WO2024176130A1

WO2024176130A1 - Tead- and her2-inhibitor combinations for treating cancer

Info

Publication number: WO2024176130A1
Application number: PCT/IB2024/051654
Authority: WO
Inventors: Sabrina BALTSCHUKAT; Emilie Chapeau; Jason FARIS; Patricia JAAKS
Original assignee: Novartis Ag
Priority date: 2023-02-23
Filing date: 2024-02-21
Publication date: 2024-08-29

Abstract

The invention relates to a pharmaceutical combination comprising a TEAD inhibitor in combination with a HER2 inhibitor, as well as methods of treating cancers using said combination.

Description

TEAD- AND HER2-INHIBITOR COMBINATIONS FOR TREATING CANCER

FIELD OF THE DISCLOSURE

The present invention relates to a pharmaceutical combination comprising a TEAD inhibitor in combination with a HER2 inhibitor, as well as methods of treating cancers using said combination.

BACKGROUND

The advent of targeted therapies for cancer has increased patient lifespan for various malignancies and helped to appreciate the complexity of tumors through the study of drug resistance mechanisms. The fact that clinical responses to targeted agents are generally incomplete and/or transient results from a multitude of factors that can be broadly put into two classes: toxicities that prevent optimal dosing of drugs and consequently limit target engagement (Brana and Siu 2012, Chapman, Solit et al. 2014), and the ability of cancers to adapt and maintain their proliferative potential against 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). Combinations of drugs can address both these factors by improving overall efficacies and at the same time targeting tumor robustness and complexity to counter resistance (Robert, Karaszewska et al. 2015, Turner, Ro et al. 2015). It is not yet clear how many drugs are required, and which processes need to be targeted in combination to overcome specific types of cancer. But it is almost certain that different pathways or drivers need to be inhibited, most likely requiring two or more drugs (Bozic, Reiter et al. 2013).

In spite of numerous treatment options for patients with specific types of cancer, there remains a need for effective and safe combination therapies that can be administered for the treatment of cancer.

SUMMARY

It is an object of the present invention to provide for a medicament to improve treatment of a cancer, in particular to improve treatment of cancer through inhibition of cell growth (proliferation) and/or induction of apoptosis (cell death). It is an object of the present invention to find novel combination therapies, which selectively synergize the inhibition of proliferation and/or the induction of apoptosis. Surprisingly, it has been found that a pharmaceutical combination comprising i) a TEAD inhibitor, and ii) a HER2 inhibitor can both synergistically inhibit proliferation and/or induce apoptosis in cancers, as demonstrated in the Examples.

Therefore, according to a first aspect of the 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 TEAD inhibitor in combination with a HER2 inhibitor.

According to a second aspect of the invention, there is hereby provided a TEAD inhibitor for use in the treatment of cancer, wherein the treatment further comprises administration of a HER2 inhibitor.

According to a third aspect of the invention, there is hereby provided a HER2 inhibitor for use in the treatment of cancer, wherein the treatment further comprises administration of a TEAD inhibitor.

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

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 : In vitro viability of the gastric cancer cell line RERF-GC-1 B was assessed using CellTiterGlo following 7-day treatment with (top) IAG933 combined with Lapatinib, (middle) IAG933 combined with TNO155 and (bottom) IAG933 combined 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/stasis, 101-200= reduction in cell number/cell death.

FIG. 2: In vitro viability of the gastric cancer cell line SNU-216 was assessed using CellTiterGlo following 7-day treatment with (top) IAG933 combined with Lapatinib, (middle) IAG933 combined with TNO155 and (bottom) IAG933 combined 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/stasis, 101-200= reduction in cell number/cell death.

FIG. 3: In vitro viability of the gastric cancer cell line NCI-N87 was assessed using CellTiterGlo following 7-day treatment with (top) IAG933 combined with Lapatinib, (middle) IAG933 combined with TNO155 and (bottom) IAG933 combined 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/stasis, 101-200= reduction in cell number/cell death.

FIG. 4: In vitro viability of the gastric cancer cell line MKN-7 was assessed using CellTiterGlo following 7-day treatment with (top) IAG933 combined with Lapatinib, (middle) IAG933 combined with TNO155 and (bottom) IAG933 combined 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/stasis, 101-200= reduction in cell number/cell death.

FIG. 5: In vitro viability of the non-small cell lung cancer cell line NCI-H2170 was assessed using CellTiterGlo following 7-day treatment with (top) IAG933 combined with Lapatinib, (middle) IAG933 combined with TNO155 and (bottom) IAG933 combined 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/stasis, 101- 200= reduction in cell number/cell death.

FIG. 6: In vitro viability of the non-small cell lung cancer cell line CALU-3 was assessed using CellTiterGlo following 7-day treatment with (top) IAG933 combined with Lapatinib, (middle) IAG933 combined with TNO155 and (bottom) IAG933 combined 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/stasis, 101-200= reduction in cell number/cell death.

FIG. 7: In vitro viability of the endometrial cell line TEN was assessed using CellTiterGlo following 7-day treatment with (top) IAG933 combined with Lapatinib and (bottom) IAG933 combined 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/stasis, 101-200= reduction in cell number/cell death.

FIG. 8: In vitro viability of the oesophageal cell line OE-19 was assessed using CellTiterGlo following 7-day treatment with (top) IAG933 combined with Lapatinib and (bottom) IAG933 combined 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/stasis, 101-200= reduction in cell number/cell death.

