Combination therapies for the treatment of cancer

Abstract

Disclosed herein are methods of treating SMARCA4 mutant cancer comprising administering a combination of the SMARCA2 inhibitor, Compound 1 or pharmaceutically acceptable salts thereof, and at least one additional therapeutic agent.

Description

31477_USCombination Therapies for the Treatment of Cancer Technical Field

[0001] The present disclosure provides combination therapy that includes administering a selective inhibitor of SMARCA2, and one or more additional pharmaceutically active agents, particularly for the treatment of cancers.Background

[0002] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is a mechanism by which such gene expression occurs. The human Switch / Sucrose Non-Fermentable (SWI / SNF) chromatin remodeling complex, also known as BAF complex, has two SWI2-like ATPases known as BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcription activator BRG1, also known as ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRM, also known as probable global transcription activator SNF2L2 and / or ATP-dependent chromatin remodeler SMARCA2, is encoded by the SMARCA2 gene on chromosome 9.

[0003] SMARCA2 and SMARCA4 are mutually exclusive ATPases within the BAF complex. If one of SMARCA2 or SMARCA4 is lost or damaged, the other compensates for the loss; thus restoring functionality to the BAF complex. SMARCA4 mutant cancer cells contain a less active or inactive SMARCA4 unit. Consequently, the cancer cell must rely on SMARCA2 function for the functionality of the BAF complex. Inhibiting or degrading SMARCA2 will prevent the BAF complex from functioning or functioning properly, and will lead to cell cycle arrest and tumor suppression.

[0004] SMARCA4 (BRG1) alterations occur in approximately 7% and 10% of all solid tumors and NSCLC, respectively, and are associated with worse overall survival (Fernando TM, etal. Nat Commun (2020); 11(1):5551; Dagogo-Jack, etal. J Thorac Oncol (2020); 15(5):766-776). SMARCA4 mutations, also occur in multiple other cancer types.

[0005] Moreover, clinical reports indicate that SMARCA4 -mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. For example, SMARCA4 somatic mutations portend poor prognosis in patients with both early stage and advanced NSCLC, especially among those that harbor KRAS-mutant tumors. The mechanism(s) by which SMARCA4 loss may modulate response to KRAS G12Ci are currently unknown but previously31477JJSreported pleiotropic functions in the regulation of cellular differentiation, DNA replication and repair as well as cell cycle progression are likely to be involved (Negrao et al., Cancer Discov.2023;13(7):1556-1571).

[0006] There is a need for new combination therapies that include administering potent and selective SMARCA2 inhibitors and one or more other therapeutic agents, such as KRAS inhibitors, particularly as part of neoadjuvant, adjuvant, advanced, or metastatic therapy, to treat cancer. It would be useful to develop more tolerable treatments than current treatments. It would be useful to develop less toxic treatments than the current treatments.

[0007] Accordingly disclosed herein are therapies that including administering a combination of a SMARCA2 inhibitor and at least one other therapeutic agent that, in some embodiments, synergistically decrease or eliminate BAF complex activity, which leads to cancer cell death. These combinations demonstrate an activity not seen with single compound therapies.Summary

[0008] Disclosed herein is a method of treating a SMARCA4 mutant cancer comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:O N NN >HJ OCompound 1,or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with at least one other therapeutic agent.

[0009] Throughout this application, Compound 1, or pharmaceutically acceptable salts thereof, is administered simultaneously, separately, or sequentially, with at least one other therapeutic agent.

[0010] Disclosed is a method of treating a SMARCA4 and KRAS mutant cancer comprising:31477JJS

[0011] administering to a patient in need thereof, a therapeutically effective amount of the SMARCA2 inhibitor Compound 1:or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with at least one other therapeutic agent. In some embodiments, the at least one other therapeutic agent is a KRAS inhibitor or a pharmaceutically acceptable salt thereof. In an embodiment, the KRAS inhibitor is selected from the group consisting of a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, and a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0012] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with at least one other therapeutic agent, in the treatment of SMARCA4 mutant cancer.

[0013] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with at least one other therapeutic agent, in the treatment of SMARCA4 and KRAS mutant cancer.

[0014] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that is selected from the group consisting of a pan-KRAS inhibitor, a KRAS G12C inhibitor, and a KRAS G12D inhibitor, in the treatment of SMARCA4 mutant cancer.

[0015] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that is selected from the group consisting of a pan-KRAS inhibitor, a KRAS G12C inhibitor, and a KRAS G12D inhibitor, in the treatment of SMARCA4 and KRAS mutant cancer.

[0016] Disclosed herein is a method of treating a SMARCA4 mutant cancer comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:31477JJSCompound 1,or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non-small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p.

[0017] Disclosed herein is a method of promoting immune cell infiltration into SMARCA4 mutant cancer, the method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:Compound 1,or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non-small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p.

[0018] Disclosed herein is a method of preventing metastasis of a SMARCA4 mutant cancer, the method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:31477JJSCompound 1,or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non-small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p.

[0019] Disclosed herein is a method of treating a SMARCA4 mutant cancer comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:Compound 1,or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab and SoC chemotherapy, wherein SoC chemotherapy is gemcitabine and cisplatin. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non-small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p. In some embodiments, the gemcitabine is dosed atl5mg / kg and the cisplatin is dosed at 2mg / kg. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p. In certain embodiments, about 200mg to about 1000 mg or about 200 mg to about 800 mg of Compound 1 is administered at least once a day. In other embodiments, Compound 1 is administered at least twice a day.31477JJS

[0020] Disclosed herein is a method of promoting immune cell infiltration into SMARCA4 mutant cancers the method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formulaCompound 1or a pharmaceutically salt thereof, in simultaneous, separate or sequential combination with pembrolizumab and SoC chemotherapy, wherein SoC chemotherapy is gemcitabine and cisplatin. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non-small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p. In some embodiments, the gemcitabine is dosed at 15mg / kg and the cisplatin is dosed at 2mg / kg. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p. In certain embodiments, about 200 to about 1000 mg or about 200 to about 800 mg of Compound 1 is administered at least once a day. In other embodiments, Compound 1 is administered at least twice a day.

[0021] Disclosed herein is a method of preventing metastasis of a SMARCA4 mutant cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formulaCompound 1or a pharmaceutically salt thereof, in simultaneous, separate or sequential combination with pembrolizumab and SoC chemotherapy, wherein SoC chemotherapy is gemcitabine and cisplatin. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non-small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer.31477JJSIn other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p. In some embodiments, the gemcitabine is dosed at 15mg / kg and the cisplatin is dosed at 2mg / kg. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p. In certain embodiments, about 200 mg to about 1000 mg or about 200 mg to about 800 mg of Compound 1 is administered at least once a day. In other embodiments, Compound 1 is administered at least twice a day.

[0022] Disclosed herein is a compound of the formula:Compound 1or a pharmaceutically salt thereof, for use in simultaneous, separate or sequential combination with pembrolizumab in treating SMARCA4 mutant cancer. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non-small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered lOmg / kg, twice per week, i.p.

[0023] Disclosed herein is a compound of the formula:Compound 1or a pharmaceutically salt thereof, for use in simultaneous, separate or sequential combination with pembrolizumab to promote immune cell infiltration into SMARCA4 mutant cancers. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non-small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p.31477_US

[0024] Disclosed herein is a compound of the formula:Compound 1or a pharmaceutically salt thereof, for use in simultaneous, separate or sequential combination with pembrolizumab to prevent metastasis of a SMARCA4 mutant cancer. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non- small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p.

[0025] Disclosed herein is a compound of the formula:Compound 1or a pharmaceutically salt thereof, for use in simultaneous, separate or sequential combination with pembrolizumab and SoC chemotherapy, wherein SoC chemotherapy is gemcitabine and cisplatin in treating a SMARCA4 mutant cancer. Gemcitabine and cisplatin are the current standard of care (SoC). The SMARCA4 mutant cancer may be lung cancer, such as, for example, non-small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p. In some embodiments, the gemcitabine is dosed at 15mg / kg and the cisplatin is dosed at 2mg / kg. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p. In certain embodiments, about 200mg to about 1000 mg or about 200 mg to about 800 mg of Compound 1 is administered at least once a day. In other embodiments, Compound 1 is administered at least twice a day.31477JJS

[0026] Disclosed herein is a compound of the formula:Compound 1or a pharmaceutically salt thereof, for use in simultaneous, separate or sequential combination with pembrolizumab and SoC chemotherapy, wherein SoC chemotherapy is gemcitabine and cisplatin to promote immune cell infiltration into SMARCA4 mutant cancers. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non- small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p. In some embodiments, the gemcitabine is dosed at 15mg / kg and the cisplatin is dosed at 2mg / kg. The pembrolizumab may be administered at a dose of lOmg / kg, twice per week, i.p. In certain embodiments, about 200mg to about 1000 mg or about 200 mg to about 800 mg of Compound 1 is administered at least once a day. In other embodiments, Compound 1 is administered at least twice a day.

[0027] A compound of the formula:Compound 1or a pharmaceutically salt thereof, for use in simultaneous, separate or sequential combination with pembrolizumab and SoC chemotherapy, wherein SoC chemotherapy is gemcitabine and cisplatin to prevent metastasis of a SMARCA4 mutant cancer. The SMARCA4 mutant cancer may be lung cancer, such as, for example, non-small cell lung cancer or bladder cancer. In one embodiment, the cancer is non-small cell lung cancer. In other embodiment, the cancer is bladder cancer. The pembrolizumab may be administered lOmg / kg, twice per week, i.p. In some embodiments, the gemcitabine is dosed atl5mg / kg and the cisplatin is dosed at 2mg / kg.31477JJSThe pembrolizumab may be administered lOmg / kg, twice per week, i.p. In certain embodiments, about 200mg to about 1000 mg or about 200 mg to about 800 mg of Compound 1 is administered at least once a day. In other embodiments. Compound 1 is administered at least twice a day.

[0028] In one embodiment, Compound 1, either as the free base or as a pharmaceutically acceptable salt may contain deuterium.Brief Description of the Figures

[0029] Figure 1. Impact on proliferation with combination of Compound 1 and cisplatin in the BRG1 -Deficient Human A549 cell model. Figure 1A shows percent inhibition of proliferation for each cisplatin concentration that was plotted against Compound 1 concentration on the X-axis as the mean value ± standard error. The dose-response curves represent the combined data from duplicate matrix plates. Figure IB shows HSA synergy scores displayed as heatmap, with high synergy scores presented in red and the summary synergy score reported as the mean.

[0030] Figure 2. Impact on proliferation with combination of Compound 1 and pemetrexed in the BRG1 -Deficient Human A549 cell model. Figure 2A shows percent inhibition of proliferation for each pemetrexed concentration that was plotted against Compound 1 concentration on the X-axis as the mean value ± standard error. The dose-response curves represent the combined data from duplicate matrix plates. Figure 2B shows HSA synergy scores displayed as heatmap, with high synergy scores presented in red and the summary synergy score reported as the mean.

[0031] Figure 3. Impact on proliferation with combination of Compound 1 and cisplatin in the BRG1 -Deficient Human RERF-LC-AI cell model. Figure 3 A shows percent inhibition of proliferation for each cisplatin concentration that was plotted against Compound 1 concentration on the X-axis as the mean value ± standard error. The dose-response curves represent the combined data from duplicate matrix plates. Figure 3B shows HSA synergy scores displayed as heatmap, with high synergy scores presented in red and the summary synergy score reported as the mean.

[0032] Figure 4. Impact on proliferation with combination of Compound 1 and paclitaxel in the BRG1 -Deficient Human RERF-LC-AI Cell Model. Figure 4A shows percent inhibition of proliferation for each paclitaxel concentration that was plotted against Compound 131477_USconcentration on the X-axis as the mean value ± standard error. The dose-response curves represent the combined data from duplicate matrix plates. Figure 4B shows HSA synergy scores displayed as heatmap, with high synergy scores presented in red and the summary synergy score reported as the mean.

[0033] Figure 5. Antitumor efficacy of Compound 1 alone or in combination with cisplatin and pemetrexed in the A549 Human NSCLC Xenograft model in mice. The data are represented as mean + SEM, n-8 per group. Figure 5A shows time-course of tumor volume change. Figure 5B shows a waterfall plot day 25, percent change treated versus control (Delta T / C) and percent regression. Abbreviation: N / A, not applicable; BID, twice daily; QD, once daily; n, number of animals per group; PO, oral administration; IP, intraperitoneal administration; d, day; SEM, standard error of the mean; *, Statistically significant when compared to vehicle (p < 0.05); #, additive by Bliss combination analysis.

[0034] Figure 6. Antitumor efficacy of Compound 1 alone or in combination with cisplatin and paclitaxel in RERF-LC-AI Human NSCLC Xenograft model in mice. The data are represented as mean ± SEM, n=8 per group. Figure 6A shows time-course of tumor volume change. Figure 6B shows a waterfall plot day 25, percent change treated versus control (Delta T / C) and percent regression. *, Statistically significant when compared to vehicle (p < 0.05); #, additive by Bliss combination analysis.

[0035] Figure 7. Treatment effect of Compound 1 in combination with pembrolizumab on tumor growth in CD34+ HSC humanized A549 Xenograft Model. Figure 7A shows treatment effect of 20 mg / kg Compound 1 in combination with pembrolizumab on tumor growth in CD34+ HSC humanized A549 Xenograft Model. Figure 7B shows treatment effect of 40 mg / kg Compound 1 in combination with pembrolizumab on tumor growth in CD34+ HSC humanized A549 Xenograft Model. The dotted line refers to the mean tumor volume at time of treatment initiation. * Greater than additive combination effect determined by Bliss Independence Method (p-value < 0.05 for Bliss and Pairwise comparisons to vehicle and single agent groups).

[0036] Figure 8. Impact on proliferation with combination of Compound 1 and Olomorasib in the BRG1 -Deficient Human NCLH2030 cell model. Figure 8 A shows percent inhibition of proliferation for each Olomorasib concentration that was plotted against Compound 1 concentration on the X-axis as the mean value ± standard error. The dose-response curves represent the combined data from triplicate matrix plates. Figure 8B shows HSA synergy scores31477JJSdisplayed as heatmap, with high synergy scores presented in red and the summary synergy score reported as the mean.

[0037] Figure 9. Impact on proliferation with combination of Compound 1 and Compound 2 in the BRG1 -Deficient Human NCI-H2030 cell model. Figure 9A shows percent inhibition of proliferation for each Compound 2 concentration that was plotted against Compound I concentration on the X-axis as the mean value ± standard error. The dose-response curves represent the combined data from triplicate matrix plates. Figure 9B shows HSA synergy scores displayed as heatmap, with high synergy scores presented in red and the summary synergy score reported as the mean.

[0038] Figure 10. Antitumor efficacy of Compound 1 and Olomorasib in the NCI-H2030 Human NSCLC Xenograft model in mice. The data are represented as mean ± SEM, n=8 per group. Figure 10A shows time-course of tumor volume change. Figure 10B shows a waterfall plot, percent change treated versus control (Delta T / C) and percent regression. *, Statistically significant when compared to vehicle (p < 0.05); #, additive by Bliss combination analysis.

[0039] Figure 11. Impact on proliferation with combination of Compound 1 and Compound 3 in the BRG1 -Deficient Human SNU-407 cell model. Figure 11A shows percent inhibition of proliferation for each Compound 3 concentration that was plotted against Compound 1 concentration on the X-axis as the mean value ± standard error. The dose-response curves represent the combined data from triplicate matrix plates. Figure 11B shows HSA synergy scores displayed as heatmap, with high synergy scores presented in red and the summary synergy score reported as the mean.

[0040] Figure 12. Impact on proliferation with combination of Compound 1 and Compound 3 in the BRGl-Deficient Human PA-TU-8988T_KRAS G12D clone Bll cell model. Figure 12A shows percent inhibition of proliferation for each Compound 3 concentration that was plotted against Compound 1 concentration on the X-axis as the mean value ± standard error. The dose-response curves represent the combined data from triplicate matrix plates. Figure 12B shows HSA synergy scores displayed as heatmap, with high synergy scores presented in red and the summary synergy score reported as the mean.

[0041] Figure 13. Impact on proliferation with combination of Compound 1 and Compound 2 in BRGl-Deficient KRAS G12S Human A549 Cells. Figure 13A shows percent inhibition of proliferation for each Compound 2 concentration that was plotted against31477JJSCompound 1 concentration on the X-axis as the mean value ± standard error. The dose-response curves represent the combined data from triplicate matrix plates. Figure 13B shows HSA synergy scores displayed as heatmap, with high synergy scores presented in red and the summary synergy score reported as the mean.

[0042] Figure 14. Impact on proliferation with combination of Compound 1 and Compound 2 in the BRG1 -Deficient Human PA-TU-8988T cell model. Figure 14A shows percent inhibition of proliferation for each Compound 2 concentration that was plotted against Compound 1 concentration on the X-axis as the mean value ± standard error. The dose-response curves represent the combined data from triplicate matrix plates. Figure 14B shows HSA synergy scores displayed as heatmap, with high synergy scores presented in red and the summary synergy score reported as the mean.

[0043] Figure 15. Antitumor efficacy of Compound 1 alone or in combination with Compound 2 in the A549 Human NSCLC Xenograft model in mice. The data are represented as mean ± SEM, n=8 per group. Figure 15A shows time-course of tumor volume change. Figure 15B shows a waterfall plot, percent change treated versus control (Delta T / C) and percent regression. *, Statistically significant when compared to vehicle (p < 0.05); #, additive by Bliss combination analysis.

[0044] Figure 16A is a graph showing the Efficacy of Compound 1 (60mg / kg BID 5on-2off, PO) in MB49 SMARCA4 KO syngeneic mice, as single agent and in combination with pembrolizumab (lOmg / kg, twice per week, i.p.). Figure 16B is a graph showing the body weight (BW) loss <-10% indicates treatment was well tolerated during study duration.

