Farnesyltransferase inhibitors for the treatment of KRAS-dependent cancers

Abstract

This specification provides a method for using compound (I), or a pharmaceutically acceptable form thereof, in combination with a KRAS inhibitor for the selective treatment of cancer.

Description

[Technical Field]

[0001] 1. Cross reference This application claims priority to U.S. Provisional Applications No. 63 / 505,272 filed on 31 May 2023, No. 63 / 580,680 filed on 5 September 2023, No. 63 / 556,282 filed on 21 February 2024, and No. 63 / 639,307 filed on 26 April 2024, each of which is incorporated by reference in whole.

[0002] Compound (I):

[0003] [ka] Methods for treating cancer are provided herein, which involve using a farnesyltransferase inhibitor (FTI), such as a pharmaceutically acceptable form thereof, in optional combination with a KRAS inhibitor. Pharmaceutical compositions, kits, and related products are also embodied within this disclosure. [Background technology]

[0004] The Kristen rat sarcoma (KRAS) gene belongs to the rat sarcoma (RAS) family of oncogenes, which also includes the Harvey rat sarcoma (HRAS) and neuroblastoma rat sarcoma (NRAS) virus oncogene homologs. When mutated and / or amplified by substitution, insertion, deletion, or combination, these genes can initiate or promote cancer growth. Activating mutations in KRAS are among the most common oncogenic driver mutations in human cancers, occurring in more than 80% of pancreatic cancers and more than 30% of colorectal, cholangiocarcinomas, and lung adenocarcinomas. These mutations are associated with both tumorigenesis and invasive tumor growth. Common KRAS substitution mutations include G12C, G12D, G12V, G13D, and G12R.

[0005] KRAS remained a challenging target for decades until the pioneering discovery of covalent inhibitors specific to the KRAS protein derived from KRAS G12C. However, the success of clinical studies using sotrasib and adagrasib led to landmark FDA designations and approvals for both drugs for the treatment of locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC). Further research efforts aim to develop other variant-specific (e.g., G12D, G12V, G12D), pan-KRAS inhibitors (targeting two or more KRAS variant forms or at least one KRAS variant form and wild-type KRAS), and pan-RAS inhibitors (targeting multiple RAS enzymes, e.g., KRAS, NRAS, and / or HRAS, and optionally including one or more variant and / or wild-type forms of RAS enzymes).

[0006] KRAS mutations are common in various cancer types, with G12C being the most common mutation in NSCLC (e.g., lung adenocarcinoma), and G12D and G12V being the most common mutations in CRC and gastrointestinal cancers such as esophageal, gastric, small intestinal, and appendiceal cancers. Various mutations have been observed in cancers including pancreatic ductal adenocarcinoma (PDAC), appendiceal adenocarcinoma, small intestinal adenocarcinoma, colorectal cancer, non-squamous NSCLC, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, germ cell cancer, cancer of unknown primary (CUP), esophageal adenocarcinoma, plasma cell neoplasms, GI-neuroendocrine neoplasms, endometrial cancer, myelodysplastic / myeloproliferative neoplasms, gastric adenocarcinoma, bladder cancer, ovarian cancer, peritoneal cancer, cervical cancer, urinary tract cancer, acute leukemia, and squamous NSCLC. Lee et al., Precision Oncol. 2022, 6, 91. For example, G12C mutations are observed at a high rate in NSCLC (40% in non-squamous cell carcinoma or lung adenocarcinoma, and 36% in squamous cell carcinoma), and to a lesser extent in colorectal cancer (CRC), PDAC, carcinomas of unknown primary (CUP), endometrial cancer, and ovarian cancer. G12D mutations are observed in CRC, non-squamous cell carcinoma, PDAC, CUP, endometrial cancer, ovarian cancer, intrahepatic cholangiocarcinoma, small intestinal adenocarcinoma, and appendiceal adenocarcinoma. G12V mutations are observed in CRC, non-squamous cell carcinoma, PDAC, CUP, endometrial cancer, ovarian cancer, intrahepatic cholangiocarcinoma, small intestinal adenocarcinoma, and appendiceal adenocarcinoma. G12R mutations are observed in PDAC and CUP cancers. G13D mutations are observed particularly in CRC, non-squamous cell carcinoma, and endometrial cancer. KRAS mutations account for the majority of RAS changes in PDAC, CRC, and lung adenocarcinoma.

[0007] Clinical responses to KRAS inhibitors in KRAS-mutated cancers such as CRC and NSCLC typically fluctuate due to the development of resistance. For example, selective irreversible KRAS G12C inhibitors show initial clinical response rates of 45% (adagrasib) and 37% (sotrasib) in patients with KRAS G12C-mutated NSCLC, but feedback reactivation of MAPK and / or mTOR signaling pathways appears to limit treatment efficacy. In a phase II trial, all patients who achieved an objective response to sotrasib progressed during treatment. Skoulidis et al., N.Engl.J.Med.2021;384:2371-81.

[0008] Oncogenic KRAS alterations also include KRAS amplification, or a combination of KRAS amplification and mutation. KRAS amplification is observed in approximately 8–9% of cancers, and amplification and mutation are observed in approximately 4% of cancers. Lee et al., 2002 (see above). KRAS amplification is observed in a range of cell types, including germ cell tumors, esophageal adenocarcinoma, gastric adenocarcinoma, bladder cancer, ovarian cancer, peritoneal cancer, gastric cancer, and squamous cell carcinoma (NSCLC).

[0009] Farnesyltransferase inhibitors Farnesylation of mutated KRAS by farnesyltransferase has long been considered a drug target. Several types of FTIs have been developed and clinically tested in various cancer types in which RAS mutations frequently occur, but all have failed due to the alternative adaptation of RAS processing using geranylgeranylation.

[0010] Tipifarnib, an FTI, has been extensively tested in clinical studies, but has not demonstrated significant antitumor activity or objective response rates in non-small cell lung cancer, small cell lung cancer, or breast cancer (Adje et al., J. Clin. Oncol. 2003, 21(9), 1760-1766; Heymach et al., Ann. Oncol. 2004, 15(8), 1187-1193; Yam et al., Invest New Drugs 2018, 36(2), 299-306). The second FTI, ronafarnib, did not show objective efficacy in colorectal cancer and did not improve progression-free survival or overall survival in combination with chemotherapy in ovarian cancer (Sharma et al., Ann. Oncol. 2002, 13(7), 1067-1071; Meier et al., Gynecol. Oncol. 2012, 126(2), 236-240). In fact, FTI compounds showed limited clinical efficacy in cancers with KRAS mutations due to alternative prenylation via the geranylgeranylation pathway (Ghimessy et al., Cancer Metastasis Rev. 2020, 39, 1159-1177). Treatment with tipifarnib for colorectal cancer (CRC) and pancreatic adenocarcinoma (PDAC) tumors, primarily caused by KRAS mutations, showed a moderate increase in stable disease compared to supportive care, but did not improve overall survival (Rao et al., J. Clin. Oncol. 2004, 22, 3950-3957; Van Cutsem et al., J. Clin. Oncol. 2004, 22, 1430-1438). On the other hand, HRAS-mutated tumors cannot utilize alternative geranylgeranylation pathways. Therefore, while FTI has been suggested for the treatment of HRAS-mutated tumors, it has not been suggested for KRAS-mutated tumors.

[0011] combination of tipifalnib and adagracib or sotracib There is no evidence to support the use of FTI in the treatment of KRAS mutant cancers, but the combination of tipifarnib with the KRAS G12C inhibitors adagrasib or sotorasib has been tested. In recent years, this combination has been shown to result in a significant increase in tumor regression compared to either drug alone in cell line-derived xenograft (CDX) models and patient-derived xenograft (PDX) models of KRAS G12C NSCLC. Patel et al.,Combination of tipifarnib with KRAS G12C inhibitors to prevent adaptive resistance,Poster presented at American Association for Cancer Research(AACR)Annual Meeting,April 2023,Orlando,Abstract #1079;Delahaye et al.,Using tipifarnib to prevent resistance to targeted therapies in oncogene-addicted tumors,Poster presented at 34 th EORTC-NCI-AACR Symposium,October 2022,Barcelona. In addition, tipifarnib suppressed the feedback activation of mTOR signaling at the level of p-S6 (S235 / 236) that occurs after monotherapy with a KRAS G12C inhibitor. Thus, FTI has the potential to overcome natural resistance mechanisms derived from monotherapy with a KRAS inhibitor and improve clinical outcomes in patients with KRAS mutant cancers. There is still a need for improved treatment of KRAS-dependent cancers.

Summary of the Invention

[0012] A method of treating cancer in a subject, comprising administering to the subject an FTI, such as compound (I):

[0013] [Chemistry] Methods are provided herein that include administering a compound of (I), or a pharmaceutically acceptable form thereof.

[0014] In another aspect, a method of treating cancer in a subject, the method comprising administering to the subject (a) a FTI such as compound (I), or a pharmaceutically acceptable form thereof, and (b) a KRAS inhibitor.