FIG. 9: In vitro viability of the oesophageal cell line TE-4 was assessed using CellTiterGlo following 7-day treatment with (top) IAG933 combined with Lapatinib and (bottom) IAG933 combined 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/stasis, 101-200= reduction in cell number/cell death.

FIG. 10: Confluency of SNU-216 gastric cancer cells following treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week. Confluency was monitored in real-time using an lncucyte®S3 live-cells analysis instrument (Sartorius).

FIG. 11 : Confluency of Calu-3 non-small cell lung cancer cell lines following treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week. Confluency was monitored in realtime using an lncucyte®S3 live-cells analysis instrument (Sartorius).

FIG. 12: (Top): Image showing number of cells and % of dead cells at 96h (Cytotox Dye (Saratorius)) in SNU-216 and NCI-N87 gastric cancer cells. Cells were monitored in real-time and number of cells and % of dead cells were calculated using the cell-by-cell module of the lncucyte®S3 live-cells analysis instrument (Sartorius).

(Bottom): Clonogenic Assay, crystal violet staining after 38 days with indicated compounds at indicated concentrations in SNU-216 and MKN-7 gastric cancer cells. IAG933 + Lapatinib at 600 nM IAG933 and 100 nM Lapatinib. IAG(933) + TNO(155) + Lapatinib at 600 nM IAG933, 200 nM TNO155 and 100 nM Lapatinib.

FIG. 13: Confluency of NCI-N87 gastric cancer cell lines following treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week. Confluency was monitored using an lncucyte®S3 live-cells analysis instrument (Sartorius).

FIG. 14: Confluency of MKN-7 gastric cancer cell lines following treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week. Confluency was monitored using an lncucyte®S3 live-cells analysis instrument (Sartorius).

FIG. 15: Confluency of RERF-GC-1 B gastric cancer cell lines following treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week. Confluency was monitored using an lncucyte®S3 live-cells analysis instrument (Sartorius).

FIG. 16: Confluency of NCI-H2170 non-small cell lung cancer cell lines following treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week. Confluency was monitored using an lncucyte®S3 live-cells analysis instrument (Sartorius).

FIG. 17: 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 following 6-day treatment with Compound A combined with Lapatinib. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100= growth arrest/stasis, 101-200= reduction in cell number/cell death.

FIG. 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 following 6-day treatment with Compound B combined with Lapatinib. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100= growth arrest/stasis, 101-200= reduction in cell number/cell death.

FIG. 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 following 6-day treatment with Compound C combined with Lapatinib. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100= growth arrest/stasis, 101-200= reduction in cell number/cell death.

FIG. 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 following 6-day treatment with Compound D combined with Lapatinib. Growth inhibition was normalized to growth on day 0, the day of drug treatment. Growth inhibition %: 0-99 = delayed proliferation, 100= growth arrest/stasis, 101-200= reduction in cell number/cell death.

FIG. 21 : Confluency of EFM192A breast (HR+/HER2+) cancer cell lines following treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed every 7 days. The media was also refreshed once a week. Confluency was monitored using an lncucyte®S3 live-cells analysis instrument (Sartorius).

FIG. 22: Confluency of OE-19 oesophageal carcinoma cell lines following treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week. Confluency was monitored using an lncucyte®S3 live-cells analysis instrument (Sartorius).

FIG. 23: Confluency of TEN endometrial carcinoma cell lines following treatment with the indicated compounds at the indicated concentrations. Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week. Confluency was monitored using an lncucyte®S3 live-cells analysis instrument (Sartorius).

FIG. 24: Female nude mice bearing subcutaneous NCI-H2170 HER2-amplified lung cancer xenograft tumors were treated with single agents or combinations of agents as indicated in the legend. IAG933 is administered p.o., while hlgG1 and Trastuzumab are administered i.p.

FIG. 25: Female SCID mice bearing subcutaneous NCI-N87 HER2-amplified gastric cancer xenograft tumors were treated with single agents or combinations of agents as indicated in the legend. Compound E is administered p.o., while hlgG1 and Trastuzumab are administered i.p.

FIG. 26: Induction of pro apoptotic proteins as BIM and BMF (mRNA and Protein) could be detected by gene expression analysis (mRNA) and westernblot (protein). (“IAG” in the figure legend refers to IAG933 and “LAP” in the figure legend refers to lapatinib).

FIG. 27: In vitro viability of the breast (HR+/HER2+) cancer cell line EFM192A was assessed using CellTiterGlo following 6-day treatment with (top) IAG933 combined with Lapatinib, (middle) Fulvestrant combined with Lapatinib + 600nM IAG933 and (bottom) IAG933 combined 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/stasis, 101-200= reduction in cell number/cell death.

DETAILED DESCRIPTION

As mentioned above, an object of the present invention is to find novel combination therapies, which selectively synergize in inhibiting proliferation and/or in inducing apoptosis.

It has surprisingly been found that the combination of a TEAD inhibitor and a HER2 inhibitor (with or without the further combination of a SHP2 inhibitor) is synergistic in a wide range of cancer models.

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

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.

In an embodiment, the TEAD inhibitor is IAG933.

