can be used in the present invention may also be obtained in the form of hydrates, or may include other solvents used for their crystallization. The compounds of the present invention can, essentially 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 those commonly used in the pharmaceutical field and are known to be harmless to the recipient, such as water, ethanol, and the like. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0111] Dosage form The combination of the present invention may, for example, involve a unit dose of about 1 to 2000 mg of each active ingredient for a subject weighing about 50 to 70 kg.

[0112] This should be understood as "administered on each of the first three days of a 7-day treatment cycle," meaning that TEAD inhibitors or their pharmaceutically acceptable salts are administered on each of the first three days of a 7-day treatment cycle and not on the subsequent four days of the 7-day treatment cycle.

[0113] Preferably, at least two treatment cycles are consecutive, i.e., the second treatment cycle follows immediately after the first treatment cycle. Therefore, for example, the present invention includes: Days 1-3: TEAD inhibitors are administered daily. Days 4-7: TEAD inhibitors not administered. Days 8-10: TEAD inhibitors administered daily, Days 11-14: No TEAD inhibitors administered.

[0114] In this example, days 1-3 and days 8-10 are administration days. Therefore, "administration day" refers to any day on which the TEAD inhibitor is administered to the patient.

[0115] If present, the third (or fourth, etc.) treatment cycle preferably follows immediately after the previous treatment cycle. Therefore, in one embodiment where three treatment cycles exist, the present invention includes: Days 1-3: TEAD inhibitors are administered daily. Days 4-7: TEAD inhibitors not administered. Days 8-10: TEAD inhibitors are administered daily. Days 11-14: TEAD inhibitors not administered. Days 15-17: TEAD inhibitors administered daily, Days 18-21: No TEAD inhibitors administered.

[0116] In one embodiment, there are three or more treatment cycles, for example, four or more treatment cycles, for example, five or more treatment cycles, for example, six or more treatment cycles, for example, eight or more treatment cycles, for example, ten or more treatment cycles.

[0117] In an alternative embodiment, 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, for example i) days 1 and 4 of a 6-day schedule, or ii) days 1 and 4 of a 7-day schedule, for example day 1 and 4 of a 7-day schedule.

[0118] As used herein, the term “daily dose” (for example, of a TEAD inhibitor) refers to the total dose (for example, of a TEAD inhibitor) administered to an individual in a single 24-hour period.

[0119] In this specification, when referring to a dose in milligrams (mg), for example, of a TEAD inhibitor, it means an equivalent amount of the free form (i.e., excluding, for example, salts or co-crystal partners and any solvent present).

[0120] 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.

[0121] Preferably, TEAD inhibitors are taken with a glass of water without chewing the capsule or tablet.

[0122] If a patient is assigned a dose level requiring multiple capsules / tablets of a TEAD inhibitor, the capsules / tablets should be taken consecutively within the shortest possible time interval, for example, within 5 minutes.

[0123] 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.

[0124] Preferably, the TEAD inhibitor is administered in a fasted state, i.e., at least one hour or two hours before a meal.

[0125] combination "Combination" refers to a combination administration in which a fixed combination in one unit dosage form or a compound of formula (I) or a pharmaceutically acceptable salt thereof and a combination partner (e.g., another drug, also referred to below as the "therapeutic agent" or "adjuvant") are administered simultaneously and independently, or separately within a time interval (in particular, these time intervals allow the combination partner to exhibit a synergistic effect). A single component may be packaged as a kit or individually. One or both of these components (e.g., powder or liquid) may be reconstituted or diluted to a desired dose before administration. The terms "co-administration" or "combination administration" or similar, as used herein, mean the administration of a selected combination partner to a single subject (e.g., a patient) requiring it, and are intended to include treatment regimens in which the drugs are not necessarily administered by the same route of administration or simultaneously. The term "pharmaceutical combination," as used herein, means a product resulting from a mixture or combination of multiple therapeutic agents, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents (e.g., the combination partners of the present invention) are administered to the patient simultaneously in the form of both a single entity or dosage. The term "non-fixed combination" means that the therapeutic agents (e.g., the combination partners of the present invention) are administered to the patient simultaneously, in parallel, or sequentially without any specific time constraints, as separate entities, and such administration results 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).