[0015] In another aspect, a method of treating KRAS-dependent cancer in a subject, the method comprising administering to the subject a FTI such as compound (I), or a pharmaceutically acceptable form thereof.

[0016] In another aspect, a method of treating KRAS-dependent cancer in a subject, the method comprising administering to the subject (a) a FTI such as compound (I), or a pharmaceutically acceptable form thereof, and (b) a KRAS inhibitor.

[0017] In another aspect, a method of delaying the emergence of resistance to a KRAS inhibitor in KRAS-dependent cancer in a subject, or overcoming resistance to a KRAS inhibitor in KRAS-dependent cancer in a subject previously treated with a KRAS inhibitor, the method comprising administering to the subject (a) a FTI such as compound (I), or a pharmaceutically acceptable form thereof, optionally in combination with (b) a KRAS inhibitor, and optionally, for subjects previously treated with a KRAS inhibitor, the KRAS inhibitor administered in combination with the FTI is the same or a different KRAS inhibitor.

[0018] While not limited to any particular theory, the use of FTIs and KRAS inhibitors provides more effective therapy compared to monotherapy alone or to standard treatments such as chemotherapy, and influences the modes of resistance that develop in response to KRAS inhibitor therapy. The FTI tipifarnib has been shown to suppress the feedback reactivation of mTOR signaling that occurs after monotherapy with a KRAS G12C inhibitor. Patel 2023 (see above), Delahaye 2022 (see above). The combination may converge at mTOR levels that block adaptive resistance to KRAS inhibitors.

[0019] In some embodiments, the combination of two drugs is synergistic. According to the methods disclosed herein, the use of a combination of an FTI, such as compound (I) or a pharmaceutically acceptable form thereof, and a KRAS inhibitor can provide, in KRAS-dependent cancers, increased efficacy, increased duration of response, increased duration of resistance pathway inhibition, faster onset of antitumor response, prevention or delay of recurrence or disease progression, and / or enhanced tumor cell death, or a combination thereof, compared to treatment with the drug alone or standard treatments such as chemotherapy. In some embodiments, this combination also reduces therapeutic resistance to KRAS inhibitors while exhibiting these improved effects, thereby mitigating the impact of the development of resistance to these therapies.

[0020] This disclosure also provides a pharmaceutical composition comprising compound (I), or an FTI such as a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition also comprises a KRAS inhibitor. In some embodiments, the pharmaceutical composition is intended for use in the methods described herein.

[0021] The Disclosure also provides a pharmaceutical kit or packaging comprising (a) a pharmaceutical composition comprising a compound (I) or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical kit or packaging also comprises a pharmaceutical composition comprising a KRAS inhibitor and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical kit or packaging comprises a pharmaceutical composition comprising a compound (I) or a pharmaceutically acceptable form thereof, and a KRAS inhibitor. [Brief explanation of the drawing]