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

In an embodiment, the HER2 inhibitor is selected from the list consisting of lapatinib, neratinib, tucatinib, trastuzumab, pyrotinib, afatinib, pertuzumab, margetuximab, canertinib, dacomitinib, sapitinib, mubritinib, posiotinib, trastuzumab deruxtecan and ado-trastuzumab emtansine. In a preferred embodiment, the HER2 inhibitor is lapatinib (e.g., lapatinib ditosylate, e.g., lapatinib ditosylate monohydrate).

In a preferred embodiment, the HER2 inhibitor is lapatinib (e.g., lapatinib ditosylate, e.g., lapatinib ditosylate monohydrate) and the TEAD inhibitor is IAG933.

In an embodiment, the treatment or combination further comprises administration of a SHP2 inhibitor.

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 I RO-7517834 / RG-6433), GH-21 (HBI-2376), BBP-398 (IACS-13909 I 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-CI-AHPC (MM-002) and TNO155, preferably selected from the group consisting of JAB-3068, Vociprotafib (RMC-4630), RLY1971 and TNO155.

In an embodiment, the SHP2 inhibitor is TNO155.

In an 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.

In an embodiment, the cancer is a TEAD dependent cancer.

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 carcinoma e.g. gastric adenocarcinoma, e.g. gastric tubular adenocarcinoma), lung cancer (e.g. non-small cell lung cancer), endometrial cancer, oesophageal cancer (e.g. oesophageal squamous-cell carcinoma, e.g. oesophagogastric junction carcinoma), uterine cancer, cervical cancer, bladder cancer, pancreatic cancer, colorectal cancer, ovarian cancer, head & neck cancer, thymoma and liver cancer.

In an embodiment, 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).

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

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

In an embodiment, 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 is composed of at least two treatment cycles. In an alternative embodiment, the TEAD inhibitor (e.g., IAG933) is administered on two days (e.g., days 1 and 4) in a 6- or 7-day (e.g., 7 day) treatment cycle, and wherein the treatment comprises at least two treatment cycles.

In an embodiment, the daily dose of the TEAD inhibitor (e.g., IAG933) on each administration day is from 15 mg to 1500 mg. In an embodiment, the daily dose of the TEAD inhibitor (e.g., IAG933) on each administration day is from 100 mg to 1500 mg. In an 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, 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, 1300 mg, 1350 mg, 1400 mg, 1450 mg or 1500 mg.

In an embodiment, the HER2 inhibitor (e.g., lapatinib) is dosed daily.

In an embodiment, 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).

In an embodiment, the combination is non-fixed.

In an embodiment, the treatment further comprises administration of letrozole.

The invention therefore provides the following numbered embodiments:

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

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

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

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

Embodiment s. The method according to Embodiment 1 , the TEAD inhibitor for use according to Embodiment 2, the HER2 inhibitor for use according to Embodiment 3, or the combination according to Embodiment 4, wherein the TEAD inhibitor is a YAP/TAZ-TEAD protein-protein interaction inhibitor.

Embodiment 6. The method according to Embodiment 1 or Embodiment 5, the TEAD inhibitor for use according to Embodiment 2 or Embodiment 5, the 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.

Embodiment 7. 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, wherein the TEAD inhibitor is IAG933.

Embodiment 8. The method according to any one of Embodiments 1 and 5 to 7, the TEAD inhibitor for use according to any one of Embodiments 2 and 5 to 7, the 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 an anti-HER2 antibody.

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

Embodiment 10. The method according to any one of Embodiments 1 and 5 to 7, the TEAD inhibitor for use according to any one of Embodiments 2 and 5 to 7, the 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, margetuximab, canertinib, dacomitinib, sapitinib, mubritinib, posiotinib, trastuzumab deruxtecan and ado- trastuzumab emtansine.

Embodiment 11. The method according to 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).

Embodiment 12. The method according to 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 administration of a SHP2 inhibitor.

Embodiment 13. The method according to 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 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 I RO-7517834 I RG-6433), GH-21 (HBI-2376), BBP-398 (IACS-13909 I 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-CI-AHPC (MM-002) and TNO155, preferably selected from the group consisting of JAB-3068, Vociprotafib (RMC- 4630), RLY1971 and TNO155.

Embodiment 14. The method according to 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.

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

Embodiment 16. The method according to 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 carcinoma e.g. gastric adenocarcinoma, e.g. gastric tubular adenocarcinoma), lung cancer (e.g. non-small cell lung cancer), endometrial cancer, oesophageal cancer (e.g. oesophageal squamous-cell carcinoma, e.g. oesophagogastric junction carcinoma), uterine cancer, cervical cancer, bladder cancer, pancreatic cancer, colorectal cancer, ovarian cancer, head & neck cancer, thymoma and liver cancer.

Embodiment 17. The method according to Embodiment 16, the TEAD inhibitor for use according to Embodiment 16 or the HER2 inhibitor for use according to Embodiment 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).

Embodiment 18. The method according to any one of Embodiments 1 and 5 to 17, the TEAD inhibitor for use according to any one of Embodiments 2 and 5 to 17 or the HER2 inhibitor for use according to any one of Embodiments 3 and 5 to 17, wherein the cancer is HER2-positive cancer. Embodiment 19. The method according to 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 mutated cancer and/or iii) the cancer has HER2 protein overexpression.

Embodiment 20. The method according to 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 (e.g. IAG933) is administered on each of the first 3 days of a 7 day treatment cycle, and wherein the treatment is composed of at least two treatment cycles.