[0045] Figure 17A is a graph showing the Efficacy of Compound 1 (60mg / kg BID 5on-2off, PO) as single agent and in combination with standard of care (SoC) chemotherapy (gemcitabine 15mg / kg + Cisplatin 2mg / kg), or pembrolizumab (lOmg / kg, twice per week, i.p.). (A). Single agent treatment of LY4050784, SoC chemo and anti-PDl results in tumor growth inhibition of -34%, 35%, and 23% respectively at the end of the 16-day dosing period. When 60 mg / kg LY4050784 were administered together with anti-PDl or anti-PDl + SoC chemo, tumor growth inhibition of -60% and -64%. After dosing stopped, both arms continued to regress and reached complete response (CR) of tumors (4 / 4) and (7 / 7) without relapse until the last observation time point at day 92 (~80 days after dosing stopped). In contrast. LY4050784 + SoC31477JJSchemo or SoC Chemo + anti-PDl only generated tumor growth inhibition of -13% and 1.4%. Figure 17B shows the body weight loss (% change) during study duration.

[0046] Figure 18A illustrates anti-tumor immune memory formation in mice achieving complete response (CR) following Compound 1 plus pembrolizumab or Compound 1 plus Standard of Care (SoC) chemo plus pembrolizumab combination therapies. (A) Experimental schematic. Mice with priori Complete Response (CR) to combination therapies were rechallenged with MB49 SMARCA4KO tumors cells. Age-matched tumor-naive mice served as controls. Figure 18B is a graph demonstrating tumor-naive mice exhibited 100% tumor take rate. In contrast, no tumor formation was detected in mice with prior CR. These results indicate the establishment of durable, tumor-specific immune memory in CR mice, consistent with the absence of tumor relapse observed after initial treatment.Detailed Description

[0047] The combinations disclosed herein contain Compound 1, or a pharmaceutically acceptable salt thereof, in combination with at least one other therapeutic agent and are useful in treating SMARCA4 mutant or SMARCA4 and KRAS mutant cancers.

[0048] Compound 1, or pharmaceutically acceptable salts thereof, is an oral, selective SMARCA2 inhibitor that inhibits the growth of SMARAC4 mutant tumors across multiple murine xenograft models of SMARCA4 mutated NSCLC. Combining Compound 1, or pharmaceutically acceptable salts thereof, with standard lung cancer therapies, such as paclitaxel, cisplatin and / or pemetrexed, synergistically inhibits SMARCA2, which inhibits the growth of SMARCA4 mutant cancers.

[0049] Compound 1 is currently the subject of a phase 1 clinical trial (NCT06561685), as a monotherapy. Compound 1 is a selective SMARCA2 inhibitor with >30 fold potency against SMARCA2, when compared to SMARCA4.31477JJS

[0050] In some embodiments, the combination of Compound 1 or a pharmaceutically acceptable salt thereof, with at least one other therapeutic agent disclosed herein is synergistic.

[0051] Compound 1 in Combination with Lung Cancer Chemotherapies to Treat SMARCA4 Mutant Cancers

[0052] Combining Compound 1, or pharmaceutically acceptable salts thereof, may be combined with lung cancer chemotherapies, to treat lung cancer.

[0053] Standard lung cancer therapies include one or more of an antineoplastic agent and / or an antifolate agent.

[0054] Antineoplastic agents are a diverse class of medications. Many antineoplastic agents are hepatotoxic, especially at higher doses. Examples of antineoplastic agents include, but are not limited to alkylating agents, platinum agents, antibiotics and cytotoxic agents, antimetabolites, purine analogues, pyrimidine analogues, biologic response modifiers, histone deacetylase inhibitors, hormonal agents, antiestrogens (including aromatase inhibitors), donadotropin releasing hormone analogues, peptide hormones, monoclonal antibodies, protein kinas inhibitors, taxanes, topoisomerase inhibitors, vinca alkaloids, and miscellaneous agents.

[0055] Examples of alkylating agents include, but are not limited to Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Lurbinectedin, Mechlorethamine, Melphalan, Procarbazine, Streptozocin, Temozolomide, Thiotepa, and Trabectedin.

[0056] Examples of platinum agents include, but are not limited to Carboplatin, Cisplatin, and Oxaliplatin.

[0057] Examples of antibiotics and cytotoxic agents include, but are not limited to Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin, Mitoxantrone, Plicamycin, and Valrubicin.

[0058] Antifolate agents inhibit the synthesis or utilization of folate, which is an essential vitamin that is needed for cell growth and division. Examples of antifolates include, but are not limited to methotrexate, pyrimethamine, proguanil, trimethoprim, sulfadoxine, pralatrexate, and pemetrexed.

[0059] Examples of antimetabolites include, but are not limited to Antifolates:Methotrexate, Pemetrexed, Pralatrexate, and Trimetrexate.31477JJS

[0060] Examples of Purine Analogues include, but are not limited to Azathioprine, Cladribine, Fludarabine, Mercaptopurine, and Thioguanine.

[0061] Examples of Pyrimidine Analogues include, but are not limited to Azacitidine. Capecitabine, Cytarabine, Decitabine, Floxuridine, Fluorouracil, Gemcitabine, and Trifluridine / Tipracil.

[0062] Examples of Biologic Response Modifiers include, but are not limited to Aldesleukin (IL-2), Denileukin Diftitox, and Interferon Gamma.

[0063] Examples of Histone Deacetylase Inhibitors include, but are not limited to Belinostat, Panobinostat, Romidepsin, and Vbrinostat.

[0064] Examples of Hormonal Agents include, but are not limited to Antiandrogens: Abiraterone, Apalutamide, Bicalutamide, Cyproterone, Enzalutamide. Flutamide, and Nilutamide.

[0065] Examples of Antiestrogens (including Aromatase Inhibitors) include, but are not limited to Anastrozole, Exemestane, Fulvestrant, Letrozole, Raloxifene, Tamoxifen, and Toremifene.

[0066] Examples of Gonadotropin Releasing Hormone Analogues include, but are not limited to Degarelix, Goserelin, Histrelin, Leuprolide, Relugolix, and Triptorelin.

[0067] Examples of Peptide Hormones include, but are not limited to Lanreotide, Octreotide, and Pasireotide.

[0068] Examples of Monoclonal Antibodies include, but are not limited to Alemtuzumab, Atezolizumab, Avelumab, Belantamab, Bevacizumab, Blinatumomab, Brentuximab, Cemiplimab, Cetuximab, Daratumumab, Dinutuximab. Dostarlimab, Durvalumab. Elotuzumab, Enfortumab, Gemtuzumab, Inotuzumab Ozogamicin, Ipilimumab, Margetuximab, Mogamulizumab, Moxetumomab Pasudotox, Naxitamab, Necitumumab, Nivolumab, Ofatumumab, Olaratumab, Panitumumab. Pembrolizumab, Pertuzumab, Polatuzumab Vedotin, Ramucirumab, Rituximab, Sacituzumab Govitecan, Tafasitamab, Teclistamab, Tisotumab Vedotin, Tositumomab, Trastuzumab, Trastuzumab Deruxtecam, Trastuzumab Emtansine. and Tremelimumab. Cemiplimab, Dostarlimab, Nivolumab, and Pembrolizumab, are examples of PD-1 inhibitors.

[0069] Examples of Protein Kinase Inhibitors include, but are not limited to Acalabrutinib, Adagrasib, Afatinib, Alectinib, Alpelisib, Asciminib, Axitinib, Binimetinib,31477JJSBortezomib, Bosutinib, Brigatinib, Cabozantinib, Carfilzomib, Ceritinib, Cobimetinib, Copanlisib, Crizotinib, Dabrafenib, Dacomitinib, Dasatinib, Duvelisib, Enasidenib, Encorafenib, Entrectinib, Erdafitinib, Erlotinib, Fedratinib, Futibatinib, Gefitinib. Gilteritinib, Glasdegib, Ibrutinib, Idelalisib, Imatinib, Infigratinib, Ivosidenib, Ixazomib, Lapatinib, Larotrectinib, Lenvatinib, Lorlatinib, Midostaurin, Mobocertinib, Momelotinib, Neratinib, Nilotinib, Niraparib, Olaparib. Olutasidenib, Osimertinib. Pacritinib. Palbociclib, Pazopanib. Pemigatinib, Pexidartinib, Pirtobrutinib, Ponatinib, Quizartinib, Regorafenib, Ribocicib, Ripretinib, Rucaparib, Ruxolitinib, Selumetinib, Sonidegib, Sorafenib, Sunitinib, Talazoparib. Tivozanib, Trametinib, Trilaciblib, Umbralisib, Vandetanib, Vemurafenib, Vismodegib, and Zanubrutinib.

[0070] Examples of taxanes include, but are not limited to Cabazitaxel, Docetaxel, and Paclitaxel.

[0071] Examples of topoisomerase inhibitors include, but are not limited to Etoposide, Irinotecan, Teniposide, and Topotecan.

[0072] Examples of vinca alkaloids include, but are not limited to Vinblastine.Vincristine, and Vinorelbine.

[0073] Examples of miscellaneous antineoplastic agents include Asparaginase (Pegaspargase), Belzutifan, Bexarotene, Cedazuridine, Eribulin, Everolimus, Hydroxyurea, Ixabepilone, Lenalidomide, Mitotane, Omacetaxine, Pomalidomide, Selinexor, Tagraxofusp, Tazemetostat, Tebentafusp, Telotristat, Temsirolimus. Thalidomide, and Venetoclax.

[0074] KRAS inhibitors are compounds that target the oncogenic KRAS mutant forms, such as KRAS G12C, KRAS G12D, and KRAS G12V. In some embodiments, the KRAS inhibitor selectively binds to KRAS, thereby inhibiting KRAS -dependent signaling and inhibits growth and survival of KRAS-overexpressing and mutated tumor cells. In some embodiments, the KRAS inhibitor is a selective KRAS G12C inhibitor, such as olomorasib. In some embodiments, the KRAS inhibitor is a pan-KRAS inhibitor, such as Compound 2. In some embodiments, the KRAS inhibitor is a KRAS G12D inhibitor, such as Compound 3.

[0075] In one embodiment, disclosed is a method of treating a SMARCA4 mutant cancer comprising administering a combination of Compound 1, or a pharmaceutically acceptable salt thereof, and neoplastic agent that is a platinum agent, to a patient in need of such treatment. In a further embodiment, the platinum agent is cisplatin.31477_US

[0076] In one embodiment, disclosed is a method of treating a SMARCA4 mutant cancer comprising administering a combination of Compound 1, or a pharmaceutically acceptable salt thereof, and an antifolate agent, to a patient in need of such treatment. In one embodiment the antifolate agent is a PD-1 inhibitor. In one embodiment the antifolate agent is pemetrexed. In another embodiment, pemetrexed is administered at a dose of about 500 mg / m2 once every three weeks.

[0077] In an embodiment, disclosed is a method of treating a SMARCA4 mutant cancer comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with at least one other therapeutic agent that is an antineoplastic. In an embodiment, the antineoplastic is an antibody. In a further embodiment, the antibody is durvalumab.

[0078] Also disclosed is a method of treating a SMARCA4 mutant cancer comprising administering a combination of Compound 1, or a pharmaceutically acceptable salt thereof, an antineoplastic agent and an antifolate agent, to a patient in need of such treatment. In one embodiment, the antineoplastic agent is a platinum agent. In at least some embodiments, the platinum agent is cisplatin. The antifolate agent may be a PD-1 inhibitor. The antifolate agent may be pemetrexed. In an embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with cisplatin and pemetrexed, to a patient in need of such treatment.

[0079] In an embodiment, the combination of Compound 1, cisplatin and pemetrexed synergistically inhibits SMARCA2. This leads to an increased antitumor effect, which results in tumor regression. In an embodiment, the synergistic effect is seen in vivo.

[0080] In an embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with two different antineoplastic agents, to a patient in need of such treatment. In an embodiment, one antineoplastic agent is a taxane. In another embodiment, one antineoplastic agent is a platinum agent. In a further embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with a taxane and a platinum agent. Compound 1, or a pharmaceutically acceptable salt thereof, may be administered with paclitaxel and platinum agent. Compound 1, or a pharmaceutically acceptable salt thereof, may also be administered with a taxane and cisplatin. In an embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with paclitaxel and cisplatin, to a patient in need of such treatment.31477JJS

[0081] In an embodiment, Compound 1 , or a pharmaceutically acceptable salt thereof, is administered with an antineoplastic that is an antibody. In a further embodiment, the antibody is a PD-1 inhibitor. In a still further embodiment, the PD-1 inhibitor is pembrolizumab. In a still further embodiment, the PD-1 inhibitor is nivolumab. In a still further embodiment, the PD-1 inhibitor is cemiplimab. In a still further embodiment, the PD-1 inhibitor is dostarlimab. In a still further embodiment, the PD-1 inhibitor is sintilimab. In a still further embodiment, the PD-1 inhibitor is tislelizumab. In a still further embodiment, the PD-1 inhibitor is spartalizumab. In a still further embodiment, the PD-1 inhibitor is camrelizumab.

[0082] In some embodiments, Compound 1 should not be co-administered simultaneously, separately or sequentially with a CYP3A4 inhibitors. Examples of CYP3A4 inhibitors include, but are not limited to Ketoconazole, itraconazole, voriconazole, posaconazole (azoles), clarithromycin, telithromycin (macrolides / ketolides), Ritonavir, cobicistat (HIV protease inhibitors) and conivaptan. Without wishing to be held to a theory, it is currently believed that higher doses of Compound 1, that is, doses above about 300 to about 400 mg may inhibit CYP3A4. Lower doses of Compound 1, below about 300 to about 400 mg, may be amenable to the simultaneous, separate or sequential administration of a CYP3A4 inhibitor. Generally, doses above about 400 mg of Compound 1 should not be administered simultaneously, separately, or sequentially with a CYP3A4 inhibitor. If above about 400 mg of Compound 1 is to be administered simultaneously, separately, or sequentially with a CYP3A4 inhibitor, blood levels of Compound 1 and any metabolites thereof, should be monitored.

[0083] Compound 1 in Combination with a KRAS Inhibitor to treat a SMARCA4 Mutant Cancer

[0084] Disclosed herein is a method of treating a SMARCA4 mutant cancer comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in combination with at least one KRAS inhibitor. Examples of KRAS inhibitors include KRAS G12C inhibitors. KRAS G12D inhibitors, and pan-KRAS inhibitors.

[0085] Examples of KRAS G12C inhibitors include covalent and non-covalent inhibitors. Further examples include sotorasib, adagrasib, and olomorasib. Further examples include BL 1823911, JDQ-443, TNO155, IBI351, GDC-6036, olomorasib, and D-1553.

[0086] The structure of olomorasib is:31477_USo

[0087] Examples of pan-KRAS inhibitors include, but are not limited to BI- 1701963, and Compound 2, or a pharmaceutically acceptable salt thereof. Compound 2 has the formula:or pharmaceutically acceptable salts thereof. In some embodiments, Compound 2 is a free base. The pan-KRAS inhibitor can be synthesized as disclosed in PCT / US 2024 / 022154.

[0088] Examples of KRAS G12D inhibitors include covalent and non-covalent inhibitors. Specific examples include, but are not limited to MRTX1133, RMC-9805, and Compound 3, which has the formula:or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutically acceptable salt of Compound 3 is the disaccharinate salt. In another embodiment, the pharmaceutically acceptable salt is the cinnamic acid salt. In some embodiments, Compound 3 is a free base. This compound can be synthesized as disclosed in PCT / US2023 / 016257. The31477JJSdi saccharinate and cinnamic acid salts can be synthesized as disclosed in US 63 / 765,158.

[0089] In one embodiment, Compound 1, or pharmaceutically acceptable salts thereof, is administered with at least one KRAS G12C inhibitor. The KRAS G12C inhibitor may be olomorasib. The olomorasib may be administered at a dose of about 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg. In one embodiment, olomorasib is administered at a dose of about 25 mg. In one embodiment, olomorasib is administered at a dose of about 50 mg. In one embodiment, olomorasib is administered at a dose of about 100 mg. In another embodiment, olomorasib is administered at a dose of about 150 mg. In one embodiment, olomorasib is administered orally, one or twice a day. In an embodiment, 25 mg is administered twice, daily. In an embodiment, 50 mg is administered twice, daily. In an embodiment, 100 mg is administered twice, daily. In a different embodiment. 150 mg is administered twice daily.

[0090] In another embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, and olomorasib. are administered with three different antineoplastic agents. In an embodiment, one antineoplastic agent is an antibody. Further, the antibody may be a PD-1 inhibitor. Still further, the antibody is pembrolizumab. In an embodiment, pembrolizumab is administered at a dose of about 200 mg. In an embodiment, pembrolizumab is administered at a dose of about 200 mg once every three weeks. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. Further, the antibody may be a PD-L1 inhibitor. Still further, the antibody is durvalumab.

[0091] In another embodiment, one antineoplastic agent is a platinum agent. In one embodiment, the platinum agent is selected from the group consisting of cisplatin and carboplatin. In a yet further embodiment, two different platinum agents are used. In an embodiment, the two platinum agents are cisplatin and carboplatin. In one embodiment, the platinum agent is cisplatin. In one embodiment, cisplatin is administered at a dose of about 75 mg / m2 once every three weeks. In one embodiment, the platinum agent is carboplatin.