[0022] [Figure 1A] Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1B] Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1C]Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1D] Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1E] Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1F]Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1G] Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1H] Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1I]Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1J] Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1K] Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1L]Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 1M] Plots of spheroid cell viability (%) against adaglasib concentration (nM) in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), NCI-H358 (Figure 1C), and A549 (Figure 1D) cell lines, with adaglasib alone or in combination with various concentrations of tipifarnib, and in NCI-H2122 (Figures 1E and 1I), NCI-H1792 (Figures 1F and 1K), NCI-H358 (Figure 1G), A549 (Figures 1H and 1M), NCI-H2030 (Figure 1J), and NCI-H23 (Figure 1L) cell lines, with adaglasib alone or in combination with various concentrations of compound (I). [Figure 2A] Plot of spheroid cell viability (%) over time (days) for the Dox-inducible shRHEB KRAS G12C NCI-H2122 cell line (Figure 2A), compared to the control A549 cell line, in and without exposure to adagrab (Figure 2B). [Figure 2B] Plot of spheroid cell viability (%) over time (days) for the Dox-inducible shRHEB KRAS G12C NCI-H2122 cell line (Figure 2A), compared to the control A549 cell line, in and without exposure to adagrab (Figure 2B). [Figure 3A]Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to NCI-H2122 cells, FTI and KRAS inhibitors, (a) compound (I) and adaglacib alone and in combination (Figures 3A and 3B, 3D immunoblots), and (b) tipifarnib and sotracib (Figure 3C, 2D immunoblots), NCI-H2030 cells, tipifarnib and adaglacib (Figure 3D, 2D immunoblots), and NCI-H1792 cells, tipifarnib and sotracib (Figure 3E, 2D immunoblots), as well as doxycycline-inducible shRNA NCI-H2122 lines after exposure to adaglacib (Figure 3F) and transfected siRNAs. Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to adagravate in the NCI-H2122 system (Figure 3G). [Figure 3B] Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to NCI-H2122 cells, FTI and KRAS inhibitors, (a) compound (I) and adaglacib alone and in combination (Figures 3A and 3B, 3D immunoblots), and (b) tipifarnib and sotracib (Figure 3C, 2D immunoblots), NCI-H2030 cells, tipifarnib and adaglacib (Figure 3D, 2D immunoblots), and NCI-H1792 cells, tipifarnib and sotracib (Figure 3E, 2D immunoblots), as well as doxycycline-inducible shRNA NCI-H2122 lines after exposure to adaglacib (Figure 3F) and transfected siRNAs. Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to adagravate in the NCI-H2122 system (Figure 3G). [Figure 3C]Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to NCI-H2122 cells, FTI and KRAS inhibitors, (a) compound (I) and adaglacib alone and in combination (Figures 3A and 3B, 3D immunoblots), and (b) tipifarnib and sotracib (Figure 3C, 2D immunoblots), NCI-H2030 cells, tipifarnib and adaglacib (Figure 3D, 2D immunoblots), and NCI-H1792 cells, tipifarnib and sotracib (Figure 3E, 2D immunoblots), as well as doxycycline-inducible shRNA NCI-H2122 lines after exposure to adaglacib (Figure 3F) and transfected siRNAs. Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to adagravate in the NCI-H2122 system (Figure 3G). [Figure 3D] Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to NCI-H2122 cells, FTI and KRAS inhibitors, (a) compound (I) and adaglacib alone and in combination (Figures 3A and 3B, 3D immunoblots), and (b) tipifarnib and sotracib (Figure 3C, 2D immunoblots), NCI-H2030 cells, tipifarnib and adaglacib (Figure 3D, 2D immunoblots), and NCI-H1792 cells, tipifarnib and sotracib (Figure 3E, 2D immunoblots), as well as doxycycline-inducible shRNA NCI-H2122 lines after exposure to adaglacib (Figure 3F) and transfected siRNAs. Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to adagravate in the NCI-H2122 system (Figure 3G). [Figure 3E]Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to NCI-H2122 cells, FTI and KRAS inhibitors, (a) compound (I) and adaglacib alone and in combination (Figures 3A and 3B, 3D immunoblots), and (b) tipifarnib and sotracib (Figure 3C, 2D immunoblots), NCI-H2030 cells, tipifarnib and adaglacib (Figure 3D, 2D immunoblots), and NCI-H1792 cells, tipifarnib and sotracib (Figure 3E, 2D immunoblots), as well as doxycycline-inducible shRNA NCI-H2122 lines after exposure to adaglacib (Figure 3F) and transfected siRNAs. Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to adagravate in the NCI-H2122 system (Figure 3G). [Figure 3F] Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to NCI-H2122 cells, FTI and KRAS inhibitors, (a) compound (I) and adaglacib alone and in combination (Figures 3A and 3B, 3D immunoblots), and (b) tipifarnib and sotracib (Figure 3C, 2D immunoblots), NCI-H2030 cells, tipifarnib and adaglacib (Figure 3D, 2D immunoblots), and NCI-H1792 cells, tipifarnib and sotracib (Figure 3E, 2D immunoblots), as well as doxycycline-inducible shRNA NCI-H2122 lines after exposure to adaglacib (Figure 3F) and transfected siRNAs. Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to adagravate in the NCI-H2122 system (Figure 3G). [Figure 3G]Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to NCI-H2122 cells, FTI and KRAS inhibitors, (a) compound (I) and adaglacib alone and in combination (Figures 3A and 3B, 3D immunoblots), and (b) tipifarnib and sotracib (Figure 3C, 2D immunoblots), NCI-H2030 cells, tipifarnib and adaglacib (Figure 3D, 2D immunoblots), and NCI-H1792 cells, tipifarnib and sotracib (Figure 3E, 2D immunoblots), as well as doxycycline-inducible shRNA NCI-H2122 lines after exposure to adaglacib (Figure 3F) and transfected siRNAs. Immunoblots of KRAS G12C NSCLC cell lines in 3D and 2D studies after exposure to adagravate in the NCI-H2122 system (Figure 3G). [Figure 4A] Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the NCI-H2122 CDX model, using tipifarnib and adaglacib (Figure 4A), tipifarnib and sotracib (Figure 4B), and compound (I) and adaglacib (Figure 4C). [Figure 4B] Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the NCI-H2122 CDX model, using tipifarnib and adaglacib (Figure 4A), tipifarnib and sotracib (Figure 4B), and compound (I) and adaglacib (Figure 4C). [Figure 4C] Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the NCI-H2122 CDX model, using tipifarnib and adaglacib (Figure 4A), tipifarnib and sotracib (Figure 4B), and compound (I) and adaglacib (Figure 4C). [Figure 5A]Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the LU2512 PDX model, using tipifarnib and adaglacib (Figure 5A), tipifarnib and sotracib (Figure 5B), and compound (I) and adaglacib (Figure 5C). [Figure 5B] Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the LU2512 PDX model, using tipifarnib and adaglacib (Figure 5A), tipifarnib and sotracib (Figure 5B), and compound (I) and adaglacib (Figure 5C). [Figure 5C] Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the LU2512 PDX model, using tipifarnib and adaglacib (Figure 5A), tipifarnib and sotracib (Figure 5B), and compound (I) and adaglacib (Figure 5C). [Figure 6A] Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the NCI-H2030 CDX model, using tipifarnib and adaglacib (Figure 6A), tipifarnib and sotracib (Figure 6B), and compound (I) and adaglacib (Figure 6C). [Figure 6B] Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the NCI-H2030 CDX model, using tipifarnib and adaglacib (Figure 6A), tipifarnib and sotracib (Figure 6B), and compound (I) and adaglacib (Figure 6C). [Figure 6C]Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the NCI-H2030 CDX model, using tipifarnib and adaglacib (Figure 6A), tipifarnib and sotracib (Figure 6B), and compound (I) and adaglacib (Figure 6C). [Figure 7A] Figure 7A shows plots of tumor volume (mm3) over time (days) in an in vivo xenograft study of compound (I) and adagravide combination in the NCI-H2030 CDX model, as well as the change in tumor volume (%) from day 0 to day 46 (Figure 7B). [Figure 7B] Figure 7A shows plots of tumor volume (mm3) over time (days) in an in vivo xenograft study of compound (I) and adagravide combination in the NCI-H2030 CDX model, as well as the change in tumor volume (%) from day 0 to day 46 (Figure 7B). [Figure 8A] Immunohistochemical staining images from NCI-H2122 endpoint tumor samples from the combination groups treated with tipifarnib and adaglacib (Figure 8A) and compound (I) and adaglacib (Figure 8B). [Figure 8B] Immunohistochemical staining images from NCI-H2122 endpoint tumor samples from the combination groups treated with tipifarnib and adaglacib (Figure 8A) and compound (I) and adaglacib (Figure 8B). [Figure 9A] Results of pharmacodynamic studies of compound (I) and adagrasib in the NCI-H2122 CDX cell line via Western blotting of mTOR and MAPK pathway proteins (Figure 9A), and IHC stained images (Figures 9B and 9C). [Figure 9B] Results of pharmacodynamic studies of compound (I) and adagrasib in the NCI-H2122 CDX cell line via Western blotting of mTOR and MAPK pathway proteins (Figure 9A), and IHC stained images (Figures 9B and 9C). [Figure 9C]Results of pharmacodynamic studies of compound (I) and adagrasib in the NCI-H2122 CDX cell line via Western blotting of mTOR and MAPK pathway proteins (Figure 9A), and IHC stained images (Figures 9B and 9C). [Figure 9D] Results of pharmacodynamic studies of compound (I) and adagrasib in the NCI-H2122 CDX cell line via Western blotting of mTOR and MAPK pathway proteins (Figure 9A), and IHC stained images (Figures 9B and 9C). [Figure 10A] Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the PA0787 PDX model using tipifarnib, compound (I), MRTX1133, tipifarnib and MRTX1133, and compound (I) and MRTX1133 (Figure 10A), compound (I), MRTX1133, and the SW1990 CDX model using compound (I) and MRTX1133 (Figure 10B). [Figure 10B] Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the PA0787 PDX model using tipifarnib, compound (I), MRTX1133, tipifarnib and MRTX1133, and compound (I) and MRTX1133 (Figure 10A), compound (I), MRTX1133, and the SW1990 CDX model using compound (I) and MRTX1133 (Figure 10B). [Figure 11] Immunoblots (2D signaling) of AsPC-1 KRAS G12D PDAC cell lines exposed to compound (I) and MRTX1133. [Figure 12A]Figure 12A shows the CR3262 PDX model using tipifarnib, compound (I), MRTX1133, tipifarnib and MRTX1133, and compound (I) and MRTX1133; Figure 12B shows the GP2D CDX model using compound (I), MRTX1133, cetuximab, compound (I) and MRTX1133, and cetuximab and MRTX1133; Figure 12C shows the CR1245 PDX model using compound (I), MRTX1133, or a combination thereof; and Figure 12C shows the GP2D model using compound (I), RMC-6236, or a combination thereof. Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the CDX model (Figure 12D), or using compound (I), MRTX1133, cetuximab, MRTX1133 and cetuximab, compound (I) and MRTX1133, or compound (I), MRTX1133 and cetuximab (Figure 12E). [Figure 12B] Figure 12A shows the CR3262 PDX model using tipifarnib, compound (I), MRTX1133, tipifarnib and MRTX1133, and compound (I) and MRTX1133; Figure 12B shows the GP2D CDX model using compound (I), MRTX1133, cetuximab, compound (I) and MRTX1133, and cetuximab and MRTX1133; Figure 12C shows the CR1245 PDX model using compound (I), MRTX1133, or a combination thereof; and Figure 12C shows the GP2D model using compound (I), RMC-6236, or a combination thereof. Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the CDX model (Figure 12D), or using compound (I), MRTX1133, cetuximab, MRTX1133 and cetuximab, compound (I) and MRTX1133, or compound (I), MRTX1133 and cetuximab (Figure 12E). [Figure 12C]Figure 12A shows the CR3262 PDX model using tipifarnib, compound (I), MRTX1133, tipifarnib and MRTX1133, and compound (I) and MRTX1133; Figure 12B shows the GP2D CDX model using compound (I), MRTX1133, cetuximab, compound (I) and MRTX1133, and cetuximab and MRTX1133; Figure 12C shows the CR1245 PDX model using compound (I), MRTX1133, or a combination thereof; and Figure 12C shows the GP2D model using compound (I), RMC-6236, or a combination thereof. Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the CDX model (Figure 12D), or using compound (I), MRTX1133, cetuximab, MRTX1133 and cetuximab, compound (I) and MRTX1133, or compound (I), MRTX1133 and cetuximab (Figure 12E). [Figure 12D] Figure 12A shows the CR3262 PDX model using tipifarnib, compound (I), MRTX1133, tipifarnib and MRTX1133, and compound (I) and MRTX1133; Figure 12B shows the GP2D CDX model using compound (I), MRTX1133, cetuximab, compound (I) and MRTX1133, and cetuximab and MRTX1133; Figure 12C shows the CR1245 PDX model using compound (I), MRTX1133, or a combination thereof; and Figure 12C shows the GP2D model using compound (I), RMC-6236, or a combination thereof. Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the CDX model (Figure 12D), or using compound (I), MRTX1133, cetuximab, MRTX1133 and cetuximab, compound (I) and MRTX1133, or compound (I), MRTX1133 and cetuximab (Figure 12E). [Figure 12E]Figure 12A shows the CR3262 PDX model using tipifarnib, compound (I), MRTX1133, tipifarnib and MRTX1133, and compound (I) and MRTX1133; Figure 12B shows the GP2D CDX model using compound (I), MRTX1133, cetuximab, compound (I) and MRTX1133, and cetuximab and MRTX1133; Figure 12C shows the CR1245 PDX model using compound (I), MRTX1133, or a combination thereof; and Figure 12C shows the GP2D model using compound (I), RMC-6236, or a combination thereof. Plots of tumor volume (mm3) over time (days) in in vivo xenograft studies of FTI and KRAS inhibitor combinations in the CDX model (Figure 12D), or using compound (I), MRTX1133, cetuximab, MRTX1133 and cetuximab, compound (I) and MRTX1133, or compound (I), MRTX1133 and cetuximab (Figure 12E). [Figure 13] Immunoblot analysis of GP2D colorectal cancer CDX tumors after treatment with compound (I), MRTX1133, or a combination of these. [Figure 14A] Plots of tumor volume (mm3) over time (days) in in vivo PDAC xenograft studies of compound (I), adagrasib, and combinations thereof in the MIA PaCa-2 KRAS G12C model (Figure 14A) and the PA1383 KRAS G12C model (Figure 14B). [Figure 14B] Plots of tumor volume (mm3) over time (days) in in vivo PDAC xenograft studies of compound (I), adagrasib, and combinations thereof in the MIA PaCa-2 KRAS G12C model (Figure 14A) and the PA1383 KRAS G12C model (Figure 14B). [Figure 15A](a)(i) CR6256 KRAS G12C model using tipifarnib, compound (I), sotrasib, tipifarnib and sotrasib, and compound (I) and sotrasib (Figure 15A), (ii) CR6256 KRAS G12C model using tipifarnib, compound (I), adaglasib, tipifarnib and adaglasib, and compound (I) and adaglasib (Figure 15B), (b) CR6243 KRAS G12C model using compound (I), adaglasib, and combinations thereof (Figure 15C), and (c) SW837 KRAS G12C CRC model using compound (I), adaglasib, and combinations thereof (Figure 15D), plotting tumor volume (mm3) over time (days) in in vivo CRC xenograft studies. [Figure 15B] (a)(i) CR6256 KRAS G12C model using tipifarnib, compound (I), sotrasib, tipifarnib and sotrasib, and compound (I) and sotrasib (Figure 15A), (ii) CR6256 KRAS G12C model using tipifarnib, compound (I), adaglasib, tipifarnib and adaglasib, and compound (I) and adaglasib (Figure 15B), (b) CR6243 KRAS G12C model using compound (I), adaglasib, and combinations thereof (Figure 15C), and (c) SW837 KRAS G12C CRC model using compound (I), adaglasib, and combinations thereof (Figure 15D), plotting tumor volume (mm3) over time (days) in in vivo CRC xenograft studies. [Figure 15C](a)(i) CR6256 KRAS G12C model using tipifarnib, compound (I), sotrasib, tipifarnib and sotrasib, and compound (I) and sotrasib (Figure 15A), (ii) CR6256 KRAS G12C model using tipifarnib, compound (I), adaglasib, tipifarnib and adaglasib, and compound (I) and adaglasib (Figure 15B), (b) CR6243 KRAS G12C model using compound (I), adaglasib, and combinations thereof (Figure 15C), and (c) SW837 KRAS G12C CRC model using compound (I), adaglasib, and combinations thereof (Figure 15D), plotting tumor volume (mm3) over time (days) in in vivo CRC xenograft studies. [Figure 15D] (a)(i) CR6256 KRAS G12C model using tipifarnib, compound (I), sotrasib, tipifarnib and sotrasib, and compound (I) and sotrasib (Figure 15A), (ii) CR6256 KRAS G12C model using tipifarnib, compound (I), adaglasib, tipifarnib and adaglasib, and compound (I) and adaglasib (Figure 15B), (b) CR6243 KRAS G12C model using compound (I), adaglasib, and combinations thereof (Figure 15C), and (c) SW837 KRAS G12C CRC model using compound (I), adaglasib, and combinations thereof (Figure 15D), plotting tumor volume (mm3) over time (days) in in vivo CRC xenograft studies. [Figure 16A] The following plots show tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies using the NCI-H358 KRAS G12C NSCLC model for the following two experiments: (a) tipifarnib, adaglacib (at two dose levels), and their combination (Figure 16A), and (b) tipifarnib, sotracib (at two dose levels), and their combination (Figure 16B). [Figure 16B]The following plots show tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies using the NCI-H358 KRAS G12C NSCLC model for the following two experiments: (a) tipifarnib, adaglacib (at two dose levels), and their combination (Figure 16A), and (b) tipifarnib, sotracib (at two dose levels), and their combination (Figure 16B). [Figure 17A] Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in NCI-H2122 NSCLC using compound (I), adaglacib, RMC-4550, BI-3406, everolimus, VT103, and combinations (all data: Figure 17A, data extraction: Figure 17B), compound (I), adaglacib, RMC-4550, or combinations (Figure 17C), compound (I), adaglacib, BI-3406, and combinations (Figure 17D), compound (I), adaglacib, everolimus, and combinations (Figure 17E), and compound (I), adaglacib, VT103, and combinations (Figure 17F). [Figure 17B] Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in NCI-H2122 NSCLC using compound (I), adaglacib, RMC-4550, BI-3406, everolimus, VT103, and combinations (all data: Figure 17A, data extraction: Figure 17B), compound (I), adaglacib, RMC-4550, or combinations (Figure 17C), compound (I), adaglacib, BI-3406, and combinations (Figure 17D), compound (I), adaglacib, everolimus, and combinations (Figure 17E), and compound (I), adaglacib, VT103, and combinations (Figure 17F). [Figure 17C]Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in NCI-H2122 NSCLC using compound (I), adaglacib, RMC-4550, BI-3406, everolimus, VT103, and combinations (all data: Figure 17A, data extraction: Figure 17B), compound (I), adaglacib, RMC-4550, or combinations (Figure 17C), compound (I), adaglacib, BI-3406, and combinations (Figure 17D), compound (I), adaglacib, everolimus, and combinations (Figure 17E), and compound (I), adaglacib, VT103, and combinations (Figure 17F). [Figure 17D] Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in NCI-H2122 NSCLC using compound (I), adaglacib, RMC-4550, BI-3406, everolimus, VT103, and combinations (all data: Figure 17A, data extraction: Figure 17B), compound (I), adaglacib, RMC-4550, or combinations (Figure 17C), compound (I), adaglacib, BI-3406, and combinations (Figure 17D), compound (I), adaglacib, everolimus, and combinations (Figure 17E), and compound (I), adaglacib, VT103, and combinations (Figure 17F). [Figure 17E] Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in NCI-H2122 NSCLC using compound (I), adaglacib, RMC-4550, BI-3406, everolimus, VT103, and combinations (all data: Figure 17A, data extraction: Figure 17B), compound (I), adaglacib, RMC-4550, or combinations (Figure 17C), compound (I), adaglacib, BI-3406, and combinations (Figure 17D), compound (I), adaglacib, everolimus, and combinations (Figure 17E), and compound (I), adaglacib, VT103, and combinations (Figure 17F). [Figure 17F]Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in NCI-H2122 NSCLC using compound (I), adaglacib, RMC-4550, BI-3406, everolimus, VT103, and combinations (all data: Figure 17A, data extraction: Figure 17B), compound (I), adaglacib, RMC-4550, or combinations (Figure 17C), compound (I), adaglacib, BI-3406, and combinations (Figure 17D), compound (I), adaglacib, everolimus, and combinations (Figure 17E), and compound (I), adaglacib, VT103, and combinations (Figure 17F). [Figure 18A] Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in the NCI-H2030 NSCLC model or the NCI-H2122 NSCLC model. (a) Compound (I), adaglacib, or one of two drug regimens of Compound (I) / adaglacib (NCI-H2030) (Figure 18A), (b) Compound (I), adaglacib, or one of two drug regimens of Compound (I) / adaglacib (NCI-H2122) (Figure 18B), (c) Compound (I), sotrasib, sotrasib / adaglacib, sotrasib / adaglacib / compound (I), and compound (I) / adaglacib (NCI-H2122) (Figure 18C), (d) adaglacib, adaglacib / RMC-6236, adaglacib / RMC-6236 / compound (I), and RMC-6236 / compound (I) (NCI-H2122) (Figure 18D), RMC-6236, and one of two drug regimens for RMC-6236 / compound (I) (NCI-H2122) (Figure 18E). [Figure 18B]Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in the NCI-H2030 NSCLC model or the NCI-H2122 NSCLC model. (a) Compound (I), adaglacib, or one of two drug regimens of Compound (I) / adaglacib (NCI-H2030) (Figure 18A), (b) Compound (I), adaglacib, or one of two drug regimens of Compound (I) / adaglacib (NCI-H2122) (Figure 18B), (c) Compound (I), sotrasib, sotrasib / adaglacib, sotrasib / adaglacib / compound (I), and compound (I) / adaglacib (NCI-H2122) (Figure 18C), (d) adaglacib, adaglacib / RMC-6236, adaglacib / RMC-6236 / compound (I), and RMC-6236 / compound (I) (NCI-H2122) (Figure 18D), RMC-6236, and one of two drug regimens for RMC-6236 / compound (I) (NCI-H2122) (Figure 18E). [Figure 18C] Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in the NCI-H2030 NSCLC model or the NCI-H2122 NSCLC model. (a) Compound (I), adaglacib, or one of two drug regimens of Compound (I) / adaglacib (NCI-H2030) (Figure 18A), (b) Compound (I), adaglacib, or one of two drug regimens of Compound (I) / adaglacib (NCI-H2122) (Figure 18B), (c) Compound (I), sotrasib, sotrasib / adaglacib, sotrasib / adaglacib / compound (I), and compound (I) / adaglacib (NCI-H2122) (Figure 18C), (d) adaglacib, adaglacib / RMC-6236, adaglacib / RMC-6236 / compound (I), and RMC-6236 / compound (I) (NCI-H2122) (Figure 18D), RMC-6236, and one of two drug regimens for RMC-6236 / compound (I) (NCI-H2122) (Figure 18E). [Figure 18D]Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in the NCI-H2030 NSCLC model or the NCI-H2122 NSCLC model. (a) Compound (I), adaglacib, or one of two drug regimens of Compound (I) / adaglacib (NCI-H2030) (Figure 18A), (b) Compound (I), adaglacib, or one of two drug regimens of Compound (I) / adaglacib (NCI-H2122) (Figure 18B), (c) Compound (I), sotrasib, sotrasib / adaglacib, sotrasib / adaglacib / compound (I), and compound (I) / adaglacib (NCI-H2122) (Figure 18C), (d) adaglacib, adaglacib / RMC-6236, adaglacib / RMC-6236 / compound (I), and RMC-6236 / compound (I) (NCI-H2122) (Figure 18D), RMC-6236, and one of two drug regimens for RMC-6236 / compound (I) (NCI-H2122) (Figure 18E). [Figure 18E] Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in the NCI-H2030 NSCLC model or the NCI-H2122 NSCLC model. (a) Compound (I), adaglacib, or one of two drug regimens of Compound (I) / adaglacib (NCI-H2030) (Figure 18A), (b) Compound (I), adaglacib, or one of two drug regimens of Compound (I) / adaglacib (NCI-H2122) (Figure 18B), (c) Compound (I), sotrasib, sotrasib / adaglacib, sotrasib / adaglacib / compound (I), and compound (I) / adaglacib (NCI-H2122) (Figure 18C), (d) adaglacib, adaglacib / RMC-6236, adaglacib / RMC-6236 / compound (I), and RMC-6236 / compound (I) (NCI-H2122) (Figure 18D), RMC-6236, and one of two drug regimens for RMC-6236 / compound (I) (NCI-H2122) (Figure 18E). [Figure 19A](a) Immunoblot analysis of NCI-H2030 NSCLC CDX tumors after initial treatment with adagrasib for 28 or 56 days, compound (I) added on day 28 to 56 days of adagrasib, or compound (I) and adagrasib for 28 or 56 days (Figure 19A), and (b) Immunoblot analysis of NCI-H2122 NSCLC CDX tumors after treatment with sotrasib, sotrasib / adagrasib, sotrasib / adagrasib / compound (I), adagrasib, compound (I) added on day 14 to adagrasib, or adagrasib / compound (I) (Figure 19B). [Figure 19B] (a) Immunoblot analysis of NCI-H2030 NSCLC CDX tumors after initial treatment with adagrasib for 28 or 56 days, compound (I) added on day 28 to 56 days of adagrasib, or compound (I) and adagrasib for 28 or 56 days (Figure 19A), and (b) Immunoblot analysis of NCI-H2122 NSCLC CDX tumors after treatment with sotrasib, sotrasib / adagrasib, sotrasib / adagrasib / compound (I), adagrasib, compound (I) added on day 14 to adagrasib, or adagrasib / compound (I) (Figure 19B). [Figure 20] Plots of tumor volume (mm3) over time (days) in an in vivo NSCLC xenograft study using four drug schedule regimens for compound (I) and adagrav. [Figure 21] Plots of tumor volume (mm3) over time (days) in in vivo NSCLC xenograft studies in the NCI-H2122 NSCLC model using compound (I), diverasib (at two dose levels), and combinations thereof. [Figure 22A](a) Plots of tumor volume (mm3) over time (days) in in vivo PDAC xenograft studies for the Capan-1 KRAS G12V CDX model using compound (I), BI-2493, and combinations thereof (Figure 22A), and (b) the PA-07-0041 KRAS G12V PDX model using compound (I), BI-2493, and combinations thereof (Figure 22B). [Figure 22B] (a) Plots of tumor volume (mm3) over time (days) in in vivo PDAC xenograft studies for the Capan-1 KRAS G12V CDX model using compound (I), BI-2493, and combinations thereof (Figure 22A), and (b) the PA-07-0041 KRAS G12V PDX model using compound (I), BI-2493, and combinations thereof (Figure 22B). [Modes for carrying out the invention]