Embodiment 21. The method according to 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 from 15 mg to 1500 mg.

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 (e.g., IAG933) on each administration day is from 100 mg to 1500 mg.

Embodiment 23. The method according to 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, 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. The method according to 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 dosed daily.

Embodiment 25. 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, 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).

Definitions

IAG933 is a YAP/TAZ-TEAD protein-protein interaction inhibitor useful in the treatment of diseases or conditions mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction, such as cancers, particularly cancers harboring (i) one or more YAP/TAZ fusions; (ii) one or more NF2/I_ATS1/LATS2 truncating mutations or deletions; or (iii) one or more functional YAP/TAZ fusions. The synthesis of IAG933 is described in WO2021/186324 (Example 155), which is incorporated by reference.

IAG933 has the following chemical structure:

the chemical name 4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4- yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide.

Lapatinib has the chemical structure

the chemical name N-{3- chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2- furyl]-quinazolinamine. It is marketed in the ditosylate monohydrate form N-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4- quinazolinamine bis(4-methylbenzenesulfonate) monohydrate as Tykerb or Tyverb. Lapatinib is also known as LAP016 and GW-572016.

The term “Compound A” as used herein 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 WO2021/186324, and a close analog of IAG933.

The term “Compound B” as used herein refers t

(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 available to purchase commercially.

The term “Compound C” as used herein refers

chlorophenoxy)-4-methylphenyl)acrylamide. Compound C is also known as K-975 and is available to purchase commercially.

The term “Compound D” as used herein refers t

(3-(4-chlorophenoxy)-4-methylphenyl)-4,5-dihydroisoxazole. The synthesis of Compound D is described in WO2020/243423.

The term “Compound E” as used herein refers

analog of IAG933. The synthesis of Compound E is described in WO2021/186324. The terms “a” and “an” and “the” and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, patients, cancers and the like, this is taken to also mean a single compound, patient, or the like.

References in this specification to “the invention” are intended to reflect embodiments of the several inventions disclosed in this specification and should not be taken as unnecessarily limiting of the claimed subject matter.

The term “synergistic effect” as used herein refers to action of two or three therapeutic agents producing an effect, for example, slowing the progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of a drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compound and which typically are not biologically or otherwise undesirable. The compound may be capable of forming acid addition salts by virtue of the presence of an amino group.

Unless otherwise specified, or clearly indicated by the text, reference to therapeutic agents useful in the pharmaceutical combination of the present invention includes both the free base of the compounds, and all pharmaceutically acceptable salts of the compounds.

The term “combination” or “pharmaceutical combination” is defined herein to refer to either a fixed combination in one dosage unit form, a non-fixed combination, or a kit of parts for the combined administration where the therapeutic agents may be administered together, independently at the same time or separately within time intervals, which preferably allows that the combination partners show a cooperative, e.g., synergistic effect. Thus, the single compounds of the pharmaceutical combination of the present invention could be administered simultaneously or sequentially. 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.

The term “fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are in the form of a single entity or dosage form.

The term “non-fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are administered to a patient as separate entities or dosage forms either simultaneously or sequentially with no specific time limits, wherein preferably such administration provides therapeutically effective levels of the two therapeutic agents in the body of the subject, e.g., a mammal or human in need thereof.

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

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, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington’s Pharmaceutical Sciences, 18^th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

The phrase “pharmaceutically acceptable” is employed herein to refer 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 problem or complication, commensurate with a reasonable benefit/risk ratio.

Generally, the term “pharmaceutical composition” is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human. The present pharmaceutical combinations can be formulated in a suitable pharmaceutical composition for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units. The pharmaceutical composition may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s). One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden. The amount of each carriers used may vary within ranges conventional in the art. The following references disclose techniques and excipients used to formulate oral dosage forms. See 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^th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003). These optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining the one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination of agents in the oral dosage form. In the latter embodiment, the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet. Clearly, the pharmaceutical combinations of the present invention can be used to manufacture a medicine.

The present invention relates to such pharmaceutical combinations or pharmaceutical compositions that are particularly useful as a medicine.

Specifically, the combinations or compositions of the present invention can be applied in the treatment of cancer.

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

The term “treatment” as used herein comprises a treatment relieving, reducing or alleviating at least one symptom in a subject, increasing progression-free survival, overall survival, extending duration of response or delaying progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer. Within the meaning of the present invention, the term “treatment” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease in a patient, e.g., a mammal, particularly the patient is a human. The term “treatment” as used herein comprises an inhibition of the growth of a tumor incorporating a direct inhibition of a primary tumor growth and I or the systemic inhibition of metastatic cancer cells.

A "subject," "individual" or "patient" is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, simians, humans, farm animals, sport animals, and pets.

As used herein, a subject is “in need of” or “in need thereof” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

The term “comprising” encompasses “including” as well as “consisting of’; e.g., a composition comprising X may consist exclusively of X or may include additional, e.g. X and Y.

The term “a therapeutically effective amount” of a compound (e.g., chemical entity or biologic agent) of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one embodiment a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

The optimal dosage of each combination partner for treatment of a cancer can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art. The amount of each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration. In some embodiments the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination that are typically administered when the agents are administered alone.

Frequency of dosage may vary depending on the compound used and the particular condition to be treated or prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.