[0092] In an embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with at least one pan-KRAS inhibitor to treat a SMARCA4 mutant cancer. In a further embodiment, the pan-KRAS inhibitor is Compound 2, or a pharmaceutically acceptable salt thereof. In an embodiment, the cancer being treated is NSCLC. In an embodiment, the cancer being treated is pancreatic cancer.31477_US

[0093] In another embodiment, Compound 1 , or a pharmaceutically acceptable salt thereof, is administered with at least one KRAS G12D inhibitor to treat a SMARCA4 mutant cancer. In a further embodiment, the pan-KRAS inhibitor is Compound 3, or a pharmaceutically acceptable salt thereof. In an embodiment, the cancer being treated is NSCLC. In an embodiment, the cancer being treated is pancreatic cancer. In an embodiment, the cancer being treated is colon cancer, which includes colorectal cancer.

[0094] Compound 1 in Combination with a KRAS Inhibitor to treat a SMARCA4 and KRAS Mutant Cancer

[0095] Disclosed herein is a method of treating a SMARCA4 and KRAS mutant cancer, the method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially with a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment. In an embodiment, the KRAS G12C inhibitor is olomorasib, or a pharmaceutically acceptable salt thereof. In an embodiment, olomorasib is the free base.

[0096] Disclosed herein is a method of treating a SMARCA4 and KRAS mutant cancer, the method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially with a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment. In an embodiment, the KRAS G12D compound is Compound 3 or a pharmaceutically acceptable salt thereof. In a further embodiment, the pharmaceutically acceptable salt of Compound 3 is the disaccharinate salt.

[0097] Disclosed herein is a method of treating a SMARCA4 and KRAS mutant cancer, the method comprising administering a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially with a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment. In an embodiment, the pan-KRAS inhibitor is Compound 2 or a pharmaceutically acceptable salt thereof.

[0098] In an embodiment, when the combination of Compound 1 and pembrolizumab were used in human NSCLC xenograft tumors, a synergistic effect was seen. This is in contrast to when pembrolizumab was used as a monotherapy, which had no effect on tumor growth, when31477JJScompared to vehicle, i.e., the control. Thus, without wishing to be bound to a theory, it appears Compound 1 helped to sensitive the cancer cells to pembrolizumab.