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. All patents, applications, published applications and other publications are incorporated in their entirety by reference. If there are multiple definitions of a term herein, the definition in this section shall prevail unless otherwise specified.

[0024] As used herein, and in the specification and the appended claims, the indefinite articles "a" and "an," and the definite article "the," include plural and singular referents unless the context clearly indicates otherwise.

[0025] Where used herein, unless otherwise specified, the terms “about” and “approximately” mean, when used in relation to the dose, volume, or weight percentage of a component of a composition or dosage form, a dose, volume, or weight percentage of 30%, 20%, 15%, 10%, or 5% of the specified dose, volume, or weight percentage.

[0026] When used herein, compound (I) has the structure shown below, which is "(S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - It can be named "Dicarbonitrile".

[0027] [ka]

[0028] Compound (I) may be prepared as described in PCT International Patent Application No. PCT / US2022 / 80565, filed on 29 November 2022 (published as PCT International Patent Application Publication No. WO2023 / 102378).

[0029] When used herein, compound (II) has the structure shown below, which is "(R)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - It can be named "Dicarbonitrile".

[0030] [ka]

[0031] When used herein, compound (III) has the structure shown below, which is "3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - It can be named "Dicarbonitrile".

[0032] [ka]

[0033] When used herein, the “pharmaceutically acceptable forms” of the compounds disclosed herein include, but are not limited to, compounds (I), (II), or (III), their tautomers, stereoisomers, mixtures of stereoisomers, or racemic mixtures, or their isotopic substitutions, pharmaceutically acceptable salts of any of the aforementioned forms, or solvates of any of the aforementioned forms. In some embodiments, the “pharmaceutically acceptable forms” include, but are not limited to, compounds (I), (II), or (III), or their pharmaceutically acceptable salts, or solvates.

[0034] As used herein, the terms “stereoisomer” or “stereoisomerically pure” mean one stereoisomer of a compound that substantially does not contain any other stereoisomers of that compound. Stereoiomers include, for example, enantiomers, diastereomers, and atropisomers. For example, a stereoisomerically pure compound having one chiral center would be one enantiomer that substantially does not contain the opposite enantiomer of that compound. For example, a stereoisomerically pure compound (I) substantially does not contain compound (II). Atropisomers are stereoisomers that arise due to bound rotation around a single bond, where an energy difference due to steric strain or other factors creates a barrier to rotation sufficient to allow for the identification and potential isolation of individual conformational isomers. Typical stereoisomerically pure compounds include one stereoisomer of the compound and less than 20% by weight of other stereoisomers of the compound in amounts greater than about 80% by weight, one stereoisomer of the compound and less than 10% by weight of other stereoisomers of the compound in amounts greater than about 90% by weight, one stereoisomer of the compound and less than 5% by weight of other stereoisomers of the compound in amounts greater than about 95% by weight, or one stereoisomer of the compound and less than 3% by weight of other stereoisomers of the compound in amounts greater than about 97% by weight. Compounds may have a chiral center and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such stereoisomerically pure forms, including mixtures thereof, are included within the scope of the embodiments provided herein. The use of such stereoisomerically pure forms of compounds, as well as the use of mixtures of these forms, including unequal mixtures and racemic mixtures, is included in the embodiments provided herein.

[0035] The stereoisomers may be synthesized asymmetrically, or they may be resolved using standard techniques such as chiral columns or chiral resolving agents. For example, Jacques, J., et al., (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268(ELEliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN,1972);Todd,M.,Separation of Enantiomers:Synthetic Methods(Wiley-VCH Verlag GmbH & Co.KGaA,Weinheim,Germany,2014);Toda,F.,Enantiomer Separation:Fundamentals and Practical Methods(Springer Science & Business Media,2007);Subramanian,G.Chiral Separation See Techniques: A Practical Approach (John Wiley & Sons, 2008) and Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0036] In certain embodiments, a pharmaceutically acceptable form is a tautomer that includes tautomers of the imidazole moiety. As used herein, the term "tautomer" is a type of isomer that includes two or more mutually convertible compounds resulting from at least one formal shift of a hydrogen atom and at least one change in valence. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. Tautomerization (i.e., the reaction that gives a pair of tautomers) can be catalyzed by an acid or a base or can occur without the action or presence of an external agent.

[0037] The term "isotope-substituted compound" refers to an isotope-enriched compound that is identical to those listed herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein include, respectively 2 H (deuterium) or 14 isotopes of hydrogen or carbon such as

[0038] The embodiments described herein may include isotope-substituted forms of compound (I), (II), or (III), or pharmaceutically acceptable forms thereof, wherein the isotope-substituted compound is substituted with one or more deuterium atoms in place of one or more hydrogen atoms on one or more atomic members of the compound or a pharmaceutically acceptable form thereof, and optionally, one or more hydrogen atoms are bonded to a carbon atom.

[0039] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is free from excessive toxicity, irritation, allergic reactions, etc., suitable for use in the subject, and corresponding to a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995). The pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids, e.g., suitable inorganic and organic addition acids. In certain embodiments, the pharmaceutically acceptable form of compound (I), (II), or (III) is the free base of compound (I), (II), or (III). In some embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt of compound (I), (II), or (III).

[0040] In certain embodiments, the pharmaceutically acceptable form is a solvate (e.g., a hydrate). As used herein, the term “solvate” refers to a complex between a compound and a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. The solvate may be a solvate of compound (I), (II), or (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the solvate is a hydrate (a solvate with water). Pharmaceutically acceptable solvates and hydrates are complexes that may include, for example, solvent / compound molar ratios of 0.1, 0.25, 0.50, 0.75, or 1, or 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4.

[0041] In this specification, if there is a discrepancy between a given structure and its name, the given structure shall be given greater weight.