The term “cancer” refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to colorectal, gastric, endometrial, prostate, adrenocortical, uterine, cervical, oesophageal, breast, kidney, ovarian cancer and the like.

The terms “tumor” and “cancer” are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors.

As used herein, the term “TEAD dependent cancer” refers to any cancer in which TEAD (i.e. TEAD1 , TEAD2, TEAD3 and/or TEAD4,), or a mutant or variant thereof, is known to be relevant, for example, in cancers where the Hippo pathway is genetically altered.

In an embodiment, the HER2 inhibitor is also an EGFR inhibitor.

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 HER2 protein overexpression.

In an 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 an embodiment, the HER2 inhibitor is a tyrosine kinase inhibitor, e.g., a tyrosine kinase inhibitor that inhibits HER2 and EGFR, e.g. lapatinib. It should be understood that the effect of trastuzumab is generally considered to be underestimated in vitro, as compared to in vivo. Without limitation, this could be due to the additional immune modulatory effect by the NK cells which leads to a more enhanced effect in vivo, especially where the model is not immune suppressed.

As used herein, the term “TEAD inhibitor” refers to a compound which has activity as an inhibitor of TEAD (i.e., TEAD1 , TEAD2, TEAD3 and/or TEAD4), or a mutant or variant thereof, that can be assayed in vitro, in vivo or in a cell line. In an example, IC50 [pM] is <10, for example <5, for example <2, for example <1 , for example <0.5, for example <0.2, for example <0.1 , in the biochemical assay as described in WO2021/186324, and/or the reporter gene cellular assay as described in WO2021/186324, and/or the proliferation cellular assay as described in WO2021/186324. WO2021/186324 is hereby incorporated by reference.

A YAP/TAZ-TEAD protein-protein interaction inhibitor as described herein refers to a TEAD inhibitor which inhibits TEAD activity by inhibiting the interaction of the YAP/TAZ complex with TEAD. Hyperactivation of YAP/TAZ, resulting in the activation of TEAD, has been reported in many cancers, e.g., malignant pleural mesothelioma. Thus, inhibiting the interaction between YAP/TAZ and TEAD is a promising mechanism by which to inhibit TEAD activity.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in W02021/087008.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in W02021/102204.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2020/214734.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in W02020/097389.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2019/222431.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2019/113236.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2019/040380.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2018/204532.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2017/058716.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2022/159986.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2022/120354. In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2022/120355.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2022/120353.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2020/243423.

In an embodiment, the TEAD inhibitor is selected from any one of the compounds disclosed in WO2020/243415.

In an embodiment, the TEAD inhibitor is IAG933, i.e., 4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-

2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N- methylnicotinamide. IAG933 has the following structure

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.

In an embodiment, the TEAD inhibitor is Compound A, i.e., 2-((2S,3S,4S)-5-Chloro-6-fluoro- 3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-

methoxybenzamide. Compound A has the following structure . 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.

The synthesis and characterization of IAG933 (Example 155) and Compound A (Example 144) is described in WO2021/186324, which is hereby incorporated by reference. In an embodiment where TNO155 is present as part of the method or combination, TNO155 is administered orally at a dose of about 1.5 mg per day, or 3 mg per day, or 6 mg per day, or 10 mg per day, or 20 mg per day, or 30 mg per day, or 40 mg per day, or 50 mg per day, or 60 mg per day, or 70 mg per day, or 80 mg per day, or 90 mg per day, or 100 mg per day.

In an embodiment where TNO155 is present as part of the method or combination, the dose per day of TNO155 is on a 21 day cycle of 2 weeks on drug followed by 1 week off drug.

In an embodiment where TNO155 is present as part of the method or combination, the dose per day of TNO155 is 20 mg.

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

In an embodiment where TNO155 is present as part of the method or combination, TNO155 is administered orally.

‘Zwitterion’ or ‘zwitterionic form’ means a compound containing both positive and negatively charged functional groups.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

Isomeric forms

Any asymmetric atom (e.g., carbon or the like) of the compound(s) that can be used in the present invention can be present in racemic or enantiomerically enriched, for example 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, if possible, be present in cis- (Z)- or trans- (E)- form.

Accordingly, as used herein a compound that can be used in the present invention can 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 (antipodes), racemates or mixtures thereof.

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.

Any resulting racemates of compounds that can be used in the present invention or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds that can be used in the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O’-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic compounds that can be used in the present or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.

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

Furthermore, the compounds that can be used in the present invention, including their salts, can 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 pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the complex where the solvent molecule is water. Dosage Forms

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

It should be understood by “administered on each of the first 3 days of a 7-day treatment cycle”, it is meant that the TEAD inhibitor or pharmaceutically acceptable salt thereof is administered on each of the first 3 days of the 7 day treatment cycle, and not on the subsequent 4 days of the 7 day treatment cycle.

Preferably, the at least two treatment cycles are consecutive, that is to say the second treatment cycle follows immediately on from the first treatment cycle. For example, the invention therefore includes the following:

Days 1-3: TEAD inhibitor administered on each day;

Days 4-7: TEAD inhibitor not administered;

Days 8-10: TEAD inhibitor administered on each day; and

Days 11-14: TEAD inhibitor not administered.

In this example, days 1-3 and 8-10 are administration days. An “administration day” thus refers to any day where the TEAD inhibitor is administered to the patient.