[0099] In another embodiment. Compound 1. when combined with a KRAS inhibitor, demonstrated synergy in SMARCA4, KRAS co-mutated tumor cells both in vitro and in vivo xenograft models.[000100] Compound 1 in Combination with a PD-1 Inhibitor (pembrolizumab) to treat a SMARCA4 Mutant Cancer[000101] SMARCA4 mutant cancers can be treated with Compound 1 or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential administration with pembrolizumab. In one embodiment, Compound 1 is the free base. The combination is expected to be administered for at least one week or at least two weeks or at least 28 days. In some cases, the combination is administered for up to about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23. or 24 days. Then, if desired, dosing of the combination (or one drug in the combination) may stop for at least one day and up to about one week, before dosing is restarted.[000102] If treatment emergent adverse events are observed, then the dose of Compound 1 may be reduced. For example, if a patient receives 600 mg of Compound 1 and pembrolizumab administered per its label, then the amount of Compound 1 would be reduced by 50 mg or 100 mg to 550 mg or 500 mg. Similarly, if a patient receives 500 mg of Compound 1 and pembrolizumab administered per its label, then the amount of Compound 1 would be reduced by 50 mg or 100 mg to 450 mg or 400 mg.[000103] Data disclosed herein demonstrates administering the combination of Compound 1 (oral administration, 60 mg / kg, dosed 5 days on followed by 2 off) and pembrolizumab (intra peritoneal administration, 10 mg / kg, twice per week) for 21 days to MB49 SMARCA4 knock out syngeneic mice afforded complete response. See Fig. 16A. When 60 mg / kg of Compound 1 and pembrolizumab were administered together, tumor growth inhibition reached about 92% on day 21 with subsequent complete response (CR) of tumors in 5 / 6 tested mice was observed. No relapse was observed until the last observation time point at day 110 (80 days after dosing stopped). The mice in this study lost < about 10% body weight, which indicates the treatment was well tolerated during the study.31477JJS[000104] In contrast, treating the MB49 SMARCA4 knockout mice with either Compound (oral administration, 60mg / kg BID 5on-2off) or pembrolizumab (intra peritoneal administration, lOmg / kg, twice per week) affored about 37% and 1.4% tumor growth inhibition, at the end of the 21 day dosing period. See Fig. 16A.[000105] This data demonstrates Compound 1 treatment can sensitize MB49 SMARCA4 knockout tumor cells to pembrolizumab. resulting in improved antitumor efficacy, when compared to Compound 1 or pembrolizumab monotherapy or vehicle.[000106] Compound 1 in Combination with a PD-1 Inhibitor (pembrolizumab) or Compound 1 in Combination with a PD-1 Inhibitor (pembrolizumab) and standard of care chemotherapy to treat a SMARCA4 Mutant Cancer[000107] SMARCA4 mutant cancers can be treated with Compound 1 or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential administration with pembrolizumab or Compound 1 or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential administration with pembrolizumab and standard of care (SoC) chemotherapy (gemcitabine 15 mg / kg plus cisplatin 2 mg / kg). In one embodiment, Compound 1 is the free base. The combination is expected to be administered for at least one week or at least two weeks or at least 28 days. In some cases, the above combinations are administered for up to about 5, 6. 7, 8, 9. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 days. Then, if desired, dosing of the combination (or one or more drugs in the combination) may stop for at least one day and up to about one week, before dosing is restarted.[000108] Single agent treatment of Compound 1, SoC chemo and pembolizumab results in tumor growth inhibition of about 34%, about 35%, and about 23% respectively at the end of the 16-day dosing period. See Fig. 17A. When 60 mg / kg of Compound 1 was administered together with pembrolizumab (lOmg / kg, twice per week, i.p.) or pembrolizumab (lOmg / kg, twice per week, i.p.) plus SoC chemo (gemcitabine 15mg / kg + Cisplatin 2mg / kg), tumor growth inhibition of about 60% and about 64% was observed. After dosing stopped, both arms continued to regress and reached complete response (CR) of tumors (4 / 4) and (7 / 7), respectively, without relapse until the last observation time point at day 92 (which is approximately 80 days after dosing stopped). In contrast, Compound 1 + SoC chemo (gemcitabine 15mg / kg + Cisplatin 2mg / kg) or SoC Chemo plus pembrolizumab (lOmg / kg, twice per week, i.p.) only generated tumor growth31477JJSinhibition of about 13% and about 1.4%. See Fig. 17A. (B). The mice in this study lost < about 10% to about 15% body weight, which indicates the treatment was well tolerated during the study. See Fig 17B.[000109] This data indicates Compound 1 treatment can sensitize MB49 SMARCA4 KO tumor cells to pembrolizumab or pembrolizumab plus SoC chemo - resulting in improved antitumor efficacy with the combination, when compared to single-agent treatment or vehicle control. See Fig. 17A. In addition, while all combinations demonstrated improved efficacy, Compound 1 plus pembrolizumab, and Compound 1 plus pembrolizumab plus SoC chemo are the only combinations that demonstrated a durable, complete response.[000110] Surprisingly, it was found that the MB49 SMARCA4 knock out (KO) mice that demonstrated complete response, i.e., the mice that were treated with 1) Compound 1 and pembrolizumab or 2) Compound 1, pembrolizumab and SoC - as described above - developed anti-tumor immune memory. Meaning, when these mice were again inoculated with MB49 SMARCA4 KO cancer cells, they did not develop tumors. This result is understood to mean the immune memory prevented the newly administered cancer cells from forming tumors. This is similar to metastasis, in which a cancer cell migrates through the body from one location to a new location, before forming a new tumor. Thus, it is expected that the mice that exhibit complete response would not experience metastasis, as the immune memory would enable the body to kill the metastatic cancer cells. In contrast, and as expected, age matched, tumor naive mice did not exhibit anti-tumor immune memory. See Fig. 17A and 17B.Uses - SMARCA4 Mutant Cancers[000111] In an embodiment, the combinations disclosed herein are for use in therapy.[000112] In an embodiment, the combinations disclosed herein are for use in inducing apoptosis in a cell.[000113] In an embodiment, the combinations disclosed herein are for use in treating cancer.[000114] Further, disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with at least one other therapeutic agent, in the treatment of SMARCA4 mutant cancer.31477JJS[000115] In one embodiment, disclosed is Compound 1 , or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that is a combination of a neoplastic agent that is a platinum agent, to treat a SMARCA4 mutant cancer. In a further embodiment, the platinum agent is cisplatin.[000116] In one embodiment, disclosed is Compound 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that is and an antifolate agent, to treat a SMARCA4 mutant cancer. In one embodiment the antifolate agent is a PD-1 inhibitor. In a further embodiment, the antifolate agent is pemetrexed.[000117] In another embodiment, disclosed is Compound 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that is an antineoplastic agent and an antifolate agent, to treat a SMARCA4 mutant cancer. In one embodiment, the antineoplastic agent is a platinum agent. In at least some embodiments, the platinum agent is cisplatin. The antifolate agent may be a PD-1 inhibitor. The antifolate agent may be pemetrexed. In an embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with cisplatin and pemetrexed, to treat a SMARCA4 mutant cancer. In an embodiment, the combination of Compound 1, cisplatin and pemetrexed synergistically inhibits SMARCA2. This leads to an increased antitumor effect, which results in tumor regression. In an embodiment, the synergistic effect is seen in vivo.[000118] In an embodiment, disclosed is Compound 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with two different antineoplastic agents, to treat a SMARCA4 mutant cancer. In an embodiment, one antineoplastic agent is a taxane. In another embodiment, one antineoplastic agent is a platinum agent. In a further embodiment. Compound 1. or a pharmaceutically acceptable salt thereof, is administered with a taxane and a platinum agent. Compound 1, or a pharmaceutically acceptable salt thereof, may be administered with paclitaxel and platinum agent. Compound 1, or a pharmaceutically acceptable salt thereof, may also be administered with a taxane and cisplatin. In an embodiment, disclosed is Compound 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that is with paclitaxel and cisplatin, to treat a SMARCA4 mutant cancer.31477JJS[000119] In an embodiment, disclosed is Compound 1 , or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that is an antineoplastic, to treat a SMARCA4 mutant cancer. In an embodiment, the antineoplastic is an antibody. In a further embodiment, the antibody is a PD- 1 inhibitor. In a still further embodiment, the PD-1 inhibitor is pembrolizumab.[000120] In an embodiment, disclosed is Compound 1. or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that is an antineoplastic, to treat a SMARCA4 mutant cancer. In an embodiment, the antineoplastic is an antibody. In a further embodiment, the antibody is durvalumab.Uses with a KRAS Inhibitor to Treat a SMARCA4 Mutant Cancer[000121] Further, disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that is selected from the group consisting of a pan-KRAS inhibitor, a KRAS G12C inhibitor, and a KRAS G12D inhibitor, in the treatment of SMARCA4 mutant cancer.[000122] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that comprises at least one of a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, or a pharmaceutically acceptable salt thereof, an antifolate agent, or a pharmaceutically acceptable salt thereof, an antineoplastic agent, or a pharmaceutically acceptable salt thereof, a KRAS inhibitor selected from the group consisting of a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, and a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is combined with no more than one KRAS inhibitor. In an embodiment, the PD-1 inhibitor is pembrolizumab. In an embodiment, the platinum agent is cisplatin. In an embodiment, the antifolate agent is pemetrexed. In an embodiment, antineoplastic agent is paclitaxel.[000123] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with a platinum agent and an antifolate, in the treatment of a SMARCA4 mutant cancer. In an embodiment, the platinum agent is cisplatin, and the antifolate is pemetrexed.31477JJS[000124] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with a with a platinum agent and an antineoplastic agent, in the treatment of a SMARCA4 mutant cancer. In an embodiment, the platinum agent is cisplatin, and the antineoplastic agent is paclitaxel.[000125] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with a with a KRAS G12C inhibitor, in the treatment of a SMARCA4 mutant cancer. In an embodiment, the KRAS G12C inhibitor is olomorasib, or a pharmaceutically acceptable salt thereof. The olomorasib may be administered at a dose of about 50 mg, 100 mg, 150 mg, or 200 mg. In one embodiment, the olomorasib is administered at a dose of about 100 mg. In another embodiment, the olomorasib is administered at a dose of about 150 mg. The olomorasib is administered orally, one or twice a day. In an embodiment. 100 mg is administered twice, daily. In a different embodiment, 150 mg is administered twice daily.[000126] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with a with a KRAS G12D inhibitor, in the treatment of a SMARCA4 mutant cancer. In an embodiment, the KRAS G12D inhibitor is a compound of the formula:[000127] Compound 3, or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is a disaccharinate salt. In an embodiment, Compound 3 is a free base.[000128] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with a with a pan-KRAS inhibitor, in the treatment of a SMARCA4 mutant cancer. In an embodiment, the pan-KRAS inhibitor is Compound 2:31477_US[000129] Compound 2, or a pharmaceutically acceptable salt thereof. In an embodiment, Compound 2 is a free base.[000130] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that is an antineoplastic, to treat a SMARCA4 mutant cancer. In an embodiment, the antineoplastic is an antibody. In a further embodiment, the antibody is durvalumab.Uses - SMARCA4 and KRAS mutant cancers[000131] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with at least one other therapeutic agent that comprises a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, or a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a SMARCA4 and KRAS mutant cancer. In an embodiment, the KRAS G12C inhibitor is olomorasib, or a pharmaceutically acceptable salt thereof. In an embodiment, the KRAS G12D compound is Compound 3 or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutically acceptable salt is the di saccharinate salt. In an embodiment, the pan-KRAS inhibitor is Compound 2 or a pharmaceutically acceptable salt thereof.[000132] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a SMARCA4 and KRAS mutant cancer. In an embodiment, the KRAS G12C inhibitor is olomorasib, or a pharmaceutically acceptable salt thereof. In an embodiment, olomorasib is the free base.[000133] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a SMARCA4 and KRAS mutant cancer. In an embodiment, the KRAS G12D31477_UScompound is Compound 3 or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutically acceptable salt is the disaccharinate salt.[000134] Disclosed herein is Compound 1 for use in simultaneous, separate or sequential combination with a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a SMARCA4 and KRAS mutant cancer. In an embodiment, the pan-KRAS inhibitor is Compound 2 or a pharmaceutically acceptable salt thereof.[000135] A SMARCA4 mutant cancer is a cancer that has mutations (damaging mutations, missense mutations, or deletions) resulting in either partial or complete loss of SMARCA4 functional protein.[000136] A KRAS mutant cancer is a cancer that has mutations (damaging mutations, missense mutations, or deletions) resulting in either partial or complete loss of KRAS functional protein.[000137] Cancers that may be treated using the disclosed methods include any cancer that is SMARCA4 mutant or SMARCA4 and KRAS mutant. More specifically, examples include but are not limited to lung cancer, endometrial cancer, ampullary cancer, GI neuroendocrine cancer, bladder cancer, esophagogastric cancer, ovarian cancer, head and neck cancer, colorectal cancer, cervical cancer, skin (non-melanoma) cancer, small bowel cancer, melanoma, mature B-cell neoplasms, bile duct cancer - such as cholangiocarcinoma, and pancreatic cancer. Specific examples of lung cancer include non-small cell lung cancer (NSCLC) and small cell lung cancer. In an embodiment, the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and esophageal cancer. In an embodiment, the cancer is selected from the group consisting of lung cancer, pancreatic cancer, and colon cancer. In a further embodiment, the cancer is lung cancer. In a further embodiment, the lung cancer is NSCLC. In a further embodiment, the lung cancer is small cell lung cancer. In another embodiment, the cancer is pancreatic cancer. In still another embodiment, the cancer is colon cancer. In another embodiment, the cancer is endometrial cancer. In another embodiment, the cancer is ampullary cancer. In another embodiment, the cancer is GI neuroendocrine cancer. In another embodiment, the cancer is bladder cancer. In another embodiment, the cancer is esophagogastric cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is head and neck cancer. In another embodiment, the cancer is cervical31477JJScancer. Tn another embodiment, the cancer is small cell lung cancer. In another embodiment, the cancer is skin, non-melanoma cancer. In another embodiment, the cancer is small bowel cancer. In another embodiment, the cancer is melanoma cancer. In another embodiment, the cancer is mature B-cell neoplasms. In another embodiment, the cancer is bile duct cancer.[000138] In another embodiment, the SMARCA4 mutant or SMARCA4 and KRAS mutant cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small-cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer, or penile cancer.[000139] In some embodiments of any of the foregoing methods, the cancer is a drug resistant cancer or has failed to respond to a prior therapy (e.g., vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 inhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, perjeta, tamoxifen, xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inihibitors, alimta. abraxane, Adriamycin®, gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, ARN810, an mTOR inhibitor, topotecan, gemzar, a VEGFR2 inhibitor, a folate receptor antagonist, demcizumab, fosbretabulin, or a PDL1 inhibitor).[000140] In some embodiments of any of the above aspects, the combinations described herein reduce the level and / or activity of SMARCA2 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of SMARCA2 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of BRG1 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).[000141] In some embodiments, the cancer harbors a mutation in GNAQ. In some embodiments the cancer harbors a mutation in GNA11. In some embodiments the cancer31477JJSharbors a mutation in PLCB4. In some embodiments the cancer harbors a mutation in CYSLTR2. In some embodiments the cancer harbors a mutation in BAP1. In some embodiments the cancer harbors a mutation in SF3B1. In some embodiments the cancer harbors a mutation in EIF1AX. In some embodiments the cancer harbors a TFE3 translocation. In some embodiments the cancer harbors a TFEB translocation. In some embodiments the cancer harbors a MITF translocation. In some embodiments the cancer harbors an EZH2 mutation. In some embodiments the cancer harbors a SUZ12 mutation. In some embodiments the cancer harbors an EED mutation.[000142] A “therapeutically effective amount” means an amount effective to treat or to prevent development of, or to alleviate the existing symptoms of, the subject (e.g., patient) being treated. For example, in one embodiment, a therapeutically effective amount of a compound disclosed herein decreases the activity of the targeted protein (e.g., KRAS, SMARCA2) by at least 5%, compared to control, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%. at least 40%, at least 45%, at least 50%, at least 55%, at least 60%. at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%.[000143] Compound 1 (as a free base) may be administered at a dose level of about 10 mg up to about 1,000 mg. Alternatively, Compound 1 may be administered at a dose level of about 10 mg up to about 1000 mg or it may be administered at a dose level of about 200 mg to about 1000 mg or about 100 mg to about 800 mg, or it may be administered at a dose level of about 200 mg to about 800 mg about or about 300 mg to about 800 mg or about 400 mg to about 600 mg, or about 300 mg to about 500 mg or about 300 mg to about 700 mg. Examples of doses that may be administered include, for example, 10 mg, 20 mg, 40 mg, 80 mg, 140 mg, 150 mg, 200 mg, 300 mg, 400 mg, 450 mg, 500 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850mg, 900 mg, 950 mg, and 1000 mg. Compound 1 may be administered once per day, twice per day, three times per day or four times per day. In one embodiment. Compound 1 is administered BID, which means twice per day. The other compounds disclosed herein may be administered in the doses disclosed herein, or according to their label.[000144] When Compound 1 is administered as a pharmaceutically acceptable salt, the salt is, for example, the HC1 salt, the besylate salt, the tosylate salt, the sulfate salt, the methanesulfonic acid salt, or the trifluoromethanesulfonic acid salt. The amount of the salt form that is administered depends on the identity of the specific salt. Salts made from heavier31477_UScounterions will necessitate administering more material than a salt made from a lighter counterion. In all cases, more Compound 1 pharmaceutically acceptable salt will be administered, when compared to the non-salt, i.e., free base, form of Compound 1.[000145] Embodiments1. A method of treating a SMARCA4 mutant cancer comprising:administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:O N NN >5HJ OCompound 1or a pharmaceutically salt thereof, in simultaneous, separate or sequential combination with at least one other therapeutic agent. In one aspect. Compound 1 is the free base.2. The method of embodiment 1, wherein the at least one other therapeutic agent is selected from a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, or a pharmaceutically acceptable salt thereof, an antifolate agent, or a pharmaceutically acceptable salt thereof, an antineoplastic agent, or a pharmaceutically acceptable salt thereof, and a KRAS inhibitor, wherein the KRAS inhibitor is selected from the group consisting of a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, and a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is combined with no more than one KRAS inhibitor.3. The method of embodiment 2, wherein the PD-1 inhibitor is pembrolizumab4. The method of embodiment 2, wherein the platinum agent is cisplatin.5. The method of embodiment 2, wherein the antifolate agent is pemetrexed.6. The method of embodiment 2, wherein the antineoplastic agent is paclitaxel.7. The method of embodiment 2, wherein the compound is administered in simultaneous, separate or sequential combination with a platinum agent and an antifolate agent.31477_US8. The method of embodiment 7, wherein the platinum agent is cisplatin, and the antifolate agent is pemetrexed.9. The method of embodiment 2, wherein the compound is administered in simultaneous, separate or sequential combination with a platinum agent and an antineoplastic agent.10. The method of embodiment 9, wherein the platinum agent is cisplatin, and the antineoplastic agent is paclitaxel.11. The method of embodiment 2, wherein the KRAS G12C inhibitor is olomorasib, or a pharmaceutically acceptable salt thereof. In a further embodiment, the KRAST G12C inhibitor is olomorasib.12. The method of embodiment 2, wherein the KRAS G12D is a compound of the formula:or a pharmaceutically acceptable salt thereof.13. The method of embodiment 12, wherein the compound is a disaccharinate salt.14. The method of embodiment 2, wherein the pan-KRAS inhibitor is a compound of the formula:or a pharmaceutically acceptable salt thereof.15. The method of embodiment 1, wherein the cancer further contains a KRAS mutation, the method comprising:31477JJSadministering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:Compound 1or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with at least one other therapeutic agent that is a KRAS inhibitor, wherein the KRAS inhibitor is preferably selected from the group consisting of a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, and a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof. In one aspect, Compound 1 is the free base.16. The method of embodiment 15, wherein the KRAS G12C inhibitor is olomorasib, or a pharmaceutically acceptable salt thereof. In a further embodiment, the KRAS G12C inhibitor is olomorasib.17. The method of embodiment 15, wherein the KRAS G12D is a compound of the formula:or a pharmaceutically acceptable salt thereof.18. The method of embodiment 17, wherein the wherein the compound is a disaccharinate salt.19. The method of embodiment 15, wherein the pan-KRAS inhibitor is a compound of the formula:31477_USor a pharmaceutically acceptable salt thereof.20. The method of any one of embodiments 1-19, wherein the cancer is selected from the group consisting of lung cancer, endometrial cancer, ampullary cancer, GI neuroendocrine cancer, bladder cancer, esophagogastric cancer, ovarian cancer, head and neck cancer, colorectal cancer, cervical cancer, skin (non-melanoma) cancer, small bowel cancer, melanoma, mature B-cell neoplasms, bile duct cancer, and pancreatic cancer.21. The method of any one of embodiments 1-20, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, and colon cancer.22. The method of embodiment 20, wherein the cancer is lung cancer.23. The method of embodiment 20, wherein the cancer is non-small cell lung cancer. 24. The method of embodiment 20, wherein the cancer is pancreatic cancer.25. The method of embodiment 20, wherein the cancer is colon cancer.26. The method of embodiment 20, wherein the cancer is endometrial cancer.27. The method of embodiment 20, wherein the cancer is ampullary cancer.28. The method of embodiment 20, wherein the cancer is GI neuroendocrine cancer. 29. The method of embodiment 20, wherein the cancer is bladder cancer.30. The method of embodiment 20, wherein the cancer is esophagogastric cancer.31. The method of embodiment 20, wherein the cancer is ovarian cancer.32. The method of embodiment 20, wherein the cancer is head and neck cancer.33. The method of embodiment 20, wherein the cancer is cervical cancer.34. The method of embodiment 20, wherein the cancer is small cell lung cancer.35. The method of embodiment 20, wherein the cancer is skin, non-melanoma cancer.36. The method of embodiment 20, wherein the cancer is small bowel cancer.37. The method of embodiment 20, wherein the cancer is melanoma cancer.38. The method of embodiment 20, wherein the cancer is mature B-cell neoplasms.31477JJS39. The method of embodiment 20, wherein the cancer is bile duct cancer.40. A compound of the formula:Compound 1or a pharmaceutically salt thereof, for use in simultaneous, separate or sequential combination with at least one other therapeutic agent in the treatment of a SMARCA4 mutant cancer. In one aspect, Compound 1 is the free base.41. The compound for use of embodiment 40, wherein the at least one other therapeutic agent is selected from a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, or a pharmaceutically acceptable salt thereof, an antifolate agent, or a pharmaceutically acceptable salt thereof, an antineoplastic agent, or a pharmaceutically acceptable salt thereof, and a KRAS inhibitor, wherein the KRAS inhibitor is selected from the group consisting of a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, and a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is combined with no more than one KRAS inhibitor.42. The compound for use of embodiment 41, wherein the PD-1 inhibitor is pembrolizumab.43. The compound for use of embodiment 41, wherein the platinum agent is cisplatin. 