[0042] As used herein, the term “pharmaceutically acceptable excipient” means a carrier, excipient, or diluent approved by a federal or state regulatory authority for use in animals, more specifically in humans, or listed in the United States Pharmacopeia or other commonly recognized pharmacopoeias. A pharmaceutical carrier refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle, together with which a therapeutic agent is administered. Such pharmaceutical carriers may be sterile liquids (e.g., water and oils (oils of petroleum, animal, plant, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.)). Water is a particular carrier for pharmaceutical compositions administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. For example, the term pharmaceutically acceptable carrier, diluent, or excipient includes any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic and absorption retardants, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active component, its use in the therapeutic compositions disclosed herein is intended. Auxiliary active components may also be incorporated into the pharmaceutical compositions. Examples of excipients that can be used in the oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.

[0043] As used herein, the terms “therapeutic dose” or “effective dose” in relation to a compound mean an amount that can treat cancer or its symptoms, or otherwise achieve a desired therapeutic or mechanistic effect, such as mitigating drug resistance.

[0044] As used herein, the terms “to treat,” “to treat,” and “treatment” are interchangeable herein and mean the overall or partial relief or improvement of a disease or one or more symptoms associated with a disease, or the slowing or cessation of further progression or worsening of those symptoms, or the relief or eradication of the cause of the disease. In some embodiments, these terms refer to an approach to obtain beneficial or desired outcomes, including, but not limited to, therapeutic or preventive benefits. The therapeutic benefits resulting from the treatment methods provided herein include the eradication or improvement of the underlying disease being treated, or the eradication or improvement of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in the subject, even though the subject may still be suffering from the underlying disease. For example, as used in relation to a subject with cancer, “to treat” means an action that reduces the severity of cancer or slows the progression of cancer, such as inhibiting cancer growth, stopping the development of cancer, causing cancer regression, delaying or minimizing one or more symptoms associated with the presence of cancer, or overcoming or delaying the emergence of drug resistance. In some embodiments, “treating” includes adjuvant therapy, which is a therapy given after a primary treatment such as surgery to reduce the chance of cancer recurrence. In some embodiments, “treating” includes neoadjuvant therapy, which is a therapy given first to shrink a tumor before a primary treatment such as surgery. In some embodiments, “treating” in accordance with the methods described herein is before, after, or concurrently with a first-line treatment, a second-line treatment, a subsequent-line treatment (second-line or subsequent-line), an adjuvant therapy, or a neoadjuvant therapy, or one or more therapies in any of these classes.

[0045] As used herein, the terms “prevention” and “preventing” refer to an approach to obtain a beneficial or desired outcome, including but not limited to a preventive benefit. For a preventive benefit, the compounds and pharmaceutical compositions disclosed herein may be administered to subjects at risk of developing cancer, subjects reporting one or more physiological symptoms of cancer, even if they have not been diagnosed with cancer, or patients in remission from cancer. The preventive benefit resulting from the therapeutic methods provided herein includes delaying or eliminating the onset of disease, delaying or eliminating the onset of symptoms of disease, slowing, stopping, or reversing the progression of disease, or any combination thereof.

[0046] As used herein, the terms “mitigate” and “mitigate” with respect to resistance to therapy include delaying or slowing down the time to the emergence of drug resistance, preventing the emergence of drug resistance, or reducing or overcoming drug resistance.

[0047] As used herein, the term “Subject” to which the administration is intended can mean, but is not limited to, humans (e.g., males or females of any age group, such as adult subjects or adolescent subjects; primates (e.g., crab-eating macaques, rhesus macaques), and / or other animals, including other mammals, such as cattle, pigs, horses, sheep, goats, cats, dogs, rabbits, rodents, and / or birds, which are commercially relevant mammals. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is an adolescent human. In some embodiments, the subject is an adult.

[0048] As used herein, the term “first-line therapy” refers to the first treatment a subject receives for cancer, for example, the first treatment after a diagnosis of cancer. First-line therapy for treating cancer includes, for example, surgery, chemotherapy, immunotherapy, or radiation, or a combination thereof. Chemotherapy may include treatment with cisplatin or carboplatin, and may optionally be combined with paclitaxel, docetaxel, gemcitabine, etoposide, or pemetrexed. Immunotherapy may include treatment with PD-1 / PD-L1 inhibitors (e.g., nivolumab, pembrolizumab, cemiplimab, atezolizumab, or durvalumab) or CTLA-4 inhibitors (e.g., ipiltumumab or tremelimumab). First-line therapy is the first treatment of cancer after a recurrence or diagnosis of metastatic disease. In some cases, the first-line therapy for CRC is the FOLFIRI regimen (leucovorin calcium (folic acid), fluorouracil (5FU), and irinotecan hydrochloride) or the FOLFOX regimen (leucovorin calcium (folic acid), fluorouracil (5FU), and oxaliplatin). In some cases, the first-line therapy for PDAC is the FOLFIRINOX regimen (leucovorin calcium (folic acid), fluorouracil (5FU), irinotecan hydrochloride, and oxaliplatin), gemcitabine in addition to nab-paclitaxel, or the NALIRIFOX regimen (liposomal irinotecan (Nal-IRI or Onivyde®), fluorouracil (5FU), leucovorin, and oxaliplatin).

[0049] As used herein, the term “second-line therapy” refers to a second therapy a subject receives for cancer after an initial therapy, for example, when the subject is refractory to or relapses to such therapy. Second-line therapy for treating cancer is used, for example, when at least one prior treatment has failed to alleviate or reduce the severity of at least one symptom associated with cancer. For example, second-line therapy may include the use of chemotherapy, immunotherapy, or radiation, or a combination thereof. In some cases, second-line therapy for CRC is the FOLFIRI regimen (leucovorin calcium (folic acid), fluorouracil, and irinotecan hydrochloride) or the FOLFOX regimen (leucovorin calcium (folic acid), fluorouracil, and oxaliplatin).

[0050] As used herein, the term “recurrent” refers to a disease that has responded to treatment (e.g., achieved complete response, partial response, or stable disease) but subsequently progressed. Treatment may include one or more elective therapies. For example, “recurrent” cancer may refer to cancer that was previously treated with an elective therapy and responded to it, for example, achieved remission, but subsequently relapsed. Cancer may relapse after multiple elective therapies, e.g., 1, 2, 3, or 4, or at least 1 or at least 2 elective therapies.

[0051] As used herein, the term “refractory” refers to a disease that has not responded to previous treatments, or has not responded at all. In some embodiments, cancer is considered refractory if it shows less than a complete response (CR) to the most recent therapy.

[0052] As used herein, the term “amplification” refers to a tumor in which the copy number of a gene has increased compared to a reference level. In some embodiments, the amplified gene is a wild-type gene. In some embodiments, the amplified gene is a mutant gene. In the context of KRAS-dependent cancer, amplification is at least 3 copies, at least 4 copies, at least 5 copies, at least 6 copies, 3 to 450 copies, 3 to 200 copies, 3 to 50 copies, or 4 to 10 copies. Preferably, at least 4 copies, or 4 to 100 copies, of the KRAS gene.

[0053] As used herein, unless otherwise indicated, the term “KRAS-dependent cancer” refers to cancer having oncogenic alterations in the KRAS gene, e.g., at the gene sequence or expression level. Such alterations include, but are not limited to, oncogenic KRAS mutations, oncogenic amplification of the KRAS gene, or combinations thereof. In some embodiments, KRAS-dependent cancer is KRAS mutant and / or KRAS amplified, or combinations thereof. In some embodiments, KRAS-dependent cancer is KRAS mutant cancer. In some embodiments, KRAS-dependent cancer is KRAS wild-type and KRAS amplified. KRAS mutations and amplifications can be determined using methods known in the art. Examples of oncogenic KRAS mutations include G12C, G12D, G12V, G12A, G12R, G12S, G13C, G13D, and Q61H. In some embodiments, the cancer being treated is KRAS amplified cancer.

[0054] As used herein, the term “Duration of Response” or “DoR” means the time from achieving a response to relapse or disease progression. In some embodiments, DoR is the time from achieving a response ≥ partial response (PR) to relapse or disease progression. In some embodiments, DoR is the time from the first record of a response to the first record of progressive disease or death. In some embodiments, DoR is the time from the first record of a response ≥ partial response (PR) to the first record of progressive disease or death.

[0055] As used herein, the term “Event-Free Survival” or “EFS” means the time from the start of treatment to disease progression, discontinuation of treatment for any reason, or any treatment failure, including death.

[0056] As used herein, the term “Overall Response Rate” or “ORR” means the proportion of patients who achieve a response. In some embodiments, ORR means the sum of the proportions of patients who achieve a complete response and / or a partial response. In some embodiments, ORR means the proportion of patients whose best response is greater than or equal to a partial response (PR).

[0057] As used herein, the term "overall survival" or "OS" means the time from the start of treatment to death from any cause.