When present, the third (fourth etc.) treatment cycles preferably immediately follow on from the previous treatment cycle. Thus, in an embodiment where there are three treatment cycles, the invention includes the following:

Days 1-3: TEAD inhibitor administered on each day;

Days 4-7: TEAD inhibitor not administered;

Days 8-10: TEAD inhibitor administered on each day;

Days 11-14: TEAD inhibitor not administered;

Days 15-17: TEAD inhibitor administered on each day; and

Days 18-21 : TEAD inhibitor not administered.

In an embodiment, there are three or more treatment cycles, e.g., four or more treatment cycles, e.g. five or more treatment cycles, e.g. six or more treatment cycles, e.g. eight or more treatment cycles, e.g. ten or more treatment cycles. In an alternative embodiment, the TEAD inhibitor is administered on two days in a 6 or 7 day treatment cycle, and wherein the treatment comprises at least two treatment cycles, e.g. on i) days 1 and 4 of a 6 day schedule or ii) days 1 and 4 of a 7 day schedule, e.g. days 1 and 4 of a 7 day schedule.

As used herein, the term “daily dose" (e.g., of a TEAD inhibitor) refers to the total dosage amount (e.g. of a TEAD inhibitor) administered to an individual in a single 24-hour day.

When referring to a dose amount (e.g., of the TEAD inhibitor) herein, e.g., in mg (milligrams), it is meant as the (equivalent) amount of (e.g., the TEAD inhibitor) in free form (i.e. , excluding, for instance, the salt or co-crystal partner as well as any solvent present).

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, e.g., a capsule or a tablet.

Preferably the TEAD inhibitor is taken with a glass of water and without chewing the capsules or tablet.

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

Preferably, the TEAD inhibitor is administered at approximately the same time 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.

Preferably, the TEAD inhibitor is administered in the fasted state, i.e., at least 1 hour before or 2 hours after a meal.

Combinations

“Combination” refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a combination partner (e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms “coadministration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term “fixed combination” means that the therapeutic agents, e.g., combination partners of the present invention, are both 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., combination partners of the present invention, are both administered to a patient as separate entities either simultaneously, concurrently, or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agents.

In the combination therapies of the invention, the therapeutic agents may be manufactured and/or formulated by the same or different manufacturers. Moreover, the therapeutic agents may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g., in the case of a kit comprising the therapeutic agents); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the therapeutic agents.

Examples

Example 1

In vitro viability of the gastric cancer cell line REFR-GC-1 B was assessed using CellTiterGlo following 7-day treatment with IAG933 combined with Lapatinib (±TNO155). Growth of REFR- GC-1 B cells was inhibited by IAG933 alone, but not by Lapatinib alone. Further, the combination of IAG933 and Lapatinib displayed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of Lapatinib (Figure 1).

Example 2

In vitro viability of the gastric cancer cell line SNU-216 was assessed using CellTiterGlo following 7-day treatment with IAG933 combined with Lapatinib (±TNO155). Growth of SNU- 216 cells was inhibited by IAG933 alone and Lapatinib alone (maximal effect with Lapatinib alone: stasis). Further, the combination of IAG933 and Lapatinib displayed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of Lapatinib (Figure 2).

Example 3 In vitro viability of the gastric cancer cell line NCI-N87 was assessed using CellTiterGlo following 7-day treatment with IAG933 combined with Lapatinib (±TNO155). Growth of NCI- N87 cells was inhibited by IAG933 alone (maximal effect: stasis) and Lapatinib alone. Further, the combination of IAG933 and Lapatinib displayed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of Lapatinib (Figure 3).

Example 4

In vitro viability of the gastric cancer cell line MKN-7 was assessed using CellTiterGlo following 7-day treatment with IAG933 combined with Lapatinib (±TNO155). Growth of MKN-7 cells was inhibited by IAG933 alone (maximal effect: stasis) and Lapatinib alone (maximal effect below stasis). Further, the combination of IAG933 and Lapatinib displayed 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).

Example 5

In vitro viability of the non-small cell lung cancer cell line NCI-H2170 was assessed using CellTiterGlo following 7-day treatment with IAG933 combined with Lapatinib (±TNO155). Growth of NCI-H2170 cells was inhibited by Lapatinib alone, but not by IAG933 alone. Further, the combination of IAG933 and Lapatinib displayed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of Lapatinib (Figure 5).

Example 6

In vitro viability of the non-small cell lung cancer cell line CALU-3 was assessed using CellTiterGlo following 7-day treatment with IAG933 combined with Lapatinib (±TNO155). Growth of CALU-3 cells was inhibited by IAG933 alone (maximal effect: stasis) and Lapatinib alone. Further, the combination of IAG933 and Lapatinib displayed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of Lapatinib (Figure 6).

Example 7

In vitro viability of the endometrial cancer cell line TEN was assessed using CellTiterGlo following 7-day treatment with IAG933 combined with Lapatinib (±TNO155). Growth of TEN cells was inhibited by IAG933 alone and Lapatinib alone (maximal effect below stasis). Further, the combination of IAG933 and Lapatinib displayed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of Lapatinib (Figure 7).