44. The compound for use of embodiment 41, wherein the antifolate agent is pemetrexed.45. The compound for use of embodiment 41, wherein the antineoplastic agent is paclitaxel.46. The compound for use of embodiment 41, wherein the compound is administered in simultaneous, separate or sequential combination with a platinum agent and an antifolate.47. The compound for use of embodiment 46. wherein the platinum agent is cisplatin, and the antifolate agent is pemetrexed.31477_US48. The compound for use of embodiment 41, wherein the compound is administered in simultaneous, separate or sequential combination with a platinum agent and an antineoplastic agent.49. The compound for use of embodiment 48, wherein the platinum agent is cisplatin, and the antineoplastic agent is paclitaxel.50. The compound for use of embodiment 41, wherein the KRAS G12C inhibitor is olomorasib, or a pharmaceutically acceptable salt thereof. In a further embodiment, the KRAS G12C inhibitor is olomorasib.51. The compound for use of embodiment 41, wherein the KRAS G12D inhibitor is a compound of the formula:or a pharmaceutically acceptable salt thereof.52. The compound for use of embodiment 51, wherein the compound is a disaccharinate salt.53. The compound for use of embodiment 41, wherein the pan-KRAS inhibitor is a compound of the formula:or a pharmaceutically acceptable salt thereof.54. The compound for use of embodiment 41, wherein the at least one other therapeutic agent is selected from the group consisting of a KRAS G12C inhibitor, or a pharmaceutically31477_USacceptable salt thereof, a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, and a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof.55. The compound for use of embodiment 54, wherein the KRAS G12C inhibitor is olomorasib, or a pharmaceutically acceptable salt thereof. In a further embodiment, the KRAS G12C inhibitor is olomorasib.56. The compound for use of embodiment 54, wherein the KRAS G12D inhibitor is a compound of the formula:or a pharmaceutically acceptable salt thereof.57. The compound for use of embodiment 56, wherein the wherein the compound is a di saccharinate salt.58. The compound for use of embodiment 54, wherein the pan-KRAS inhibitor is a compound of the formula:or a pharmaceutically acceptable salt thereof.59. The compound for use of embodiment of any one of embodiments 40-58, wherein the cancer is selected from the group consisting of lung cancer, endometrial cancer, ampullary cancer, GI neuroendocrine cancer, bladder cancer, esophagogastric cancer, ovarian cancer, head and neck cancer, colorectal cancer, cervical cancer, skin (non-melanoma) cancer, small bowel cancer, melanoma, mature B-cell neoplasms, bile duct cancer, and pancreatic cancer.31477JJS60. The compound for use of embodiment of any one of embodiments 40-59, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, and colon cancer.61. The compound for use of embodiment 59. wherein the cancer is lung cancer.62. The compound for use of embodiment 59, wherein the lung cancer is non-small cell lung cancer.63. The compound for use of embodiment 59. wherein the cancer is pancreatic cancer.64. The compound for use of embodiment 59, wherein the cancer is colon cancer.65. The compound for use of embodiment 59, wherein the cancer is endometrial cancer.66. The compound for use of embodiment 59, wherein the cancer is ampullary cancer.67. The compound for use of embodiment 59, wherein the cancer is GI neuroendocrine cancer.68. The compound for use of embodiment 59, wherein the cancer is bladder cancer. 69. The compound for use of embodiment 59, wherein the cancer is esophagogastric cancer.70. The compound for use of embodiment 59, wherein the cancer is ovarian cancer. 71. The compound for use of embodiment 59, wherein the cancer is head and neck cancer.72. The compound for use of embodiment 59, wherein the cancer is cervical cancer. 73. The compound for use of embodiment 59. wherein the cancer is small cell lung cancer.74. The compound for use of embodiment 59, wherein the cancer is skin, non-melanoma cancer.75. The compound for use of embodiment 59, wherein the cancer is small bowel cancer.76. The compound for use of embodiment 59, wherein the cancer is melanoma cancer.77. The compound for use of embodiment 59. wherein the cancer is mature B-cell neoplasms.78. The compound for use of embodiment 59, wherein the cancer is bile duct cancer. 79. A method of treating a SMARCA4 mutant cancer comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula31477JJSCompound 1or a pharmaceutically salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, wherein the cancer is lung cancer. In one aspect, Compound 1 is the free base.80. The method according to embodiment 79, wherein the lung cancer is non-small cell lung cancer (NSCLC).81. The method according to embodiment 79 or 80, further comprising simultaneous, separate or sequential combination with pemetrexed.82. The method according to embodiment 81. further comprising simultaneous, separate or sequential combination with cisplatin or carboplatin.83. The method according to embodiment 81, further comprising simultaneous, separate or sequential combination with cisplatin and carboplatin.84. The method according to embodiment 81, further comprising simultaneous, separate or sequential combination with cisplatin.85. The method according to embodiment 81, further comprising simultaneous, separate or sequential combination with carboplatin.86. The method according to embodiment 79 or 80, further comprising simultaneous, separate or sequential combination with paclitaxel or nab-paclitaxel.87. The method according to embodiment 79 or 80, further comprising simultaneous, separate or sequential combination with paclitaxel and nab-paclitaxel.88. The method according to embodiment 79 or 80, further comprising simultaneous, separate or sequential combination with paclitaxel.89. The method according to embodiment 79 or 80, further comprising simultaneous, separate or sequential combination with nab-paclitaxel.90. The method according to any one of embodiments 86-89, further comprising simultaneous, separate or sequential combination with carboplatin.31477_US91. A method of promoting immune cell infiltration into SMARCA4 mutant tumors the method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formulaCompound 1or a pharmaceutically salt thereof, in simultaneous, separate or sequential combination with pembrolizumab. In one aspect, Compound 1 is the free base. In one embodiment, the tumor is lung cancer, such as non- small cell lung cancer. In another embodiment, the cancer is bladder cancer. In another aspect. Compound 1 and pembrolizumab are administered for at least about two weeks. In one embodiment, about 200 to about 800 mg or about 300 mg to about 700 mg or about 200 mg to about 600 mg or about 400 mg to about 600 mg of Compound 1 is administered at least once a day. In some embodiments, Compound 1 is administered twice a day.92. A method of preventing metastasis of a SMARCA4 mutant cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formulaCompound 1or a pharmaceutically salt thereof, in simultaneous, separate or sequential combination with pembrolizumab wherein the cancer is lung or bladder cancer, and wherein Compound 1 and pembrolizumab are administered for at least about one week. In one aspect, Compound 1 is the free base. In another aspect, Compound 1 and pembrolizumab are administered for at least about two weeks. In one embodiment, the cancer is lung cancer. In another embodiment, the cancer is bladder cancer. In one embodiment, about 200 mg to about 1000 mg, about 200 mg to about 800 mg or about 300 mg to about 700 mg or about 200 mg to about 600 mg or about 400 mg to about31477JJS600 mg of Compound 1 is administered at least once a day. In some embodiments, Compound 1 is administered twice a day.93. The method or use according to any one of embodiments 1-92, wherein about 300 mg of Compound 1 is administered twice daily.94. The method or use according to any one of embodiments 1-92, wherein about 350 mg of Compound 1 is administered twice daily.95. The method or use according to any one of embodiments 1-92, wherein about 400 mg of Compound 1 is administered twice daily.96. The method or use according to any one of embodiments 1-92, wherein about 450 mg of Compound 1 is administered twice daily.97. The method or use according to any one of embodiments 1-92, wherein about 500 mg of Compound 1 is administered twice daily.98. The method or use according to any one of embodiments 1-92, wherein about 550 mg of Compound 1 is administered twice daily.99. The method or use according to any one of embodiments 1-92, wherein about 600 mg of Compound 1 is administered twice daily.100. The method or use according to any one of embodiments 1-92, wherein about 650 mg of Compound 1 is administered twice daily.101. The method or use according to any one of embodiments 1-92, wherein about 700 mg of Compound 1 is administered twice daily.102. The method or use according to any one of embodiments 1-92, wherein about 750 mg of Compound 1 is administered twice daily.103. The method or use according to any one of embodiments 1-92, wherein about 800 mg of Compound 1 is administered twice daily.104. The method or use according to any one of embodiments 1-92, wherein about 850 mg of Compound 1 is administered twice daily.105. The method or use according to any one of embodiments 1-92, wherein about 900 mg of Compound 1 is administered twice daily.106. The method or use according to any one of embodiments 1-92, wherein about 950 mg of Compound 1 is administered twice daily.31477JJS107. The method or use according to any one of embodiments 1 -92, wherein about 1000 mg of Compound 1 is administered twice daily.108. A compound of the formulaO II N NN >OCompound 1or a pharmaceutically salt thereof, for use in simultaneous, separate or sequential combination with pembrolizumab in the treatment of SMARCA4 mutant cancer. In one embodiment, the cancer is lung cancer. In one aspect, Compound 1 is the free base.109. The compound for use according to embodiment 108, wherein the lung cancer is non-small cell lung cancer (NSCLC).110. The compound for use according to embodiment 108 or 109, further comprising simultaneous, separate or sequential combination with pemetrexed.111. The compound for use according to embodiment 110, further comprising simultaneous, separate or sequential combination with cisplatin or carboplatin.112. The compound for use according to embodiment 110, further comprising simultaneous, separate or sequential combination with cisplatin and carboplatin.113. The compound for use according to embodiment 110, further comprising simultaneous, separate or sequential combination with cisplatin.114. The compound for use according to embodiment 110, further comprising simultaneous, separate or sequential combination with carboplatin.115. The compound for use according to embodiment 108 or 109, further comprising simultaneous, separate or sequential combination with paclitaxel or nab-paclitaxel.116. The compound for use according to embodiment 108 or 109, further comprising simultaneous, separate or sequential combination with paclitaxel and nab-paclitaxel.117. The compound for use according to embodiment 108 or 109, further comprising simultaneous, separate or sequential combination with paclitaxel.31477JJS118. The compound for use according to embodiment 108 or 109, further comprising simultaneous, separate or sequential combination with nab-paclitaxel.119. The compound for use according to embodiment 115 to 118, further comprising simultaneous, separate or sequential combination with carboplatin.120. A compound of the formula:O II N NN >5Hll OCompound 1or a pharmaceutically salt thereof, for use in simultaneous, separate or sequential combination with pembrolizumab in promoting immune cell infiltration into SMARCA4 mutant tumors. In one aspect, Compound 1 is the free base. In an embodiment, the tumor is lung cancer, such as non-small cell lung cancer. The pembrolizumab may be administered lOmg / kg, twice per week, i.p.121. The compound for use according to embodiment 120, wherein Compound 1 and pembrolizumab are administered simultaneously, separately or sequentially with standard of care (SoC) chemotherapy, which comprises gemcitabine 15mg / kg plus cisplatin 2mg / kg.122 A compound of the formula:O II N N N YHJ OCompound 1or a pharmaceutically salt thereof, for use in simultaneous, separate or sequential combination with pembrolizumab in preventing metastasis of a SMARCA4 mutant lung or SMARCA4 mutant bladder cancer, and wherein Compound 1 and pembrolizumab are administered for at least about one week. In one aspect, Compound 1 is the free base. In another aspect, Compound 1 and pembrolizumab are administered for at least about two weeks. In one31477JJSembodiment, the cancer is lung cancer. In another embodiment, the cancer is bladder cancer. The pembrolizumab may be administered lOmg / kg, twice per week, i.p.123. The compound for use according to embodiment 122, wherein Compound 1 is the free base, Compound 1 and pembrolizumab are administered for at least about one week, and the lung cancer is non-small cell lung cancer.124. The compound for use according to embodiment 122, wherein Compound 1 is the free base, Compound 1 and pembrolizumab are administered for at least about one week, and the cancer is bladder cancer.125. The compound for use according to any one of embodiments 108-124, wherein about 300 mg of Compound 1 is administered twice daily.126. The compound for use according to any one of embodiments 108-124, wherein about 350 mg of Compound 1 is administered twice daily.127. The compound for use according to any one of embodiments 108-124, wherein about 400 mg of Compound 1 is administered twice daily.128. The compound for use according to any one of embodiments 108-124, wherein about 450 mg of Compound 1 is administered twice daily.129. The compound for use according to any one of embodiments 108-124, wherein about 500 mg of Compound 1 is administered twice daily.130. The compound for use according to any one of embodiments 108-124, wherein about 550 mg of Compound 1 is administered twice daily.131. The compound for use according to any one of embodiments 108-124, wherein about 600 mg of Compound 1 is administered twice daily.132. The compound for use according to any one of embodiments 108-124, wherein about 650 mg of Compound 1 is administered twice daily.133. The compound for use according to any one of embodiments 108-124, wherein about 700 mg of Compound 1 is administered twice daily.134. The compound for use according to any one of embodiments 108-124, wherein about 750 mg of Compound 1 is administered twice daily.135. The compound for use according to any one of embodiments 108-124, wherein about 800 mg of Compound 1 is administered twice daily.31477JJS136. The compound for use according to any one of embodiments 108- 124, wherein about 850 mg of Compound 1 is administered twice daily.137. The compound for use according to any one of embodiments 108-124, wherein about 900 mg of Compound 1 is administered twice daily.138. The compound for use according to any one of embodiments 108-124, wherein about 950 mg of Compound 1 is administered twice daily.139. The compound for use according to any one of embodiments 108-124, wherein about 1000 mg of Compound 1 is administered twice daily.Examples[000146] Compound 1 was used as a free base in the examples below unless noted otherwise.[000147] Compound 2 was used as a free base in the examples below.[000148] Compound 3 was used as a free base in the examples below.[000149]Example 1[000150] In vitro study evaluating the antiproliferative activity of Compound 1 in combination with standard of care (SOC) cisplatin and pemetrexed in BRG1 -Deficient Human Non-Small Cell Lung Carcinoma Cell Lines, A549 and RERF-LC-AITest Compounds:[000151] Compound 1 can be synthesized as described in PCT / US2023 / 021793.[000152] Cisplatin was sourced from Teva (Cincinnati, Ohio, United States) and paclitaxel was sourced from Sigma Aldrich (St. Louis. Missouri, United States). Compound 1. paclitaxel, and pemetrexed were dissolved in DMSO to generate 20 mM stock solutions. Cisplatin was provided as a 1 mg / mL (3.33 mM) solution.Cell lines[000153] The following human NSCLC cell lines were purchased for use in these studies. A549 (CCL-185) cells were acquired from the American Type Culture Collection (ATCC) (Gaithersburg, Maryland, United States). RERF-LC-AI (CSC-C6515J) cells were acquired from31477JJSCreative Bioarray (Shirley, New York, United States). The BRG1 status and mutation profile for each of the two cell lines is shown in Table 1.[000154] A549 cells were cultured and assayed in RPMI-1640 medium (containing 4.5g / L Glucose, 10 mM HEPES, 2 mM L-Glutamine, 1.5 g / L Sodium Bicarbonate, 1 mM Sodium Pyruvate) with 10% characterized FBS and IX Antibiotic / Antimycotic. RERF-LC-AI cells were cultured and assayed in EMEM with 1 mM Pyruvate. 0.1 mM NEAA, IX Antibiotic-Antimycotic and 10% characterized FBS. All cell lines were grown in the indicated culture medium and incubated in a humidified 37 °C / 5% C02Z 95% atmospheric air incubator.Table 1. Cell Line Mutation ProfilePrimary / Cell Line Metastatic BRG1 Status Other Driving MutationsKRAS p.G12S, STK11 p.Q37*, KEAP1 p.G333C, ATR A549 Primary BRG1 p.H736YspliceRERF-LC-AI Metastatic BRG1 p.E1496* TP53 p.Q104*, NF1 p.E1699*, NOTCH4 G796fs p., point mutation; fs, frameshift; *, early stop codon; LOF, loss of function; Amp, amplification; splice, splicing variant. Mutation profile was curated from Cell Model Passport (Sanger Institute Database) and Cancer Dependency Map (BROAD Institute).Assay Methods[000155] Cells were plated in poly-D-lysine coated 96-well plates at a seeding density of one hundred cells / well in complete media 2-3 hours prior to treatment with compounds.Checkerboard-matrix analysis was utilized to assess the combinations of Compound 1 with either cisplatin, paclitaxel, or pemetrexed in a 10 x 6 matrix format. The matrix was comprised of a series of nine concentrations of Compound 1 (800 nM to 3.13 nM, 1:2 serial dilutions) in each column and a series of five concentrations of paclitaxel (8 nM to 0.1 nM, 1:3 serial dilutions), cisplatin (1 pM to 12.35 nM, 1:3 serial dilutions for RERF-LC-AI; and, 3 pM to 187.5 nM, 1:2 serial dilutions for A549), or pemetrexed (800 nM to 50 nM, 1:2 serial dilutions) in each row. Cells were dosed with Compound 1 and either cisplatin, paclitaxel, or pemetrexed simultaneously in a total volume of lOOuL at non-constant ratios. Final DMSO concentrations in the assay were kept below 0.2%. After a 10-day incubation, 100 mL Cell-titer GLO reagent was added per well and mixed on a Heidolph Titramax 1000 plate shaker at 600 RPM for 10 minutes. Assay plates were read on the Biotek Synergy Neo2 with filter cubes 42-LUM and 114-LUM installed for luminescence emission.[000156] Each matrix was done in duplicate.31477JJSData Analysis[000157] To determine the percent inhibition in each sample, the max inhibition luminescence signal (highest concentration of Compound 1 and highest concentration of SOC agent) was subtracted from the luminescence signal for each sample and the max-inhibition-subtracted signal was normalized to the DMSO signal, which was defined as 100% activity. Percent inhibition (%) was defined as the percent of activity subtracted from 100. Data was analyzed using Biotek Gen5 v3.10, Microsoft Excel, and Graphpad Prism v9.1.2. Data was analyzed using four-parameter logistic regression (LL4) to fit single agent dose response curves. The data was plotted in Graphpad Prism v9.1.2.[000158] The averaged percentage inhibition values for the duplicate matrix plates were uploaded to Synergy Finder 3.0 for generation of Highest Single Agent (HSA) synergy scores. The HSA model quantifies the degree of synergy observed as the excess response over the maximum single compound effect. Therefore, HSA synergy scores (yHSA) assume that the expected combination effect equals to the higher effect of individual compounds:YHSA=EA,B,...,N - max(EA, EB,..„ EN),where EA,B,.. ,,N is the combination effect between N compounds and EA, EB,..., EN are the measured responses of the single compounds. Summary synergy scores are defined as the excess response to a drug interaction than expected. This is defined as the mean of the synergy scores generated from each data point. Summary synergy scores < -10 are interpreted as antagonistic; scores between -10 to 10 are interpreted as additive; and scores >10 are interpreted as synergistic.Results & Discussion[000159] The impact of Compound 1 in combination with SOC agents on cell growth in a panel of BRGl-mutant NSCLC tumor cell lines was evaluated by monitoring cell proliferation using an in-house cell-titer GLO viability assay after compound treatment for 10 days.Significant antiproliferative effect was observed for all single agent treatments alone over the concentration ranges tested in this study.[000160] In the combinations of Compound 1 with cisplatin, pemetrexed or paclitaxel, it was observed mainly additive combinations (HSA synergy scores in the range -10 to 10).However, as indicated in Figures 1-4, combinations demonstrating strong synergy with HSA synergy scores >10 were identified. In the matrix experiments with the A549 cells, it was31477JJSobserved regions with synergy scores > 10 within the concentration ranges of 100-400 nM Compound 1 combined with 750-1500 nM cisplatin, 100-400 nM Compound 1 combined with 0.89-2.67 nM paclitaxel, and 12.5-50 nM Compound 1 combined with 200-400 nM pemetrexed. Lastly, for the matrix combination experiments with RERF-LC-AI cells, it was observed regions with synergy scores >10 within the concentration ranges of 6.25-100 nM Compound 1 combined with 37-1000 nM cisplatin, 25-100 nM Compound 1 combined with 0.89-2.67 nM paclitaxel, and 6.25-50 nM Compound 1 (LY4050784) combined with 100-400 nM pemetrexed.[000161] The above results demonstrate that Compound 1 in combination with either cisplatin, paclitaxel or pemetrexed resulted in additive and synergistic combination impacts on cellular proliferation in BRGl-mutant human NSCLC tumor cell lines (see Figures 1-4). These results show that Compound 1 used in combination with lung standard of care agents can result in beneficial improvements in antiproliferative effects in BRGl-mutant NSCLC tumor cells over single agents alone.Example 2[000162] In vivo efficacy study characterizing the tumor growth inhibition of Compound 1 in combination with cisplatin and pemetrexed in a human tumor A549 xenograft non-small cell lung carcinoma model in miceTest Compounds:[000163] Compound 1 can be synthesized as described in PCT / US2023 / 021793. Compound 1 was then prepared as a spray dried dispersion (SDD) with HPMC-AS-MG (Shin-Etsu Chemical Co., Ltd. Lot # 3013034) (Active pharmaceutical ingredient is 24.77% by weight). Compound 1 SDD was formulated by water bath sonication with vehicle (0.5% CMC / 0.2% Tween 80 in water). The compound was formulated once per week, stored at 4 °C, and vortexed before dosing.[000164] Pemetrexed (Lot No. A681362) was formulated with 0.9% injectable saline. The formulation was water bath sonicated to produce a clear solution. Pemetrexed was formulated at the beginning of each 14-day cycle week and stored at 4 °C between the three daily doses.[000165] Cisplatin was diluted from commercial stocks (Lot No. 22K05KA) using phosphate buffered saline (PBS). Cisplatin was formulated fresh for each dose administered.[000166] Cell Lines31477JJS[000167] The A549 (SMARCA4 mutant / KRAS G12S) human NSCLC cell line was obtained from the American Type Culture Collection (ATCC, Virginia, United States). A549 cells were maintained in RPMI-1640 media supplemented with 10% fetal bovine serum. All cultures were maintained in a humidified incubator at 37 °C under 5% CO2 / 95% air, free of Mycoplasma and pathogenic human and murine viruses. Following recovery from frozen stocks, low cell passages (up to 6) were used in the experiments.Animal Model[000168] Female athymic nude mice were obtained from Envigo (Harlan Laboratories) and acclimated for 1 week before initiating the experiment. Logarithmically growing A549 cells [5 x 106 / 200 pL, single-cell suspensions of over 95% viability in Hank’s Balanced Saline Solution medium mixed with an equal volume of Matrigel] were subcutaneously injected into the right hind flank of each mouse. When the average tumor volume reached 150 - 250 mm3, the mice were randomized into different groups and treated with vehicle, Compound 1 and / or cisplatin and pemetrexed by oral gavage (PO) or intraperitoneal injection (IP) according to the experimental design shown in the table below. Animals had access to chow and water ad libitum. Tumor volume and body weight were measured twice per week.