[0058] As used herein, the term “Progression-Free Survival” or “PFS” means the time from the initiation of treatment to tumor progression or death. In some embodiments, PFS means the time from the first administration of the compound to the first occurrence of disease progression or death for any cause. In some embodiments, the PFS rate is calculated using the Kaplan-Meier estimate.

[0059] As used herein, the terms “Time to Progression” or “TTP” mean the time from the start of treatment to tumor progression. TTP does not include death.

[0060] As used herein, the term “Time to Response” or “TTR” means the time from the first dose of the compound to the first recording of a response. In some embodiments, TTR means the time from the first dose of the compound to the first recording of response ≥ partial response (PR).

[0061] 6.1 Compounds In some embodiments, the methods provided herein include administering an FTI. In some embodiments, the FTI is tipifarnib, ronafarnib, FTI277, BMS214662, or compound (I), or a pharmaceutically acceptable form thereof. In some embodiments, the method includes administering compound (I), or an enantiomer (e.g., compound (II)), a mixture of enantiomers, or a racemate thereof (e.g., compound (III)), or a pharmaceutically acceptable form thereof, and optionally targeting a (b) KRAS inhibitor. In some embodiments, the methods provided herein include administering compound (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof. In some embodiments, the method includes administering a mixture of compound (I) and compound (II), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in a ratio of 1000:1 to 51:49. In some embodiments, the method includes administering compound (III), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0062] Preparations of compound (I), (II), or (III) provided herein are described in PCT international application PCT / US2022 / 80565 (published as PCT international application publication WO2023 / 102378).

[0063] In some embodiments, the KRAS inhibitor is a KRAS inhibitor that selectively inhibits one or more variant forms of KRAS, and arbitrarily, selectively inhibits variant forms more selectively than wild-type KRAS. In some embodiments, the KRAS inhibitor is a KRAS G12C inhibitor, a KRAS G12D inhibitor, a KRAS G12V inhibitor, a KRAS G13D inhibitor, a KRAS G12R inhibitor, a KRAS G12S inhibitor, or a pan-KRAS inhibitor (e.g., a pan-RAS inhibitor or a "RAS(ON)" inhibitor that targets the mutant and / or wild-type protein in its active (or "ON") GTP-bound state). In some embodiments, the KRAS inhibitor selectively inhibits the inactive (or "OFF") KRAS wild-type and KRAS mutant proteins. In some embodiments, the pan-KRAS inhibitor selectively inhibits more than one variant form of KRAS.

[0064] In some embodiments, the KRAS inhibitor is a KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is adagrasib (KRAZATI®, MRTX849, Amgen), sotrasib (LUMAKRAS®, AMG-510, Amgen), divaracib (GDC-6036, Genentech / Roche), linperlisib (YL-15293), RM007, D-1553 (InvestisBio), JDQ443 (Novartis), LY3537982 (Eli Lilly), LY3499446, ERAS-601, ERAS-007, BI 1823911 (Boehringer) Ingelheim), JAB-21822 (Grecilasib), MK-1084, MK-1086, MK-1087, L-15293, D3S-001, RMC-6291 (Revolution), HBI-2438, FMC-376 (Frontier), BBO-8520 (BridgeBio), ZG19018 (Suzhou Zelgen), UCT-001024 (1200 Pharma), TEB-17231 (Yingli Pharma's 280Bio unit), HYP-2A (Sichuan Huiyu), ABSK071 (Abbisko), IBI351 (GFH925, Innovent / Genfleet), ARS-853, ARS-1620, or JNJ-74699157 (ARS-3248). In some embodiments, the KRAS G12C inhibitor is adagracib. In some embodiments, the KRAS G12C inhibitor is sotracib. In some embodiments, the KRAS G12C inhibitor is adagracib and the cancer is NSCLC. In some embodiments, the KRAS G12C inhibitor is adagracib and the cancer is CRC. In some embodiments, the KRAS inhibitor is a KRAS G12C (off) inhibitor. In some embodiments, the KRAS inhibitor is a KRAS G12C (on) inhibitor.

[0065] In some embodiments, the KRAS inhibitor is a KRAS G12D inhibitor. In some embodiments, the KRAS G12D inhibitor is MRTX1133 (Mirati), TH-Z827 (Mao et al., Cell Discov. 2022, 8, 5), TH-Z835, KD-8, BI-KRAS12D1-3 (Boehringer Ingelheim), BI-KRASG12D3 (Boehringer Ingelheim, Hofmann et al., Cancer Discovery 2022, 12, 924), RMC-9805 (Revolution), ASP3082, ASP4396, LY3962673, INCB161734, HRS-4642, or QTX3046 (Quanta). In some embodiments, the KRAS G12D inhibitor is MRTX1133. In some embodiments, the KRAS G12D inhibitor is MRTX1133, and the cancer is pancreatic cancer or PDAC. In some embodiments, the KRAS G12D inhibitor is MRTX1133, and the cancer is CRC. In some embodiments, compound (I), when combined with a KRAS G12D inhibitor such as MRTX1133, induced an increase in the depth and / or duration of inhibition of ERK, p90, or mTOR phosphorylation (e.g., measured by S6K and S6 levels), or an increase in cell cycle arrest (measured by Rb phosphorylation) or cell death (measured by cleaved caspase 3).

[0066] In some embodiments, the KRAS inhibitor is a KRAS G12V inhibitor.

[0067] In some embodiments, the KRAS inhibitor is a KRAS G13D inhibitor.

[0068] In some embodiments, the KRAS inhibitor is a KRAS G12R inhibitor.

[0069] In some embodiments, the KRAS G12R inhibitor is KRAS G12R inhibitor 1 (Shokat). In some embodiments, the KRAS inhibitor is a KRAS G12S inhibitor.

[0070] In some embodiments, the KRAS G12S inhibitor is G12Si-5 (Shokat).

[0071] In some embodiments, the KRAS inhibitor is a pan-KRAS inhibitor. In some embodiments, the pan-KRAS inhibitor inhibits at least two variants of KRAS. In some embodiments, the pan-KRAS inhibitor inhibits at least one variant of KRAS and wild-type KRAS. In some embodiments, the pan-KRAS inhibitor is BI-2852, BI-pan-KRAS1-4 (BI1701963), RSC-1255, RMC-6236, RSC-1255, QTX3034 (Quanta), JAB-23425 (Beijing Jacobio), BI-2493, LY4066434, or VRTX-153 (VRise). In some embodiments, the pan-KRAS inhibitor is BI-2852. In some embodiments, the KRAS inhibitor is a pan-RAS inhibitor. In some embodiments, the pan-RAS inhibitor inhibits at least two variants of KRAS. In some embodiments, the pan-RAS inhibitor selectively inhibits at least two of KRAS, NRAS, and HRAS, or at least one variant of KRAS, NRAS, or HRAS. In some embodiments, the KRAS inhibitor is a pan-RAS inhibitor that is a RAS(on) inhibitor (selective for the activity or "on" state of the target protein). In some embodiments, the pan-RAS inhibitor is selective for the activity, GTO binding, or "on" state of both variants and wild-type variants of KRAS, NRAS, and HRAS. In some embodiments, the KRAS inhibitor is a pan-KRAS inhibitor that selectively inhibits wild-type and variant forms of KRAS in an inactive (or "off") state. In some embodiments, the pan-RAS inhibitor inhibits at least one variant form of KRAS and the wild-type form of KRAS. In some embodiments, the KRAS inhibitor inhibits KRAS G12D, wild-type KRAS, wild-type NRAS, and wild-type HRAS, or any combination thereof. In some embodiments, the pan-RAS inhibitor is RMC-6236. In some embodiments, the pan-RAS inhibitor is RSC-1255.

[0072] In some embodiments, the KRAS inhibitor inhibits KRAS G12D and KRAS G12V. In some embodiments, the pan-RAS inhibitor is RMC-6236, and the cancer is lung cancer, non-small cell lung cancer, pancreatic cancer, PDAC, or CRC. In some embodiments, the cancer is KRAS G12D, G12V, G12R, G12A, or mutated G12S, or G12D, G12V, or mutated G12R. In some embodiments, the cancer is CRC, and is a G13X and / or Q61X KRAS mutated cancer.

[0073] In some embodiments, the KRAS inhibitor is BI-2852, and the cancer is KRAS-amplifying gastric or esophageal cancer.

[0074] In some embodiments, the KRAS inhibitor is BI-1701963. In some embodiments, BI-1701963 inhibits both mutant and wild-type inactive KRAS forms.

[0075] 6.2 Pharmaceutical compositions, kits, and packaging In some embodiments, pharmaceutical compositions comprising compound (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient are provided herein. In some embodiments, the pharmaceutical composition comprises compound (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0076] In some embodiments, pharmaceutical compositions comprising a KRAS inhibitor and a pharmaceutically acceptable excipient are provided herein.

[0077] In some embodiments, pharmaceutical compositions comprising compound (I) or a pharmaceutically acceptable form thereof, an FTI, a KRAS inhibitor, and a pharmaceutically acceptable excipient are provided herein.