In vitro viability of the oesophagal cancer cell line OE-19 was assessed using CellTiterGlo following 7-day treatment with IAG933 combined with Lapatinib (±TNO155). Growth of OE-19 cells was inhibited by IAG933 alone (maximal effect below stasis) and Lapatinib alone. Further, the combination of IAG933 and Lapatinib displayed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of Lapatinib (Figure 8).

In vitro viability of the oesophagal cancer cell line TE-4 was assessed using CellTiterGlo following 7-day treatment with IAG933 combined with Lapatinib (±TNO155). Growth of TE-4 cells was inhibited by Lapatinib alone, but not with IAG933 alone. Further, the combination of IAG933 and Lapatinib displayed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of Lapatinib (Figure 9).

IAG933 alone and IAG933 combinations with Lapatinib (Figure 10 - top) or Trastuzumab (Figure 10 - bottom) impede cell growth on-treatment and delay outgrowth upon compound wash-out in a SNU-216 gastric cancer model. Double combinations delay cell outgrowth beyond IAG933 alone and triple combinations with TNO155 prevent outgrowth altogether. Growth was monitored using lncucyte®S3 live-cells analysis instrument (Sartorius). Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week.

The combination of IAG933 and Lapatinib (Figure 11 - top) prevents cell growth on-treatment and delays outgrowth upon compound washout in a Calu-3 non-small cell lung cancer model. Addition of TNO155 further delays cell outgrowth. IAG933 and Trastuzumab (Figure 11 - bottom) with or without TNO155 delays cell growth on-treatment. Growth was monitored using lncucyte®S3 live-cells analysis instrument (Sartorius). Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week.

12 In a cell death assay (Figure 12 - top) IAG933 with Lapatinib or Trastuzumab leads to reduced number of cells and increased % of dead cells in NCI-N87 and SNU-216 gastric cancer cells. Addition of TNO155 increases these effects. In a clonogenic assay (Figure 12 - bottom) following crystal violet staining after 38 days: cell death and no clonal outgrowth was observed with the combination of IAG933+Lapatinib±TNO155 in SNU-216 gastric cancer cells and MKN-7 gastric cancer cells. SNU-216 and, to a lesser extent MKN-7 were sensitive to IAG933 single agent in long term treatment.

IAG933 + Lapatinib at 600 nM IAG933 and 100 nM Lapatinib. IAG(933) + TNO(155) + Lapatinib at 600 nM IAG933, 200 nM TNO155 and 100 nM Lapatinib.

Example 13

IAG933 and Lapatinib (Figure 13 — top) or Trastuzumab (Figure 13 — bottom) combination prevents cell growth on-treatment and leads to delayed outgrowth upon compound wash-out in a NCI-N87 gastric cancer model. Further inclusion of TNO155 leads to an additional delay of outgrowth for IAG933 with Trastuzumab and completely prevents cell growth for IAG933 with Lapatinib even upon compound wash-out. Growth was monitored using lncucyte®S3 live- cells analysis instrument (Sartorius). Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week.

Example 14

IAG933 and Lapatinib (Figure 14 - top) or Trastuzumab (Figure 14 - bottom) combination prevents cell growth on-treatment and leads to delayed outgrowth upon compound wash-out in a MKN-7 gastric cancer model. Further inclusion of TNO155 leads to an additional delay of outgrowth for IAG933 with Trastuzumab and completely prevents cell growth for IAG933 with Lapatinib even upon compound wash-out. Growth was monitored using lncucyte®S3 live-cells analysis instrument (Sartorius). Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week.

Example 15

IAG933 alone and IAG933 and Lapatinib (Figure 15 - top) or Trastuzumab (Figure 15 - bottom) combinations prevent cell growth on-treatment and lead to growth delay upon compound wash-out, with effects being more pronounced for combinations, in a RERF-GC- 1 B gastric cancer model. Further inclusion of TNO155 leads to completely prevents cell growth even upon compound wash-out with both combinations. Growth was monitored using lncucyte®S3 live-cells analysis instrument (Sartorius). Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week.

IAG933 and Lapatinib with or without TNO155 (Figure 16 - top) completely abolishes cell growth, with no surviving cells as revealed by the absence of proliferation upon compound wash-out, in the NCI-H2170 non-small cell lung cancer model. IAG933 and Trastuzumab (Figure 16 - bottom) combination inhibited cell proliferation and addition of TNO155 lead to more pronounced cell killing, revealed by the compound wash-out after which few surviving resumed growth. Cell proliferation was monitored using lncucyte®S3 live-cells analysis instrument (Sartorius). Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment.

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 following 6-day treatment with Compound A combined with Lapatinib. Growth of both SNU-216 cells and NCI-H2170 cells were inhibited by Compound A alone and by Lapatinib alone. Further, the combination of Compound A and Lapatinib displayed synergistic growth inhibition compared to either treatment alone in both cell lines.

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 following 6-day treatment with Compound B combined with Lapatinib. Growth of both SNU-216 cells and NCI-H2170 cells were inhibited by Lapatinib alone, but not by Compound B alone. The combination of Compound B and Lapatinib displayed synergistic growth inhibition compared to either treatment alone in both cell lines.

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 following 6-day treatment with Compound C combined with Lapatinib. Growth of both SNU-216 cells and NCI-H2170 cells were inhibited by Lapatinib alone, but not by Compound C alone (at least outside very high concentrations of Compound C). The combination of Compound C and Lapatinib displayed synergistic growth inhibition compared to either treatment alone in both cell lines.