[0126] In the combination therapy 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 (i) assembled into a combination therapy before the combination product is delivered to the physician (e.g., in the case of a kit containing the therapeutic agents), (ii) assembled into a combination therapy by the physician himself (or under the guidance of the physician) immediately before administration, or (iii) assembled into a combination therapy by the patient himself, for example, during continuous administration of the therapeutic agents. [Examples]

[0127] Example 1 The in vitro survival rate of the gastric cancer cell line REFR-GC-1B was evaluated using CellTiterGlo after 7 days of treatment with IAG933 in combination with lapatinib (±TNO155). REFR-GC-1B cell growth was inhibited by IAG933 alone, but not by lapatinib alone. Furthermore, 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).

[0128] Example 2 In vitro survival of the gastric cancer cell line SNU-216 was evaluated using CellTiterGlo after 7 days of treatment with IAG933 in combination with lapatinib (±TNO155). SNU-216 cell growth was inhibited by IAG933 alone and lapatinib alone (maximum effect with lapatinib alone: ​​quiescence). Furthermore, 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 2).

[0129] Example 3 The in vitro survival rate of the gastric cancer cell line NCI-N87 was evaluated using CellTiterGlo after 7 days of treatment with IAG933 in combination with lapatinib (±TNO155). Growth of NCI-N87 cells was inhibited by IAG933 alone (maximum effect: quiescence) and lapatinib alone. Furthermore, 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).

[0130] Example 4 In vitro survival of the gastric cancer cell line MKN-7 was evaluated using CellTiterGlo after 7 days of treatment with IAG933 in combination with lapatinib (±TNO155). MKN-7 cell growth was inhibited by IAG933 alone (maximum effect: quiescence) and lapatinib alone (maximum effect less than quiescence). Furthermore, 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 IAG933. Further combination with TNO155 was beneficial at lower concentrations of lapatinib (Figure 4).

[0131] Example 5 In vitro survival of the non-small cell lung cancer cell line NCI-H2170 was evaluated using CellTiterGlo after 7 days of treatment with IAG933 in combination with lapatinib (±TNO155). Growth of NCI-H2170 cells was inhibited by lapatinib alone, but not by IAG933 alone. Furthermore, 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).

[0132] Example 6 In vitro survival of the non-small cell lung cancer cell line CALU-3 was evaluated using CellTiterGlo after 7 days of treatment with IAG933 in combination with lapatinib (±TNO155). CALU-3 cell growth was inhibited by IAG933 alone (maximum effect: quiescence) and lapatinib alone. Furthermore, 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).

[0133] Example 7 In vitro survival of the endometrial cancer cell line TEN was evaluated using CellTiterGlo after 7 days of treatment with IAG933 in combination with lapatinib (±TNO155). TEN cell growth was inhibited by IAG933 alone and lapatinib alone (maximum effect below quiescence). Furthermore, 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).

[0134] Example 8 In vitro survival of the esophageal cancer cell line OE-19 was evaluated using CellTiterGlo after 7 days of treatment with IAG933 in combination with lapatinib (±TNO155). OE-19 cell growth was inhibited by IAG933 alone (maximum effect below quiescence) and lapatinib alone. Furthermore, 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 8).

[0135] Example 9 In vitro survival of the esophageal cancer cell line TE-4 was evaluated using CellTiterGlo after 7 days of treatment with IAG933 in combination with lapatinib (±TNO155). TE-4 cell growth was inhibited by lapatinib alone, but not by IAG933 alone. Furthermore, 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 9).