[000169] This study was run with 8 mice per treatment group.Table 2. Study DesignDoseTreatment (mg / k Dose Scheduleg)Vehicle NA PO, BID x 28Compound 1 60 PO, BID x 28 (5d on, Id off)Cisplatin +4 + 50 (IP, Q14D x 2) + (IP, (QD x 3, rest 11 days) x 2) PemetrexedCompound 1 +60+4+ PO, BID x 28 (5d on, Id off) + (IP, Q14D x 2)+ (IP, (QD x 3, Cisplatin +50 rest 11 days) x 2)PemetrexedAbbreviation: N / A, not applicable; BID, twice daily; QD, once daily; n. number of animals per group; PO, oral administration; IP, intraperitoneal administration: d, day.Data Analysis[000170] Tumor volume was estimated by using the formula: v = 1 x w2 x 0.536, where 1 = larger of measured diameter and w = smaller of perpendicular diameter. Delta T / C% (%dT / C)31477JJSwas calculated when the endpoint tumor volume in a treated group was at or above baseline tumor volume. The formula is 100*(T-BL) / (C-BL), where T and C are mean endpoint tumor volumes in the treated or control group, respectively. Baseline (BL) is the grand mean of the tumor volumes for all groups at the baseline (randomization) day. Percent tumor growth inhibition (TGI%) was defined as 100 minus delta T / C%. Percent regression (regression%) was calculated when the endpoint volume was below baseline. The statistical analysis of the tumor volume data began with a data transformation to a log scale to equalize variance across time and treatment groups. The log volume data were analyzed with a two-way repeated measures analysis of variance by time and treatment using the MIXED procedures in SAS software (Version 9.3). The correlation model for the repeated measures is Spatial Power. Compound treated groups were compared to the vehicle control group for statistical analyses.Combination Analysis[000171] The Bliss Independence method (Bliss, C., Annals of Applied Biology 1939: 26; 585-615) was used to estimate the tumor volume combination treatment effect. LoglO tumor volume for the control, single agent 1, single agent 2, and the combination of single agents 1 and 2 groups were analyzed using the previously described RM ANOVA model with an added two-way interaction contrast of the following form to estimate the Bliss Effect:logio T'b’control—l°gio ^^Single Agent 1—l°glO ^^Single Agent 2 T logio ^^combination wherelog10TVtis the mean tumor volume for treatment t[000172] Assuming that tumor volumes can, in theory or in actuality, reach zero (complete regression), this approach is mathematically equivalent to the Bliss Independence method when analyzing tumor volume on the log scale.[000173] If the combination effect is exactly additive, then by definition of Bliss Independence, the two-way interaction contrast estimate equals zero. If the contrast estimate is statistically different from zero e.g., not additive (p < 0.05), then we conclude that the combination effect is either greater than (synergistic) or less than (antagonistic) additive if the observed combination mean volume is less than or greater than the expected additive response tumor volume EARTV). respectively. The follow equation was used to estimate EARTV. _ Ks ingle Agent 1 ^^single Agent 2EARTV ~ - == - ^Control31477JJS[000174] If the interaction contrast test and all pairwise comparisons between the control and each single agent treated group versus the combination treated group are all statistically significant (p < 0.05), and the observed combination mean volume is less than the EAR volume, then the combination effect is declared greater than additive (synergistic).[000175] If the interaction contrast test is statistically significant (p < 0.05) and the observed combination mean volume is greater than the EAR volume, then the combination effect is declared less than additive (antagonistic) regardless of the pairwise comparison results.[000176] If the interaction test is not statistically significant (p > 0.05), but all pairwise comparisons versus the combination group are significant (p < 0.05), then the combination effect is declared additive, otherwise the combination effect is inconclusive (no effect).[000177] It is important to note that the LS Means used for the combination analysis and reported output, were estimated from a RM ANOVA model consisting of only the 4 groups related to each combination (i.e., control, single agent 1, single agent 2, and combination), and not by fitting each group separately as was done for the Tumor Growth Inhibition (TGI) analysis. While the estimated LS Means and Standard Errors should be similar, they may not match exactly.Results & Discussion[000178] In this study, the in vivo efficacy of Compound 1 in combination with cisplatin and pemetrexed, was investigated in the A549 human NSCLC xenograft model in mice. A549 tumor cells harbour a SMARCA4 mutation. Female Nude mice were injected with A549 cells, followed by randomization on Day 14, post-cell implantation. 60 mg / kg Compound 1, and / or 4 mg / kg cisplatin and 50 mg / kg pemetrexed were used for this study. The tumor-bearing mice received oral twice a day (BID) dosing of vehicle, Compound 1 and / or IP injection of cisplatin and pemetrexed as specified in the study design. All statistical analyses comparing compound treated to vehicle treated animals were performed using treatment Day 28 tumor and body weight measurements.[000179] Single-agent treatment with a 40 mg / kg dose of Compound 1 or 4mg / kg cisplatin and 50 mg / kg pemetrexed resulted in 95% or 41% tumor growth inhibition, respectively.Compound 1 dose of 60 mg / kg in combination with 4mg / kg cisplatin and 50 mg / kg pemetrexed demonstrated a beneficial increase of antitumor activity, resulting in sustained tumor regression.31477JJSTumor regression of 13% was observed for the combination. Bliss combination analysis defined the combination as statistically additive. All single and dual therapies were well tolerated throughout the study. Weight loss was observed in mice receiving chemotherapy (cycle start on dayl and day 14), but the body weights recovered well without any dosing holidays. The results are shown in Figure 5.[000180] As can be seen from Figure 5, Compound 1 exhibited significant antitumor activity resulting in tumor growth inhibition when used as a monotherapy and enhanced antitumor activity resulting in tumor regression when dosed in combination with cisplatin and pemetrexed in the A549 human NSCLC xenograft model.[000181] In summary, combining Compound 1 with cisplatin and pemetrexed increased antitumor effect in vivo, resulting in tumor regression.Example 3[000182] In vivo efficacy study characterizing the tumor growth inhibition by Compound 1 in combination with cisplatin and paclitaxel in a human tumor RERF-LC-AI xenograft non-small cell lung carcinoma model in miceTest Compounds:[000183] Compound 1 can be synthesized as described in PCT / US2023 / 021793. Compound 1 was then prepared as a spray dried dispersion (SDD) with HPMC-AS-MG (Shin-Etsu Chemical Co., Ltd. Lot # 3013034) (active pharmaceutical ingredient 25.25% by weight).Compound 1 SDD was formulated by water bath sonication with vehicle (0.5% CMC / 0.2% Tween 80 in water). The compound was formulated once per week, stored at 4 °C, and vortexed before dosing.[000184] Paclitaxel (Lot No. GF9986AA) was diluted from commercial stocks using phosphate buffered saline (PBS). The compound was formulated fresh for each dose administered.[000185] Cisplatin (Lot No. 22K05KA) was diluted from commercial stocks using PBS. The compound was formulated fresh for each dose administeredCell Lines[000186] The RERF-LC-AI (BRG1 mutant) human NSCLC cell line was obtained from Creative Bioarray (Shirley, NY, USA). RERF-LC-AI cells were maintained in EMEM supplemented with 10% heat-inactivated FBS. All cultures were maintained in a humidified31477JJSincubator at 37 °C under 5% CO2 / 95% air, free of Mycoplasma and pathogenic human and murine viruses. Following recovery from frozen stocks, low cell passages (up to 6) were used in the experiments.[000187] The animal model used in Example 2 was used. This study was run with 8 mice per treatment group.Table 3. Study DesignXenograft Treatment Dose (mg / kg) Dose ScheduleModel (n=8) Vehicle NA PO, BID x 28 RERF-LC-AI Compound 1 40 PO, BID x 28 RERF-LC-AI Cisplatin+Paclitaxel 4 + 10 (IP, Q14D x 2) + (IP, Q14D x 2) RERF-LC-AI Compound 1+ PO, BID x 28 (5d on, Id off) + (IP,40+4+10 RERF-LC-AI Cisplatin+Paclitaxel Q14D x 2) + (IP, Q14D x 2)Abbreviation: BID = twice daily, n = number of animals per group, PO = oral administrationData AnalysisSee Data Analysis section of Example 2.Results and Discussion[000188] In this study, the in vivo efficacy of Compound 1 in combination with cisplatin + paclitaxel, was investigated in a human NSCLC xenograft model in mice. RERF-LC-AI tumor cells, which harbor an inactivating SMARCA4 mutation, were injected into female nude mice, followed by randomization on Day 26, post-cell implantation. The tumor-bearing mice received oral BID dosing of vehicle or Compound 1 (40 mg / kg) and / or IP injection of the cisplatin (4 mg / kg) + paclitaxel (10 mg / kg) treatment, Q14D, as specified in the study design. All statistical analyses comparing compound treated to vehicle treated animals were performed using treatment Day 28 tumor and body weight measurements.[000189] Single-agent treatment with Compound 1 or the cisplatin + paclitaxel treatment resulted in statistically significant tumor growth inhibition of 87% or 49%, respectively (Figure 6). Compound 1 in combination with cisplatin + paclitaxel demonstrated a beneficial increase in antitumor activity, resulting in tumor regression of 17%. Bliss combination analysis defined the combination as statistically additive. All single and combination therapies were well tolerated throughout the study.31477JJS[000190] As shown in Figure 6, Compound 1 exhibited significant antitumor activity resulting in tumor growth inhibition when used as a monotherapy and enhanced antitumor activity resulting in tumor regression when administered in combination with cisplatin + paclitaxel in the RERF-LC-AI human NSCLC xenograft model.[000191] In summary, combining Compound 1 with cisplatin and paclitaxel increased antitumor effect in vivo, resulting in tumor regression.Example 4[000192] In vivo study characterizing the activity of Compound 1 in combination with pembrolizumab in a human lung adenocarcinoma A549 Xenograft Model engrafted with CD34+ Hematopoetic Stem cellsTest Compounds[000193] Compound 1 (API 25.26%) was formulated by water bath sonication with vehicle (0.5% CMS / 0.2% Tween 80 in water) to a final concentration of 7.92mg / ml or 15.84 mg / ml. The compound was formulated once per week and stored at 4 °C.[000194] Pembrolizumab (NDC0006-3026-02 from Merck, 25 mg / ml) was diluted freshly for each dosing to a final concentration of 0.1 mg / ml in saline solution.Cell Lines[000195] The A549 (BRG1 loss of function mutation) human non-small cell lung cancer cell line was obtained from the Collection of European Authenticated Cell Cultures (ECACC, United Kingdom). A549 cells were maintained in Ham's F12K (Kaighn's) supplemented with 10 mM HEPES. 2 mM glutamine and 10% fetal bovine serum. All cultures were maintained in a humidified incubator at 37 °C under 5% CO2 / 95% air, free of Mycoplasma and pathogenic human and murine viruses.Animal Model[000196] Female FcResolv® huNOG mice (model No. HSCCB-19164-F) were obtained from Taconic Biosciences and acclimated for 1 week before initiating the experiment. Prepared A549 cells [2.5 xl06 in 100 pL, single-cell suspensions of over 90% viability in Hank’s Balanced Saline Solution, mixed with an equal volume of Matrigel (100 pL)] were subcutaneously injected into the right hind flank of each mouse. When the average tumor volume reached approximately 200 mm3, the mice were randomized into different groups and treated31477JJSwith vehicle or Compound 1 , 20 mg / kg or 40mg / kg by oral gavage (PO) twice daily (BID), or with pembrolizumab, 10 mg / kg, by intraperitoneal (IP) injection, twice weekly (BIW) for 24 days. Animals were dosed by body weight (10 pL / g). Animals had access to chow ad libitum. Tumor volume and body weight were measured twice per week. The study was run with 5 animals per treatment group.Tumor Growth Inhibition Analysis[000197] Tumor volumes were transformed to a loglO scale to equalize variance across time and treatment. LoglO volume and body weight were separately analyzed using a two-way repeated measures analysis of variance model (RM ANOVA) consisting of time, treatment, and the interaction between time and treatment using the MIXED procedure of the SAS software package (Version 9.4). Spatial Power covariance structure was used to model the correlation of observations across time for the same subject. Kenward and Roger (Biometrics 1997:53;983-997) denominator degrees of freedom (DDFM) calculations were used for tests of fixed effects. Post-hoc pairwise t-tests were used to compare tumor volumes and body weights of treated groups to the control group on the summarized day, p-values < 0.05 were considered statistically significant. The MIXED procedure was also used separately for each treatment group to calculate least squares means (LS Means) and standard errors for each time point for the purpose of plotting and inclusion in summary tables.Efficacy Calculations[000198] Efficacy was calculated at the end of the treatment if number of remaining control group subjects was at least half the baseline sample size or greater than 4. Otherwise, efficacy was calculated on the most recent observation day prior to the end of treatment where these conditions were met.% Delta T / C% Delta[T / C] was defined as 100 times the ratio of the tumor volume change from Baseline at time t of the treated group versus the tumor volume change from Baseline of the control group at time t, where t is greater than than t Baseline and treated group change from Baseline is greater than zero (equation 1)% Delta[T / C] = 100 x — 4- (1)where,31477JJSTVt xis the tumor volume of group X at time t, t > tBaseiineTt= TVt Trmnt— TVBaseiine, Tt> 0ACf=^t.Ctrl ~ TVBaseliTie’ > 0TVBaseUneis the grand mean of all tumors at tBaseline.% Tumor Regression% Regression was defined as 100 times the ratio of the tumor volume change from Baseline of the treated group versus Baseline tumor volume at time t, where t is greater than tBaseUneand treated group change from Baseline is less than or equal to zero (equation 2)ATt% Regression = 100 x — - ,t > tBaseline(2)* V Baseline% Tumor Growth Inhibition (TGI)% TGI was defined as 100 minus % Delta T / C or % Regression as applicable (equation 3)o / TCI = f100"% DeltalT / Q’ *Tt >0 / 0[ 100 — % Regression, ATt< 0l JCombination AnalysisSee Combination Analysis in Example 2.Results & Discussion[000199] Loss-of-function mutations in SMARCA4 are common in non-small cell lung cancer (NSCLC) and create a synthetic lethal dependency on SMARCA2 activity. Inhibition of SMARCA2 by a selective SMARCA2 inhibitor, such as Compound 1, has demonstrated antitumor activity in preclinical models. The anti-PD-1 antibody pembrolizumab is approved for metastatic NSCLC. In this study, we investigated the potential combination benefit of Compound 1 with pembrolizumab in CD34+ HSC-humanized mice transplanted with SMARCA4-mutant NSCLC A549 cells to evaluate the single-agent and combination effects of Compound 1 and pembrolizumab on tumor growth over a 24-day treatment period.31477JJS[000200] Administration of single-agent Compound 1 (20 mg / kg or 40 mg / kg BID, PO) exhibited dose-dependent anti-tumor activity resulting in a Delta T / C of 68 % or 32% in 24-day study, whereas administration of single agent pembrolizumab (10 mg / kg BIW, IP) did not result in significant anti-tumor activity, when compared to vehicle control (Figure 7).[000201] The data shown in Figure 7 suggest that Compound 1 treatment can sensitize A549 xenograft cells to pembrolizumab resulting in improved anti-tumor efficacy with the combination compared to single agent treatment or vehicle control.[000202] In summary, Compound 1 sensitized the tumor cells to pembrolizumab treatment resulting in enhanced combination activity, while pembrolizumab alone had no effect on tumor growth compared to vehicle controlExample 5[000203] In vitro studies evaluating the antiproliferative activity of Compound 1 in Combination with KRAS inhibitors in the BRG1 -Deficient, KRAS G12C Non-Small Cell Lung Carcinoma Cell Line.Test Compounds[000204] Compound 1, Olomorasib, and Compound 3 were dissolved in DMSO to generate 20 mM stock solutions.Cell Lines[000205] NCI-H2030 (CRL-5914) cells were acquired from the American Type Culture Collection (ATCC) (Gaithersburg, Maryland, United States). The BRG1 status and driver mutation profile for NCI-H2030 is shown in Table 4.[000206] NCI-H2030 cells were cultured and assayed in RPMI-1640 medium (containing 4.5g / L Glucose, 10 mM HEPES, 2 mM L-Glutamine, 1.5 g / L Sodium Bicarbonate, 1 mM Sodium Pyruvate) with 10% characterized FBS and IX Antibiotic / Antimycotic. All cell lines were grown in the indicated culture medium and incubated in a humidified 37 °C / 5% CO2 / 95% atmospheric air incubator.Table 4. Cell Line Mutation ProfilePrimary / Cell Line BRG1 Status Other Driving Mutations MetastaticKRAS p.G12C, TP53 p.G262V,NCI-H2030 Primary BRG1 LOFSTK11 p.E317*, SETD2 p.G1563Vp., point mutation; *, early stop codon; LOF, loss of function.31477JJSMutation profile was curated from Cell Model Passport (Sanger Institute Database) and Cancer Dependency Map (BROAD Institute).Assay Methods[000207] Cells were plated in poly-D-lysine coated 96-well plates at a seeding density of one hundred cells / well in complete media 2-3 hours prior to treatment with compounds.Checkerboard-matrix analysis was utilized to assess the combinations of Compound 1 with either Olomorasib or Compound 2 in a 10 x 6 matrix format. The matrix was comprised of a series of nine concentrations of Compound 1 (800 nM to 3.13 nM, 1:2 serial dilutions) in each column and a series of five concentrations of Olomorasib (100 nM to 0.024 nM, 1:8 serial dilutions), or Compound 2 (200 nM to 0.78 nM, 1:4 serial dilutions) in each row. Cells were dosed with Compound 1 and either Olomorasib or Compound 2 simultaneously in a total volume of 100 uL at non-constant ratios. Final DMSO concentrations in the assay were kept below 0.2%. After a 10-day incubation, 100 uL Cell-titer GLO reagent was added per well and mixed on a Heidolph Titramax 1000 plate shaker at 600 RPM for 10 minutes. Assay plates were read on the Biotek Synergy Neo2 with filter cubes 42-LUM and 114-LUM installed for luminescence emission. Each matrix experiment was done in triplicate.Data Analysis[000208] To determine the percent inhibition in each sample, the max inhibition luminescence signal (highest concentration of Compound 1 and highest concentration of either Olomorasib or Compound 2) was subtracted from the luminescence signal for each sample and the max-inhibition-subtracted signal was normalized to the DMSO signal, which was defined as 100% activity. Percent inhibition (%) was defined as the percent of activity subtracted from 100. Data was analyzed using Biotek Gen5 v3.10, Microsoft Excel, and Graphpad Prism v9.1.2. Data was analyzed using four-parameter logistic regression (LL4) to fit single agent dose response curves. The data was plotted in Graphpad Prism v9.1.2.[000209] The averaged percentage inhibition values for the triplicate matrix plates were uploaded to Synergy Finder 3.0 for generation of Highest Single Agent (HSA) synergy scores. The HSA model quantifies the degree of synergy observed as the excess response over the maximum single compound effect. Therefore, HSA synergy scores (yHSA) assume that the expected combination effect equals to the higher effect of individual compounds:YHSA=£ ,B,...,V - max(EA, EB,..., EN),31477JJSwhere EA,B,...,Nis the combination effect between N compounds and EA, EB,..., EN are the measured responses of the single compounds. Summary synergy scores are defined as the mean of the synergy scores generated from each data point. Further, synergy is interpreted as an increased excess response to a drug interaction greater than expected. Synergy scores < -10 are interpreted as strongly antagonistic; scores >10 are interpreted as strongly synergistic; scores between -5 to 5 are interpreted as additive; scores between -5 to -10 are considered moderately antagonistic; and scores between 5 to 10 are considered moderately synergistic.Results and Discussion[000210] The impact of Compound 1 in combination with either Olomorasib or Compound 2 on cell growth in NCI-H2030 cells was evaluated by monitoring cell proliferation using an inhouse Cell-Titer GLO viability assay after compound treatment for 10 days. In the combination of Compound 1 with the KRAS G12C inhibitor, Olomorasib, in NCI-H2030 cells, was observed synergistic combinations for Compound 1 (25 nM to 400 nM range) with Olomorasib (0.20 nM to 12.5 nM range) (Figure 8). In the combination of Compound 1 with the isoform specific pan-KRAS inhibitor, Compound 2, was observed synergistic combinations for Compound 1 (25 nM to 400 nM range) with Compound 2 (3.13 nM to 50 nM range) (Figure 9).[000211] As can be seen from Figures 8 and 9, the data shows that Compound 1 in combination with either the KRAS G12C inhibitor, Olomorasib, or the isoform specific pan-KRAS inhibitor, Compound 2, resulted in areas of strong synergy (HSA score >10) in the BRG1-deficient, KRAS G12C co-mutated NSCLC cell line, NCI-H2030. These results indicate that combinations of Compound 1 with KRAS inhibitors, such as Olomorasib or Compound 2, may have enhanced benefits to patients exhibiting BRG1 and KRAS co-mutated NSCLC.[000212] In summary, combining Compound 1 with KRAS G12C selective inhibitor (olomorasib), or isoform selective pan-KRAS inhibitor (Compound 2) showed synergistic activity in vitro.Example 6[000213] In vivo efficacy study characterizing the tumor growth inhibition by Compound 1 in combination with Olomorasib in a Human Tumor NCLH2030 Xenograft non-small cell lung carcinoma model in mice.31477JJSTest Compounds[000214] Compound 1 was prepared as a spray dried dispersion (SDD) with HPMC-AS-MG (Shin-Etsu Chemical Co., Ltd. Lot # 3013034) (active pharmaceutical ingredient is 25.3% by weight). Compound 1 SDD was formulated by water bath sonication with vehicle (0.5% CMC / 0.2% Tween 80 in water). The compound was formulated once per week, stored at 4oC, and vortexed before dosing.[000215] Olomorasib, KRAS G12C inhibitor (Lot# AAL-A15961-155-1) was formulated with DMSO, added at 5% final volume, and briefly vortexed until the compound was completely dissolved. The formulation was then adjusted to the final calculated volume with 47.5% PEG400 147.5% water I 5% Cremophor EL. The compound was formulated once per week, stored at 4 oC, and vortexed before dosing.Cell Lines[000216] The NCI-H2030 (SMARCA4 mutant / KRAS G12C) human NSCLC cell line was obtained from the American Type Culture Collection (ATCC, Virginia, United States). NCI-H2030 cells were maintained in RPML1640 media (Gibco A 10491) supplemented with 10% fetal bovine serum (Cytiva SH30071.03). All cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air, free of Mycoplasma and pathogenic human and murine viruses. Pollowing recovery from frozen stocks, low cell passages (up to 6) were used in the experiments.Animal Model[000217] Pemale Nod Scid Gamma (NSG) mice (20-22 grams) were obtained from Jackson Labs (Bar Harbor, Maine) and acclimated for 1 week before initiating the experiment. Logarithmically growing NCI-H2030 cells [5x106 / 200 pL, single-cell suspensions of over 95% viability in Hank’s Balanced Saline Solution (HBSS) medium mixed with an equal volume of Matrigel] were subcutaneously injected into the right hind flank of each mouse. When the average tumor volume reached 150 - 250 mm3, the mice were randomized into different groups and treated with vehicle, Compound 1 and / or olomorasib by oral gavage according to the experimental design shown in the table below. Animals had access to chow and water ad libitum. Tumor volume and body weight were measured twice per week. This study was run with 8 mice per treatment group.31477JJSTable 5. Experimental DesignDose Xenograft Treatment Dose Schedule(mg / kg) Model (n=8) Vehicle NA PO, BID x 28 NCI-H2030 Compound 1 20 PO, BID x 28 NCI-H2030 Compound 1 40 PO, BID x 28 NCI-H2030 Olomorasib 10 PO, BID x 28 NCI-H2030 Compound 1+ Olomorasib 20+10 PO, BIDx28 + PO, BIDx28 NCI-H2030Compound 1+ Olomorasib 40+10 PO, BIDx28 + PO, BIDx28 NCI-H2030 Abbreviation: BID = twice daily, n = number of animals per group. PO = oral administrationData Analysis[000218] Same method as in Example 2.[000219] Combination Analysis[000220] Same method as in Example 2.Results & Discussion[000221] In this study, the in vivo efficacy of Compound 1 in combination with Olomorasib, was investigated in the NCI-H2030 human NSCLC xenograft model in mice. The NCI-H2030 tumor cells are co-mutated, harboring a SMARCA4 mutation and the KRAS G12C mutation. Female NSG mice were injected with NCI-H2030 cells, followed by randomization on Day 32, post-cell implantation. Low and mid doses of the compounds were used so that the combination benefit could be observed. 20 mg / kg or 40 mg / kg, low and mid doses of Compound 1 respectively, and a clinically relevant combination dose of 10 mg / kg Olomorasib were used for this study. The tumor-bearing mice received oral BID dosing of vehicle, Compound 1 and / or Olomorasib for 28 days. All statistical analyses comparing compound treated to vehicle treated animals were performed using treatment Day 28 tumor and body weight measurements.[000222] Single-agent treatment with a 20 mg / kg or 40 mg / kg dose of Compound 1 or a 10 mg / kg dose of Olomorasib resulted in 29%, 42% or 99% tumor growth inhibition, respectively. Compound 1 doses of 20 mg / kg or 40 mg / kg in combination with 10 mg / kg Olomorasib demonstrated synergistically increased antitumor activity, by Bliss combination analysis, resulting in sustained tumor regression, demonstrating 44% and 71% regression, respectively, as determined on Day 28 of dosing. Single-agent and combination treatments were well tolerated in this study.31477_US[000223] As can be seen from Figure 10, Compound 1 exhibited significant antitumor activity resulting in tumor growth inhibition when used as a monotherapy and synergistic antitumor activity resulting in tumor regression when dosed in combination with Olomorasib in the NCI-H2030 human NSCLC xenograft model. All single and dual therapies were well tolerated throughout the study.