20 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 following 6-day treatment with Compound D combined with Lapatinib. Growth of both SNU-216 cells and NCI-H2170 cells were inhibited by Lapatinib alone, but not by Compound D (at least outside very high concentrations of Compound D). The combination of Compound D and Lapatinib displayed synergistic growth inhibition compared to either treatment alone in both cell lines.

Example 21

IAG933 and lapatinib (Figure 21) combination (+/-Fulvestrant) leads to enhanced growth control beyond IAG933 alone or lapatinib alone in a EFM192A breast cancer (HR+/HER2+) model. Growth was monitored using lncucyte®S3 live-cells analysis instrument (Sartorius). Compound treatment was refreshed once a week/ every 7 days.

Example 22

IAG933 and lapatinib (Figure 22) combination leads to enhanced growth control beyond IAG933 alone or lapatinib alone in an OE-19 oesophageal carcinoma model. Further inclusion of TNO155 leads to further enhanced growth control. Growth was monitored using lncucyte®S3 live-cells analysis instrument (Sartorius). Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week.

Example 23

IAG933 and lapatinib (Figure 23) combination leads to enhanced growth control beyond IAG933 alone or lapatinib alone in a TEN endometrial carcinoma model. Further inclusion of TNO155 leads to further enhanced growth control. Growth was monitored using lncucyte®S3 live-cells analysis instrument (Sartorius). Compound treatment was refreshed on day 7 and treatment was removed on day 14. Cells were left untreated for the remaining days of the experiment, with media refreshment once a week.

Example 24

NCI-H2170 HER2-amplified lung cancer xenograft model is used in a pharmacology study in mice. The two control groups, vehicle and hlgG1 kappa LC, as well as the treatment group with IAG933, display a fast tumor growth and mean tumor sizes reach 1000mm³ in 9-20 days. Trastuzumab therapy leads to a moderate reduction of tumor growth and a mean tumor volume of 649mm³ at day 22. The combination of Trastuzumab and IAG933 stabilized the tumor growth and mean value of 414mm³ was obtained at day 28 post first dose.

Example 25 NCI-N87 HER2-amplified gastric cancer xenograft model is used in a pharmacology study in mice. The tumors treated with control therapies: vehicle and hlgG1 kappa LC, reach sizes of 931 and 664mm³ in 26 days. Trastuzumab and Compound E therapies leads to a tumor stasis and mean tumor volumes at day 26 are of 194 and 279mm³, respectively. The combination of Trastuzumab and Compound E triggers a near complete tumor regression with a mean value of 17 mm³ obtained at day 26 post first dose. For the latter group, the treatments are stopped at day 28 and tumors are further monitored until day 98. A sustained anti-tumor effect is observed with a mean tumor size of 160mm³ at day 98, still below the size at randomization.

Example 26

HER2 inhibition was found to lead to a downregulation of the MAPK pathway, which increases Bim expression and activation, whereas YAP-TEAD inhibition leads to an increase of BMF. Bim and BMF are pro apoptotic proteins. As such, higher expression results in a higher degree of apoptosis and cell death.

Example 27

In vitro viability of the breast (HR+/HER2+) cancer cell line EFM192A was assessed using CellTiterGlo following 6-day treatment with IAG933 combined with Lapatinib (±TNO155) or Fulvestrant combined with Lapatinib + IAG933. Growth of EFM192A cells was inhibited by Lapatinib alone, to a lesser extent by IAG933 (below stasis) alone and no inhibition was achieved by Fulvestrant alone. Further, the combination of IAG933 and Lapatinib displayed synergistic growth inhibition compared to either treatment alone. Further combination with TNO155 was beneficial at lower concentrations of Lapatinib. Further, the combination of Fulvestrant and Lapatinib + IAG933 did not displayed additional synergistic growth inhibition compared to IAG933 + Lapatinib (±TNO155) (Figure 27).

Claims

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

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

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

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

5. The method according to 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 according to 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- methylphenyljacrylamide (Compound C), 3-bromo-5-(3-(4-chlorophenoxy)-4- methylphenyl)-4,5-dihydroisoxazole (Compound D), VT3989, and IK-930.

7. The method according to 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 according to 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 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 method according to 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, margetuximab, canertinib, dacomitinib, sapitinib, mubritinib, posiotinib, trastuzumab deruxtecan and ado-trastuzumab emtansine.

11 . The method according to 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 administration of 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 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-CI-AHPC (MM- 002) and TNO155, preferably selected from the group consisting of JAB-3068, Vociprotafib (RMC-4630), RLY1971 and TNO155.

14. The method according to 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 carcinoma e.g. gastric adenocarcinoma, e.g. gastric tubular adenocarcinoma), lung cancer (e.g. non-small cell lung cancer), endometrial cancer, oesophageal cancer (e.g. oesophageal squamous-cell carcinoma, e.g. oesophagogastric junction carcinoma), uterine cancer, cervical cancer, bladder cancer, pancreatic cancer, colorectal cancer, ovarian cancer, head & neck cancer, thymoma and liver cancer.

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 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 HER2 positive cancer.

19. The method according to 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 mutated cancer and/or iii) the cancer has HER2 protein overexpression.

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 is composed 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 from 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 (e.g., IAG933) on each administration day is from 100 mg to 1500 mg.

23. The method according to 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, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg or 1500 mg.

24. The method according to 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 dosed 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).