[0136] Example 10 In the SNU-216 gastric cancer model, IAG933 alone and IAG933 in combination with lapatinib (Figure 10-top) or trastuzumab (Figure 10-bottom) inhibited cell growth during treatment and delayed growth during compound washout. The dual combination delayed cell growth more than IAG933 alone, and the triple combination with TNO155 completely inhibited growth. 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, and the culture medium was refreshed once a week.

[0137] Example 11 In the Calu-3 non-small cell lung cancer model, the combination of IAG933 and lapatinib (Figure 11-top) inhibited cell growth during treatment and delayed growth during compound washout. The addition of TNO155 further delayed cell growth. With or without TNO155, IAG933 and trastuzumab (Figure 11-bottom) delayed cell growth during treatment. 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 the culture medium refreshed once a week.

[0138] Example 12 In cell death assays (Figure 12-top), IAG933 with lapatinib or trastuzumab resulted in a reduction in cell number and an increase in the percentage of dead cells in NCI-N87 and SNU-216 gastric cancer cells. The addition of TNO155 enhanced these effects. In clonal genicity assays after crystal violet staining at 38 days (Figure 12-bottom), no cell death or clonal growth was observed in SNU-216 and MKN-7 gastric cancer cells with the IAG933 + lapatinib ± TNO155 combination. SNU-216 and MKN-7 were less sensitive to IAG933 monotherapy in long-term treatment.

[0139] IAG933 + lapatinib: 600nM IAG933 and 100nM lapatinib. IAG(933) + TNO(155) + lapatinib: 600nM IAG933, 200nM TNO155 and 100nM lapatinib.

[0140] Example 13 The combination of IAG933 with lapatinib (Figure 13-top) or trastuzumab (Figure 13-bottom) inhibited cell growth during treatment in the NCI-N87 gastric cancer model and resulted in delayed growth during compound washout. Further inclusion of TNO155 resulted in further delay of IAG933 growth with trastuzumab and completely inhibited IAG933 cell growth with lapatinib even during compound washout. 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 the medium refreshed once a week.

[0141] Example 14 The combination of IAG933 with lapatinib (Figure 14-top) or trastuzumab (Figure 14-bottom) inhibited cell growth during treatment in the MKN-7 gastric cancer model and resulted in delayed growth during compound washout. Further inclusion of TNO155 resulted in further delay of IAG933 growth with trastuzumab and completely inhibited IAG933 cell growth with lapatinib even during compound washout. 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 the medium refreshed once a week.

[0142] Example 15 In the RERF-GC-1B gastric cancer model, IAG933 alone and IAG933 in combination with lapatinib (Figure 15-top) or trastuzumab (Figure 15-bottom) inhibited cell growth during treatment and resulted in delayed growth during compound washout, with the combined effects being more pronounced. Further inclusion of TNO155 completely inhibited cell growth in both combinations, even during compound washout. 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 the medium refreshed once a week.

[0143] Example 16 Regardless of the presence or absence of TNO155, IAG933 and lapatinib (Figure 16-top) completely abolished cell growth and eliminated viable cells in the NCI-H2170 non-small cell lung cancer model, as evidenced by the absence of proliferation during compound washout. The combination of IAG933 and trastuzumab (Figure 16-bottom) inhibited cell proliferation, and the addition of TNO155 resulted in more pronounced cell death, as evidenced by compound washout, after which growth resumed with little viability. Cell proliferation was monitored using an Incucyte® S3 live cell analyzer (Sartorius). Compound treatments were refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment.

[0144] Example 17 In vitro survival rates for gastric cancer cell line SNU-216 and non-small cell lung cancer cell line NCI-H2170 were evaluated using CellTiterGlo after 6 days of treatment with compound A in combination with lapatinib. Growth of both SNU-216 and NCI-H2170 cells was inhibited by compound A alone and lapatinib alone. Furthermore, the combination of compound A and lapatinib showed synergistic growth inhibition in both cell lines compared to either treatment alone.