[000224] In summary, combination of Compound 1 with Olomorasib demonstrated synergistic antitumor activity and sustained tumor regression in vivo (see Figure 10).Example 7[000225] In vitro studies evaluating the antiproliferative activity of Compound 1 in Combination with KRAS G12D inhibitor, Compound 3, in BRG1 -Deficient Human colorectal and pancreatic carcinoma cell linesTest Compounds[000226] Compound 1 and Compound 3 were dissolved in DMSO to generate 20 mM stock solutions.Cell Lines[000227] The following human cell lines were purchased for use in these studies. PA-TU-8988T (ACC- 162) cells were acquired from the German Collection of Microorganisms and Cell Cultures (DSMZ) (Braunschweig, Germany). The PA-TU-8988T cell line contains homozygous KRAS G12V. Clustered regularly interspaced short palindromic repeats (CRISPR) gRNAs and single -strand donors were designed to introduce homozygous KRAS G12D (WEY-00008-02). Sanger sequencing was used to confirm the presence of the homozygous knock in, and the PA-TU-8988T_KRAS G12D clone Bll was selected for use in combination analysis and registration in OncoCell (CL-6377-002). SNU-407 (C0009016) cells were acquired from AddexBio (San Diego, California, United States). The BRG1 status and mutation profile for each of the cell lines is shown in Table 6.31477JJSTable 6. Cell Line Mutation ProfilePrimary / Cell Line BRG1 Status Other Driving Mutations MetastaticBRG1 P109fs*194,P.R466C,SNU-407 Metastatic P.Y507H, KRAS p.G12D, TP53 S90fs*33, PIK3CA H1047R P.M1109VPA-TU-8988T Metastatic BRG1 LOF KRAS p.G12V, TP53 p.R282W, SMAD4 LOF PA-TU-8988T KRAS p.G12D (engineered from CRISPR knock in),Metastatic BRG1 LOFclone Bll TP53 p.R282W, SMAD4 LOFp., point mutation; fs, frameshift; *, early stop codon; LOF, loss of function; Amp, amplification; splice, splicing variant. Mutation profile was curated from Cell Model Passport (Sanger Institute Database) and Cancer Dependency Map (BROAD Institute).Assay Methods[000228] Cells were plated in poly-D-lysine coated 96-well plates in complete media 2-3 hours prior to treatment with compounds, refer to Table 4 for seeding densities. Checkerboardmatrix analysis was utilized to assess the combinations of Compound 1 with Compound 3 in a 10 x 6 matrix format. The matrix was comprised of a series of nine concentrations of Compound 1 in each row and a series of five concentrations of Compound 3 in each column, refer to Table 4 for compound dilution details. Cells were dosed with Compound 1 and Compound 3 simultaneously in a total volume of 100 uL at non-constant ratios. Final DMSO concentrations in the assay were kept below 0.2%. After a 10-day incubation, 100 uL Cell-titer GLO reagent (Promega, G7571) was added per well and mixed on a Heidolph Titramax 1000 plate shaker at 600 RPM for 10 minutes. Assay plates were read on the Biotek Synergy Neo2 with filter cubes 42-LUM and 114-LUM installed for luminescence emission. Each matrix was done in duplicate.Table 7. Seeding Densities and Compound Dilution Series by Cell Line Cell Line Seeding Density Compound 1 Dilution Series Compound 3 Dilution Series 6000nM to 0.9 InM, 1:3 lOOOnM to O.lOnM, 1:10 SNU-407 300 cells / welldilution series dilution seriesPA-TU-8988T 2000nM to 0.30nM, 1:3 200nM to 0.78nM, 1:4300 cells / wellclone Bll dilution series dilution seriesData Analysis[000229] To determine the percent inhibition in each sample, the max inhibition luminescence signal (highest concentration of Compound 1 and highest concentration of31477JJSCompound 3) was subtracted from the luminescence signal for each sample and the maxinhibition-subtracted signal was normalized to the DMSO signal, which was defined as 100% activity. Percent inhibition (%) was defined as the percent of activity subtracted from 100. Data was analyzed using Biotek Gen5 v3.10, Microsoft Excel, and Graphpad Prism v9.1.2. Data was analyzed using four-parameter logistic regression (LL4) to fit single agent dose response curves. The data was plotted in Graphpad Prism v9.1.2.[000230] The averaged percentage inhibition values for the duplicate matrix plates were uploaded to Synergy Finder 3.0 for generation of Loewe synergy scores.[000231] The averaged percentage inhibition values for the duplicate matrix plates were uploaded to Synergy Finder 3.0 for generation of Highest Single Agent (HSA) synergy scores. The HSA model quantifies the degree of synergy observed as the excess response over the maximum single compound effect. Therefore, HSA synergy scores (yHSA) assume that the expected combination effect equals to the higher effect of individual compounds:7HSA=A’ ; . N - max(EA, EB,..., EN),where EA,B,...,N is the combination effect between N compounds and EA, EB,..., ^AVC the measured responses of the single compounds. Summary synergy scores are defined as the excess response to a drug interaction than expected. This is defined as the mean of the synergy scores generated from each data point. Summary synergy scores < -10 are interpreted as antagonistic; scores between -10 to 10 are interpreted as additive; and scores >10 are interpreted as synergistic.Results and Discussion[000232] The impact of Compound 1 in combination with Compound 3 on cell growth in PA-TU-8988T_KRAS G12D clone B 11 cells was evaluated by monitoring cell proliferation using an in-house Cell-Titer GLO viability assay after compound treatment for 10 days. In the combination of Compound 1 with the KRAS G12D inhibitor, Compound 3, in SNU-407 cells, it was observed synergistic combinations for Compound 1 (25 nM to 2000 nM range) with Compound 3 (1 nM range) (Figure 11). In the combination of Compound 1 with the KRAS G12D inhibitor, Compound 3, in PA-TU-8988T_KRAS G12D clone Bll cells, it was observed synergistic combinations for Compound 1 (25 nM to 667 nM range) with Compound 33 (3 nM to 200 nM range) (Figure 12). In conclusion, the above results demonstrate that Compound 1 in combination with either the KRAS G12D inhibitor, Compound 3, resulted in areas of strong31477JJSsynergy (HSA score >10) in BRG1 -deficient, KRAS G12D or KRAS G12V co-mutated human colorectal and pancreatic adenocarcinoma cell lines.[000233] These results indicate that combination of Compound 1 with KRAS inhibitors, such as Compound 3, may have enhanced benefits to patients exhibiting BRG1 and KRAS comutated colorectal adenocarcinoma and pancreatic adenocarcinoma.[000234] In summary, synergy was observed for combinations of Compound 1 with Compound 3 in vitro (see Figures 11 and 12).Example 8[000235] In vitro study evaluating the antiproliferative activity of Compound 1 in Combination with pan KRAS inhibitor Compound 2 in the BRG1 -Deficient Non-Small Cell Lung Carcinoma cell line A549.Test Compounds[000236] Compounds 1 and 2 were dissolved in DMSO to generate 10 mM stock solutions. For long term storage, small aliquots were prepared and stored at -80 °C.Cell Lines[000237] A549 cells were acquired from ATCC.[000238] A549 cells were cultured and assayed in RPML1640 medium (containing 4.5g / L Glucose, 10 mM HEPES, 2 mM L-Glutamine, 1.5 g / L Sodium Bicarbonate, 1 mM Sodium Pyruvate) with 10% characterized FBS and IX Penicillin-Streptomycin. The cell lines were grown in the indicated culture medium and incubated in a humidified 37 °C / 5% CO2 / 95% atmospheric air incubator.Table 8. Cell Line Mutation ProfilePrimary / Cell Line BRG1 Status Other Driving Mutations MetastaticBRG1 LOF KRAS p.G13D, TP53 C.1O86-1G>T, A549 Metastaticp.Q729fs*4 STK11 p.Q37*, KEAP1 p.G333C p., point mutation; *, early stop codon; LOF, loss of function. Mutation profile was curated from Cell Model Passport (Sanger Institute Database) and Cancer Dependency Map (BROAD Institute). Notebook reference:C00283-004.Assay Methods[000239] Cells were plated in 96-well plates at a seeding density of one hundred cells / well in complete media overnight prior to treatment with compounds. Checkerboard-matrix analysis31477JJSwas utilized to assess the combinations of Compound 1 with Compound 2 in an 8 x 8 matrix format. The matrix was comprised of a series of nine concentrations of Compound 1 (113.2 nM to 0.052 nM, 1:3 serial dilutions) in each column and a series of eight concentrations of Compound 2 (900 nM to 7 nM, 1:2 serial dilutions for A549) in four 96- well plates, each plate contains three replicates of two doses of Compound 1. Cells were dosed with Compound 1 and Compound 2 simultaneously in a total volume of 100 uL at non-constant ratios. Compound dispensing in microplates and DMSO volume normalization was performed using the D300e Digital Dispenser (Tecan) with the aid of the Synergy Wizard in the D300e Control Software. Final DMSO concentrations in the assay were kept below 0.2%. Meanwhile, 100 pL of Cell-titer-Glo reagent was added to each well of the plate without added compounds and mixed on a Coming LSE platform rocker at 600 RPM for 15 minutes. This plate was read on Molecular Devices-SpectraMax Paradigm Multi-Mode Microplate Reader with luminescence emission as time 0.[000240] After a 7-day incubation, 100 mL Cell-titer GLO reagent was added per well to the assay plates and mixed on a rocker at 600 RPM for 15 minutes. Assay plates were read on the Molecular Devices-SpectraMax Paradigm Multi-Mode Microplate Reader with luminescence emission. Each matrix experiment was done in triplicate.Data Analysis[000241] Cell growth inhibition (% of DMSO control) from triplicate wells were averaged and analyzed using Microsoft Excel and GraphPad Prism 10. Cell growth curves were plotted using GraphPad Prism 10 with Non-linear regression curve fitting.Calculations for % Inhibition (Absolute ECsos)% inhibition = ((DMSO-test) / (DMSO-Day 0))*100[000242] The averaged percentage inhibition values for the triplicate matrix plates were uploaded to Synergy Finder 3.0 for generation of Highest Single Agent (HSA) synergy scores. The HSA model quantifies the degree of synergy observed as the excess response over the maximum single compound effect. Therefore, HSA synergy scores (yHSA) assume that the expected combination effect equals to the higher effect of individual compounds:YHSA=A’ ,B.....N - max(EA, EB,..., EN),where EA,B,...,N is the combination effect between N compounds and EA, EB,..., EN are the31477JJSmeasured responses of the single compounds. Summary synergy scores are defined as the mean of the synergy scores generated from each data point. Further, synergy is interpreted as an increased excess response to a drug interaction greater than expected. Combination scores < -10 are interpreted as antagonistic; scores >10 are interpreted as synergistic (greater than additive); scores between -10 to 10 are interpreted as additive.Results & Discussion[000243] In this study, the anti-proliferative effects of Compound 1, alone and in combination with pan-KRAS inhibitor Compound 2, were evaluated in a BRG1 loss of function non-small cell lung cancer cell line containing KRAS co-mutation, A549 (KRAS G12S).Following incubation of the cell line with serial dilutions of the compounds (top dose < EC90 for each compound), alone or in combination in a matrix format for 7 -days, the cells were evaluated with Cell-Titer GLO viability assay.[000244] As shown in Figure 13, the in vitro combination results in enhanced antiproliferative potency and efficacy compared to each single agent alone. In A549 cells the efficacy for cell growth inhibition increases from 70% with single agent Compound 1 to >90% in the combination with Compound 2 indicating that in a BRG1 -deficient context both BRM and mutant KRAS can act as co-drivers for regulating tumor cells growth. At combination doses achieving greater than 80% cell growth inhibition, additive (HSA score >-10 and <10) and greater than additive effects (HSA score >10) were observed in all three cell lines evaluated according to SynergyFinder.[000245] These results indicate that combinations of Compound 1 with Compound 2 may have enhanced benefits to NSCLC patients harboring BRG1 and KRAS co-mutations (See Figure 13).[000246] In summary, synergy was observed for in vitro combinations of Compound 1 with pan-KRAS inhibitor Compound 2 (See Figure 13).Example 9[000247] In vitro studies evaluating the antiproliferative activity of Compound 1 in Combination with pan-KRAS inhibitor Compound 2 in BRG1 -Deficient Human Pancreatic Carcinoma Cell Lines.31477JJSTest Compounds[000248] Compounds 1 and 2 were dissolved in DMSO to generate 20 mM stock solutions.Cell Lines[000249] PA-TU-8988T (ACC- 162) cells were acquired from the German Collection of Microorganisms and Cell Cultures (DSMZ) (Braunschweig, Germany). The PA-TU-8988T cell line contains homozygous KRAS G12V. Clustered regularly interspaced short palindromic repeats (CRISPR) gRNAs and single -strand donors were designed to introduce homozygous KRAS G12D (WEY-00008-02). The BRG1 status and mutation profile for the cell line is shown in Table 9.[000250] PA-TU-8988T cells were cultured and assayed in RPML1640 medium (containing 4.5g / L Glucose. 10 mM HEPES, 2 mM L-Glutamine, 1.5 g / L Sodium Bicarbonate, 1 mM Sodium Pyruvate) with 10% characterized FBS and IX Antibiotic / Antimycotic. All cell lines were grown in the indicated culture medium and incubated in a humidified 37°C / 5% CO2 / 95% atmospheric air incubator.Table 9. Cell Line Mutation ProfilePrimary / Cell Line BRG1 Status Other Driving MutationsMetastaticPA-TU-8988T Metastatic BRG1 LOF KRAS p.G12V, TP53 p.R282W, SMAD4 LOFAssay Methods[000251] Cells were plated in poly-D-lysine coated 96-well plates in complete media 2-3 hours prior to treatment with compounds, refer to Table 7 for seeding densities. Checkerboardmatrix analysis was utilized to assess the combinations of Compound 1 with Compound 2 in a 10 x 6 matrix format. The matrix was comprised of a series of nine concentrations of Compound 1 in each row and a series of five concentrations of Compound 2 in each column, refer to Table 7 for compound dilution details. Cells were dosed with Compound 1 and KRAS inhibitor Compound 2 simultaneously in a total volume of 100 uL at non-constant ratios. Final DMSO concentrations in the assay were kept below 0.2%. After a 10-day incubation, 100 mL Cell-titer GLO reagent (Promega, G7571) was added per well and mixed on a Heidolph Titramax 1000 plate shaker at 600 RPM for 10 minutes. Assay plates were read on the Biotek Synergy Neo2 with filter cubes 42-LUM and 114-LUM installed for luminescence emission.[000252] Each matrix was done in duplicate.31477JJSTable 10. Seeding Densities and Compound Dilution Series by Cell Line Compound 1 Dilution Compound 2 Dilution Cell Line Seeding DensitySeries Series2000nM to 0.30nM, 1:3 lOOOnM to 12.35nM, 1:3 dilution PA-TU-8988T 100 cells / welldilution series seriesData Analysis[000253] To determine the percent inhibition in each sample, the max inhibition luminescence signal (highest concentration of Compound 1 and highest concentration of KRAS inhibitor Compound 2) was subtracted from the luminescence signal for each sample and the max-inhibition- subtracted signal was normalized to the DMSO signal, which was defined as 100% activity. Percent inhibition (%) was defined as the percent of activity subtracted from 100. Data was analyzed using Biotek Gen5 v3.10, Microsoft Excel, and Graphpad Prism v9.1.2. Data was analyzed using four-parameter logistic regression (LL4) to fit single agent dose response curves. The data was plotted in Graphpad Prism v9.1.2.[000254] The averaged percentage inhibition values for the duplicate matrix plates were uploaded to Synergy Finder 3.0 for generation of Loewe synergy scores.[000255] The averaged percentage inhibition values for the duplicate matrix plates were uploaded to Synergy Finder 3.0 for generation of Highest Single Agent (HSA) synergy scores. The HSA model quantifies the degree of synergy observed as the excess response over the maximum single compound effect. Therefore, HSA synergy scores (yHSA) assume that the expected combination effect equals to the higher effect of individual compounds:YHSA=£A,B.....V - max(EA, EB,..., EN),where EA,B,...,N is the combination effect between N compounds and EA, EB,..., EN are the measured responses of the single compounds. Summary synergy scores are defined as the excess response to a drug interaction than expected. This is defined as the mean of the synergy scores generated from each data point. Summary synergy scores < -10 are interpreted as antagonistic; scores between -10 to 10 are interpreted as additive; and scores >10 are interpreted as synergistic.Results & Discussion[000256] The impact of Compound 1 in combination with Compound 2 on cell growth in PA-TU-8988T cells was evaluated by monitoring cell proliferation using an in-house Cell-Titer31477_USGLO viability assay after compound treatment for 10 days. In the combination of Compound 1 with the isoform specific pan-KRAS inhibitor, Compound 2, in PA-TU-8988T cells, was observed synergistic combinations for Compound 1 (25 nM to 2000 nM range) with Compound 2 (37 nM to 1000 nM range).[000257] As shown in Figure 14, the Compound 1 combination with the isoform specific pan-KRAS inhibitor, Compound 2, resulted in areas of strong synergy (HSA score >10) in BRG1 -deficient, KRAS G12V co-mutated human pancreatic adenocarcinoma cell lines. These results indicate that combinations of Compound 1 with KRAS inhibitors, such Compound 2, may have enhanced benefits to patients exhibiting BRG1 and KRAS mutated pancreatic adenocarcinoma.[000258] In summary, synergy was observed for in vitro combinations of Compound 1 with pan-KRAS inhibitor Compound 2 (See Figure 14).Example 10[000259] In vivo efficacy study characterizing the tumor growth inhibition by Compound 1 in combination with Compound 2 in a human tumor A549 Xenograft Non-Small Cell Lung Carcinoma model in mice.Test Compounds[000260] Compound 1 was prepared as a spray dried dispersion (SDD) with HPMC-AS-MG (Shin-Etsu Chemical Co., Ltd. Lot # 3013034) (active pharmaceutical ingredient is 25.3% by weight). Compound 1 SDD was formulated by water bath sonication with vehicle (0.5% CMC / 0.2% Tween 80 in water). The compound was formulated once per week, stored at 4oC, and vortexed before dosing.[000261] Compound 2 was formulated with 1% HEC / 0.25% Tween 80 / 0.05% Antifoam. The formulation was vortexed and sonicated to produce a consistent homogenous suspension of drug. The compound was formulated once per week, stored at 4 °C, and vortexed before dosing.Cell Lines[000262] The A549 (BRG1 mutant / KRAS G12S) human NSCLC cell line was obtained from the American Type Culture Collection (ATCC, Virginia, United States). A549 cells were maintained in RPMI-1640 media supplemented with 10% fetal bovine serum. All cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air, free of Mycoplasma and31477JJSpathogenic human and murine viruses. Following recovery from frozen stocks, low cell passages (up to 6) were used in the experiments.Animal Model[000263] Female athymic nude mice were obtained from Envigo (Harlan Laboratories) and acclimated for 1 week before initiating the experiment. Logarithmically growing A549 cells [5 x 106 / 200 pL, single-cell suspensions of over 95% viability in Hank’s Balanced Saline Solution (HBSS) medium mixed with an equal volume of Matrigel] were subcutaneously injected into the right hind flank of each mouse. When the average tumor volume reached 150 - 250 mm3, the mice were randomized into different groups and treated with vehicle, Compound 1 and / or Compound 2 by oral gavage according to the experimental design shown in Table 11. Animals had access to chow and water ad libitum. Tumor volume and body weight were measured twice per week.[000264] This study was run with 8 mice per treatment group.Table 11. Experimental DesignDoseTreatment Dose Schedule n (mg / kg)Vehicle N / A PO, BID x 28 8 Compound 1 40 PO, BID x 28 8 Compound 2 30 PO, BID x 28 8 Compound 1 + Compound 2 40 + 30 PO, BIDx28 + PO, BIDx28 8Abbreviation: N / A, not applicable; BID, twice daily; n, number of animals per group; PO, oral administration Data Analysis[000265] See Data Analysis section from Example 2.Results and Discussion[000266] In this study, the in vivo efficacy of Compound 1 in combination with Compound 2, was investigated in the A549 human NSCLC xenograft model in mice. A549 tumor cells are co-mutated, harbouring a SMARCA4 mutation and the KRAS G12S mutation. Female Nude mice were injected with A549 cells, followed by randomization on Day 16. post-cell implantation. Doses of the compounds to exhibit a moderate response were used so that the combination benefit could be observed. 40 mg / kg of Compound 1 and 30 mg / kg of Compound 2 were used for this study. The tumor-bearing mice received oral BID dosing of vehicle.Compound 1 and / or Compound 2 for 28 days. All statistical analyses comparing compound31477JJStreated to vehicle treated animals were performed using treatment Day 28 tumor and body weight measurements.[000267] Single-agent treatment with a 40 mg / kg dose of Compound 1 or a 30 mg / kg dose of Compound 2 resulted in 76% or 41% tumor growth inhibition, respectively (see Figure 15). Compound 1 dose of 40 mg / kg in combination with 30 mg / kg Compound 2 demonstrated synergistically increased antitumor activity, by Bliss combination analysis, resulting in sustained tumor regression, demonstrating 23% regression, as determined on Day 28 of dosing (see Figure 15). Single-agent and combination treatments were well tolerated in this study.[000268] As shown in Figure 15, Compound 1 exhibited significant antitumor activity resulting in tumor growth inhibition when used as a monotherapy and synergistic antitumor activity resulting in tumor regression when dosed in combination with Compound 2 in the A549 human NSCLC xenograft model. All single and dual therapies were well tolerated throughout the study.[000269] In summary, the combination of Compound 1 with Compound 2 resulted in synergistic antitumor activity and sustained tumor regression, in vivo.Example 11[000270] In vivo efficacy study characterizing the anti-tumor memory formation in mice, following complete response after the administration of Compound 1 in combination with pembrolizumab or Compound 1 in combination with standard of care chemotherapy (gemcitabine and cisplatin) plus pembrolizumab in MB49 SMARCA4 knockout mice.[000271] The MB49 Smarca4 KO mouse bladder cancer cell line was generated in house (Benchling BN24-7873). The MB49 Smarca4 KO cells were maintained in DMEM supplemented with 10% fetal bovine serum. All cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air, free of Mycoplasma and pathogenic human and murine viruses.[000272] C57BL / 6J mice were obtained from Jackson Laboratory and acclimated for 1 week before initiating the experiment. Prepared MB49 Smarca4 KO cells [2 xl05 in 200 pL, single-cell suspensions of over 95% viability in Hank’s Balanced Saline Solution] were subcutaneously injected into the right hind flank of each mouse. When the average tumor volume reached approximately 150 mm3, the mice were randomized into different groups and treated31477JJSwith vehicle or LY4050784, 60 mg / kg or Gemcitabine 15 mg / kg & Cisplatin 2mg / kg by intraperitoneal (IP) injection weekly (Q7D), or with anti-PD-1 antibody, 10 mg / kg, by intraperitoneal (IP) injection, twice weekly (BIW) for 16 days. Animals were dosed by body weight (10 pL / g). Animals had access to chow ad libitum. Tumor volume and body weight were measured twice per week.Study Design[000273] The study was run with 4-7 animals per treatment group.Group Animal Treatment Route Frequency Dosenumber1 6 Vehicle PO (BID x 5; rest 2) x 4 0 mg / kg2 6 Compound 1 PO (BID x 5; rest 2) x4 60 mg / kg3 6 Gemcitabine + Cisplatin IP / IP Q7D x 4 / Q7D x 4 15 / 2mg / kg4 6 Anti-PD-1 antibody IP BIW x 4 10 mg / kg5 6 Compound 1+ Gemcitabine PO / IP / IP (BID x 5; rest 2) x4 / 60 / 15 / 2mg / kg + Cisplatin Q7D x 4 / Q7D x 46 4 Compound 1 + anti-PD-1 PO / IP (BID x 5; rest 2) x4 Z 60 / 10 mg / kg antibody BIW x 47 6 Gemcitabine + Cisplatin + IP / IP / TP Q7D x 4 / Q7D x 4 / 15 / 2 / 10 mg / kg anti-PD-1 antibody BIW x 48 7 Compound 1 + Gemcitabine PO / (BID x 5; rest 2) x4 / 60 / 15 / 2 / 10+ Cisplatin + anti-PD-1 IP / IP / IP Q7D x 4 / Q7D x 4 / mg / kgantibody BIW x 4The MB49 SMARCA4 Knock-out tumor cells rechallenge study was run with the complete responders from efficacy study and age matched naive mice. Prepared MB49 Smarca4 KO cells [2 xlO5in 200 pL, single-cell suspensions of over 95% viability in Hank’s Balanced Saline Solution] were subcutaneously injected into the left hind flank of each mouse. Tumor volume and body weight were measured twice per week.Group Mice number Mice used Cells implanted9 10 Naive mice MB49 Smarca4 Knock-out cells 10 4 Complete responders from LY4050784 MB49 Smarca4 Knock-out cells+ anti-PD-1 antibody treated group 611 7 Complete responders from LY4050784 MB49 Smarca4 Knock-out cells+ Gemcitabine + Cisplatin + anti-PD-1antibody treated group 8Results[000274] As monotherapies, Compound 1. gemcitabine + cisplatin, and anti-PD-1 antibody achieved tumor growth inhibition (TGI) of -34%, 35%, and 23%, respectively, at the end of the dosing period (Day 16) relative to vehicle control. Among combination regimens, Compound 1 plus anti-PD-1 antibody and the triple combination of Compound 1 plus anti-PD-1 antibody plus31477JJSgemcitabine + cisplatin emerged as the most effective, achieving -60% and -64% tumor regression at the end of dosing. Tumors continued to regress after dosing cessation, achieving 4 / 4 complete responses (CRs) and 7 / 7 CRs, respectively. Complete responses proved durable through at least 110 days of the study. In contrast, Compound 1 combined with gemcitabine + cisplatin (without anti-PD-1) achieved only -13% TGI. while gemcitabine + cisplatin plus anti-PD-1 antibody (without Compound 1) yielded a TGI of 1.4% on Day 16 (Figures 5.1, Figures 5.2, Table 5.1). Greater than 10% body weight loss was observed with Compound 1 monotherapy and the triple combination but fully recovered following treatment cessation (Table 5.1, Figure 5.3).[000275] To evaluate whether anti-tumor immune memory had formed, a subsequent rechallenge study was performed in which MB49 SMARCA4-knockout tumor cells were reimplanted into complete responders alongside age-matched naive controls. CR mice completely suppressed tumor growth, whereas naive mice exhibited a 100% take rate with rapid tumor progression, confirming robust and durable immunological memory formation. See Figs 18A and 18B.[000276] These data suggest that LY4050784 treatment sensitizes SMARCA4-deficient tumors to anti-PD-1 antibody, resulting in markedly improved anti-tumor efficacy with the combination. These results provide a rationale for evaluating the clinical combination of LY4050784 and pembrolizumab.[000277] This data supports a mechanistic rationale for Compound 1 sensitizing SMARCA4-deficient tumors to anti-PD-1 (such as pembrolizumab) therapy.