[0145] Example 18 In vitro survival rates for gastric cancer cell line SNU-216 and non-small cell lung cancer cell line NCI-H2170 were evaluated using CellTiterGlo after 6 days of treatment with compound B in combination with lapatinib. Growth of both SNU-216 and NCI-H2170 cells was inhibited by lapatinib alone, but not by compound B alone. The combination of compound B and lapatinib showed synergistic growth inhibition in both cell lines compared to either treatment alone.

[0146] Example 19 In vitro survival rates for gastric cancer cell line SNU-216 and non-small cell lung cancer cell line NCI-H2170 were evaluated using CellTiterGlo after 6 days of treatment with compound C in combination with lapatinib. Growth of both SNU-216 and NCI-H2170 cells was inhibited by lapatinib alone, but not by compound C alone (at least except at very high concentrations of compound C). The combination of compound C and lapatinib showed synergistic growth inhibition in both cell lines compared to either treatment alone.

[0147] Example 20 In vitro survival rates for gastric cancer cell line SNU-216 and non-small cell lung cancer cell line NCI-H2170 were evaluated using CellTiterGlo after 6 days of treatment with compound D in combination with lapatinib. Growth of both SNU-216 and NCI-H2170 cells was inhibited by lapatinib alone but not by compound D (at least except at very high concentrations of compound D). The combination of compound D and lapatinib showed synergistic growth inhibition in both cell lines compared to either treatment alone.

[0148] Example 21 The combination of IAG933 and lapatinib (Figure 21) (+ / - fulvestrant) resulted in enhanced growth control compared to IAG933 alone or lapatinib alone in an EFM192A breast cancer (HR+ / HER2+) model. Growth was monitored using an Incucyte® S3 live cell analyzer (Sartorius). Compound treatment was refreshed weekly / every 7 days.

[0149] Example 22 The combination of IAG933 and lapatinib (Figure 22) resulted in enhanced growth regulation in the OE-19 esophageal cancer model compared to IAG933 alone or lapatinib alone. Further inclusion of TNO155 resulted in further enhancement of growth regulation. 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 the medium refreshed once a week.

[0150] Example 23 The combination of IAG933 and lapatinib (Figure 23) resulted in enhanced growth control in the TEN endometrial cancer model compared to IAG933 alone or lapatinib alone. Further inclusion of TNO155 resulted in further enhancement of growth control. Growth was monitored using an Incucyte® S3 live cell analyzer (Sartorius). The compound treatment was refreshed on day 7 and removed on day 14. Cells were left untreated for the remainder of the experiment, with the medium refreshed once a week.

[0151] Example 24 The NCI-H2170 HER2-amplified lung cancer xenograft model was used for pharmacological studies in mice. Two control groups, treated with vehicle and hIgG1 kappa LC, and IAG933, showed rapid tumor growth, with an average tumor size of 1000 mm at 9-20 days. 3 Trastuzumab therapy resulted in a moderate reduction in tumor growth and an average tumor volume of 649 mm² at day 22. 3 This results in a stabilization of tumor growth, reaching 414 mm, thanks to the combination of trastuzumab and IAG933. 3 The average value was obtained on day 28 after the first dose.

[0152] Example 25 The NCI-N87 HER2-amplified gastric cancer xenograft model will be used for pharmacological studies in mice. Tumors treated with control therapy: vehicle and hIgG1 kappa LC were 931 and 664 mm at day 26, respectively. 3had reached the size. Trastuzumab and Compound E therapy resulted in tumor stasis, and the average tumor volume on day 26 was 194 and 279 mm 3 respectively. The combination of trastuzumab and Compound E induced almost complete tumor regression, with an average of 17 mm 3 obtained on day 26 after the first administration. In the latter group, treatment was stopped on day 28, and the tumors were further monitored until day 98. A sustained antitumor effect was observed with an average tumor size of 160 mm 3 on day 98, still less than the size at randomization.