Claims

31477JJSCLAIMS1. A method of treating a SMARCA4 mutant cancer comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:Compound 1,or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab.

2. The method according to claim 1, wherein the SMARCA4 mutant cancer is lung cancer or bladder cancer.

3. The method according to claim 2, wherein the lung cancer is non-small cell lung cancer.

4. The method according to claim 2, wherein the cancer is bladder cancer.

5. The method according to claim 1, wherein the pembrolizumab is administered lOmg / kg, twice per week, i.p.

6. The method according to any one of claims 1 to 5, further comprising the simultaneous, separate or sequential administration of gemcitabine and cisplatin.

7. The method according to claim 6, wherein the gemcitabine is dosed atl5mg / kg and the cisplatin is dosed at 2mg / kg.

8. The method according to any one of claims 1-7, wherein about 200 to about 800 mg of Compound 1 is administered at least once a day.

9. The method according to claim 8, wherein Compound 1 is administered at least twice a day.

10. The method according to any one of claims 1-9, wherein Compound 1 is:31477JJS11. A method of of preventing metastasis of a SMARCA4 mutant cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formulaCompound 1or a pharmaceutically salt thereof, in simultaneous, separate or sequential combination with pembrolizumab and SoC chemotherapy, wherein SoC chemotherapy is gemcitabine and cisplatin.

12. The method according to claim 11, wherein the SMARCA4 mutant cancer is lung cancer, or bladder cancer.

13. The method of claim 12, wherein the lung cancer is non-small cell lung cancer.

14. The method of claim 12, wherein the cancer is bladder cancer.

15. The method of any one of claims 11 to 14, wherein Compound 1 about 200mg to about 1000 mg or about 200 mg to about 800 mg of Compound 1 is administered at least once a day.

16. The method according to any one of claims 12-15, wherein Compound 1 is:

17. A method of treating a SMARCA4 mutant cancer comprising:administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:31477JJSor a pharmaceutically salt thereof, in simultaneous, separate or sequential combination with at least one other therapeutic agent.

18. The method of claim 17, wherein the at least one other therapeutic agent is selected from a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, or a pharmaceutically acceptable salt thereof, an antifolate agent, or a pharmaceutically acceptable salt thereof, an antineoplastic agent, or a pharmaceutically acceptable salt thereof, and a KRAS inhibitor, wherein the KRAS inhibitor is selected from the group consisting of a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, and a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is combined with no more than one KRAS inhibitor.

19. The method of claim 18, wherein the PD-1 inhibitor is pembrolizumab.

20. The method of claim 18, wherein the platinum agent is cisplatin.

21. The method of claim 18, wherein the antifolate agent is pemetrexed.

22. The method of claim 18, wherein the antineoplastic agent is paclitaxel.

23. The method of claim 18, wherein the compound is administered in simultaneous, separate or sequential combination with a platinum agent and an antifolate agent.

24. The method of claim 23, wherein the platinum agent is cisplatin, and the antifolate agent is pemetrexed.

25. The method of claim 17, wherein the compound is administered in simultaneous, separate or sequential combination with a platinum agent and an antineoplastic agent.

26. The method of claim 25, wherein the platinum agent is cisplatin, and the antineoplastic agent is paclitaxel.

27. The method of claim 18, wherein the KRAS G12C inhibitor is olomorasib, or a pharmaceutically acceptable salt thereof.

28. The method of claim 18, wherein the KRAS G12C inhibitor is olomorasib.31477JJS29. The method of any one of claims 17 to 28, wherein the compound is:

30. The method of claim 17, wherein the cancer further contains a KRAS mutation, the method comprising:administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:Compound 1or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with at least one other therapeutic agent that is a KRAS inhibitor, wherein the KRAS inhibitor is preferably selected from the group consisting of a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, a KRAS G12D inhibitor, or a pharmaceutically acceptable salt thereof, and a pan-KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein the KRAS G12C inhibitor is olomorasib. or a pharmaceutically acceptable salt thereof.

32. The method of claim 30, wherein the KRAS G12C inhibitor is olomorasib.

33. The method of any one of claims 30 to 32, comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula:31477JJS34. The method of any one of claims 17-33, wherein the cancer is selected from the group consisting of lung cancer, endometrial cancer, ampullary cancer, GI neuroendocrine cancer, bladder cancer, esophagogastric cancer, ovarian cancer, head and neck cancer, colorectal cancer, cervical cancer, skin (non-melanoma) cancer, small bowel cancer, melanoma, mature B-cell neoplasms, bile duct cancer, and pancreatic cancer.

35. The method of any one of claims 17-34, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, and colon cancer.

36. The method of claim 34, wherein the cancer is lung cancer.

37. The method of claim 34, wherein the cancer is non-small cell lung cancer.

38. The method of claim 34, wherein the cancer is pancreatic cancer.

39. The method of claim 34, wherein the cancer is colon cancer.

40. The method of claim 34, wherein the cancer is bladder cancer.

41. The method of claim 34, wherein the cancer is small cell lung cancer.

42. A method of promoting immune cell infiltration into SMARCA4 mutant tumors, the method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the formulaO N NN >5HJ OCompound 1or a pharmaceutically salt thereof, in simultaneous, separate or sequential combination with pembrolizumab.

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