[0153] Example 26 HER2 inhibition has been found to lead to downregulation of the MAPK pathway, which increases the expression and activation of BIM, while YAP-TEAD inhibition leads to an increase in BMF. BIM and BMF are apoptosis-promoting proteins. Therefore, higher expression results in a higher degree of apoptosis and cell death.

[0154] Example 27 The in vitro viability of breast (HR+ / HER2+) cancer cell line EFM192A was evaluated using CellTiterGlo after 6 days of treatment with IAG933 combined with lapatinib (±TNO155) or fulvestrant combined with lapatinib + IAG933. The growth of EFM192A cells was inhibited less by lapatinib alone than by IAG933 alone (less than stasis), and inhibition was not achieved by fulvestrant alone. Furthermore, 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. Furthermore, the combination of fulvestrant and lapatinib + IAG933 did not show further synergistic growth inhibition compared to IAG933 + lapatinib (±TNO155) (Figure 27).

Claims

1. A method for treating cancer in a subject requiring such treatment, comprising administering a therapeutically effective dose of a TEAD inhibitor to the subject in combination with a HER2 inhibitor.

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

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

4. i) a TEAD inhibitor, ii) a HER2 inhibitor, and optionally a combination including iii) an SHP2 inhibitor.

5. The TEAD inhibitor is a YAP / TAZ-TEAD protein-protein interaction inhibitor, according to 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.

6. 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-(pyridine-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthoamide (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, according to the method according to claim 1 or 5, the TEAD inhibitor for use according to claim 2 or 5, the HER2 inhibitor for use according to claim 3 or 5, or the combination according to claim 4 or 5.

7. The method according to claim 6, wherein the TEAD inhibitor is IAG933, 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.

8. The HER2 inhibitor is an anti-HER2 antibody, according to the method according to any one of claims 1 or 5 to 7, the TEAD inhibitor for use according to any one of claims 2 or 5 to 7, the HER2 inhibitor for use according to any one of claims 3 or 5 to 7, or the combination according to any one of claims 4 to 7.

9. The method according to 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 HER2 inhibitor is selected from the list consisting of lapatinib, neratinib, tucatinib, trastuzumab, pirotinib, afatinib, pertuzumab, margetuximab, canertinib, dacomitinib, sapitinib, mbritinib, poziotinib, trastuzumab deruxtecan, and adtrastuzumab emtansine, according to the method according to any one of claims 1 or 5 to 7, a TEAD inhibitor for use according to any one of claims 2 or 5 to 7, a HER2 inhibitor for use according to any one of claims 3 or 5 to 7, or a combination according to any one of claims 4 to 7.

11. The method according to claim 10, the HER2 inhibitor being lapatinib (e.g., lapatinib ditosylate, e.g., lapatinib ditosylate monohydrate), 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.

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

13. The aforementioned SHP2 inhibitors are 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-1 The method according to claim 12, a TEAD inhibitor for use according to claim 12, a HER2 inhibitor for use according to claim 12, or any combination according to any one of claims 4 to 11, wherein the TEAD inhibitor for use according to claim 12, a HER2 inhibitor for use according to claim 12, or any combination according to any one of claims 4 to 11.

14. The method according to claim 13, wherein the SHP2 inhibitor is TNO155, 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.

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

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

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

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

20. The method according to any one of claims 1 or 5 to 19, 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 comprises at least two treatment cycles, the TEAD inhibitor for use according to any one of claims 2 or 5 to 19, or the HER2 inhibitor for use according to any one of claims 3 or 5 to 19.

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

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

23. The daily dose of the TEAD inhibitor (e.g., IAG933) for 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. The method according to claim 22, wherein the amount is g, 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, a TEAD inhibitor for use according to claim 22, or a HER2 inhibitor for use according to claim 22.

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

25. The method according to any one of claims 1 or 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), a TEAD inhibitor for use according to any one of claims 2 or 5 to 24, or a HER2 inhibitor for use according to any one of claims 3 or 5 to 24.

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