[0078] Pharmaceutical compositions can be prepared using techniques and procedures well known in the art (see, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Twelfth Edition 2021). The pharmaceutical compositions provided herein may be administered as a single dose or regularly at specific time intervals, such as once daily (QD) or twice daily (BID).

[0079] In some embodiments, the pharmaceutical composition contains approximately 0.1 to 1000 mg of compound (I), or FTI such as a pharmaceutically acceptable form thereof, for example, approximately 0.1 to 2.5 mg, 0.5 to 5 mg, 0.5 to 10 mg, 0.5 to 25 mg, 0.5 to 50 mg, 0.5 to 75 mg, 0.5 to 100 mg, 0.5 to 200 mg, 0.5 to 250 mg, 0.5 to 300 mg, 0.5 to 600 mg, 0.5 to 900 mg, 1 to 5 mg, 1 to 10 mg, 1 to 25 mg, 1 to 50 mg, 1 to 75 mg, 1 to 100 mg, 1 to 300 mg, 1 to 600 mg, 1 to 900 mg, 20 to 100 mg, 20 to 200 mg, 20 Contains free base equivalents selected from FTIs such as compound (I) in amounts of ~250 mg, 20~300 mg, 40~75 mg, 50~75 mg, 50~100 mg, 50~150 mg, 50~200 mg, 50~250 mg, 50~300 mg, 75~100 mg, 100~200 mg, 125~200 mg, 150~300 mg, 200~250 mg, 200~400 mg, 300~600 mg, 250~500 mg, 400~600 mg, 500~750 mg, 600~900 mg, 700~100 mg, 650~1000 mg, and 800~1000 mg, or its pharmaceutically acceptable form.In some embodiments, the pharmaceutical composition is approximately 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, approximately 1 mg, approximately 1.5 mg, approximately 1.6 mg, approximately 1.7 mg, approximately 1.8 mg, approximately 1.9 mg, approximately 2 mg, approximately 2.5 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg The formulation contains approximately 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, and approximately 1000 mg of compound (I) or a free base equivalent selected from FTIs such as a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical composition containing compound (I) or an FTI such as a pharmaceutically acceptable form thereof is formulated into tablets such as film-coated tablets. In some embodiments, a pharmaceutical composition containing compound (I), or an FTI such as a pharmaceutically acceptable form thereof, is formulated into a capsule.

[0080] In some embodiments, the pharmaceutical composition includes 10 to 1000 mg of a KRAS inhibitor (in terms of free base / acid equivalent), for example, an amount selected from 10 to 300 mg, 10 to 200 mg, 10 to 150 mg, 10 to 100 mg, 10 to 50 mg, 25 to 400 mg, 25 to 300 mg, 25 to 200 mg, 25 to 150 mg, 25 to 100 mg, 25 to 50 mg, 50 to 400 mg, 50 to 300 mg, 50 to 200 mg, 50 to 150 mg, 50 to 100 mg, 100 to 400 mg, 100 to 300 mg, 100 to 200 mg, 150 to 250 mg, 175 to 225 mg, 200 to 400 mg, and 200 to 300 mg. In some applications, the pharmaceutical composition is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 105 mg, approximately 110 mg, approximately 115 mg, approximately 120 mg, approximately 125 mg, approximately 130 mg, approximately 135 mg, approximately 140 mg, approximately 145 mg, approximately 150 mg, approximately 155 mg, approximately 1 Contains 60 mg, approximately 165 mg, approximately 170 mg, approximately 175 mg, approximately 180 mg, approximately 185 mg, approximately 190 mg, approximately 195 mg, approximately 200 mg, approximately 205 mg, approximately 210 mg, approximately 215 mg, approximately 220 mg, approximately 225 mg, approximately 230 mg, approximately 235 mg, approximately 240 mg, approximately 245 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 320 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, or approximately 400 mg. In some embodiments, the KRAS inhibitor is adaglacib, and the pharmaceutical composition optionally contains 200 mg of adaglacib as a tablet, and optionally contains colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, and microcrystalline cellulose. In some embodiments, the KRAS inhibitor is sotracib, and the pharmaceutical composition optionally contains 120 mg or 320 mg of sotracib as a tablet, and optionally contains microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate.

[0081] In some embodiments, pharmaceutical compositions are provided for administration to a subject in dosage forms such as tablets, capsules, microcapsules, pills, powders, granules, lozenges, suppositories, injections, syrups, patches, creams, lotions, ointments, gels, sprays, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions, containing an appropriate amount of the compound or a pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical compositions provided herein are in the form of tablets. In some embodiments, the pharmaceutical compositions provided herein are in the form of capsules.

[0082] It is understood that the precise dosage and duration of treatment are functions of the disease being treated and may be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test data. It should also be noted that the concentration and dosage values ​​may vary depending on the severity of the condition being alleviated. Furthermore, it should be understood that for any particular subject, specific drug regimens may be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition, and that the concentration ranges described herein are illustrative and not intended to limit the scope or practice of the claimed pharmaceutical composition.

[0083] The pharmaceutical composition is intended to be administered by appropriate routes, including but not limited to oral, parenteral, rectal, topically, locally, intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, mucous membrane, inhalation, or topically to the ear, nose, eye, or skin. The pharmaceutical composition is in liquid, semi-liquid, or solid form and is formulated in a manner suitable for each route of administration. In some embodiments, the pharmaceutical composition provided herein is administered orally. For oral administration, capsules and tablets can be formulated.

[0084] In some embodiments, a pharmaceutical kit is provided herein comprising (a) a FTI such as compound (I) or a pharmaceutically acceptable form thereof, and optionally (b) a KRAS inhibitor. In some embodiments, a pharmaceutical kit is provided herein comprising a pharmaceutical composition comprising (a) a pharmaceutically acceptable excipient, and optionally (b) a KRAS inhibitor, and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical kit further includes instructions detailing a dosing regimen for administering compound (I) or a pharmaceutically acceptable form thereof, and optionally for administering a KRAS inhibitor for one or more cycles. In some embodiments, the pharmaceutical kit includes a color-coded system detailing a dosing regimen for each drug for one or more cycles. In some embodiments, the pharmaceutical kit is pharmaceutical packaging.

[0085] In some embodiments, the pharmaceutical kit or pharmaceutical packaging includes instructions for administering the contents of the kit. For example, in some embodiments, the instructions may be color-coded in one color to indicate a dosing regimen for administering an FTI, such as compound (I) or a pharmaceutically acceptable form thereof, during a 28-day treatment cycle, for example, administering it once or twice daily on days 1-7, 1-7 and 15-21, 1-14, 1-21, or once or twice daily on each day of the 28-day treatment cycle, while different colors may be used to indicate a dosing regimen for administering a KRAS inhibitor during a 28-day treatment cycle, for example, administering a KRAS inhibitor once or twice daily on each day of the 28-day treatment cycle.

[0086] 6.3 Method, medication regimen and schedule 6.3.1 Therapeutic Use and Methods In some embodiments, methods for treating cancer in a subject are provided herein, comprising administering to the subject an FTI, such as compound (I) or a pharmaceutically acceptable form thereof. In some embodiments, methods for treating cancer in a subject are provided herein, comprising administering to the subject (a) an FTI, such as compound (I) or a pharmaceutically acceptable form thereof, and (b) a KRAS inhibitor. In some embodiments, the cancer is a KRAS-dependent cancer. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of an FTI, such as compound (I) or a pharmaceutically acceptable form thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a KRAS inhibitor. In some embodiments, the administration comprises administering to the subject a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable form thereof, or a KRAS inhibitor, or a combination thereof, and a pharmaceutically acceptable excipient.

[0087] In another embodiment, a method for delaying the emergence of resistance to a KRAS inhibitor in a subject with KRAS-dependent cancer, or for overcoming resistance to a KRAS inhibitor in a subject with KRAS-dependent cancer previously treated with a KRAS inhibitor, comprising administering to the subject (a) a compound (I), or a pharmaceutically acceptable form thereof, in combination with (b) a KRAS inhibitor, in an optional manner. In some embodiments, the subject has been previously treated with the same or different KRAS inhibitors and may be relapsed or refractory to such treatment. In some embodiments, the subject has not been previously treated with a KRAS inhibitor.

[0088] In some embodiments, cancer is a solid tumor. In some embodiments, cancer is an advanced solid tumor. In some embodiments, cancer is an adenocarcinoma. In some embodiments, cancer is lung cancer, pancreatic cancer, gynecological cancer, gastrointestinal cancer, breast cancer, neoplasm (metastatic neoplasm, germ cell cancer, plasma cell neoplasm, or myelodysplastic / myeloproliferative neoplasm), carcinoma of unknown primary origin (CUP), or leukemia. In some embodiments, cancer is leukemia or acute leukemia. In some embodiments, lung cancer is non-small cell lung cancer (NSCLC), non-squamous NSCLC, squamous NSCLC, or lung adenocarcinoma. In some embodiments, gastrointestinal cancers are colorectal cancer (CRC), colon cancer, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer, appendiceal cancer, small intestine cancer, stomach cancer, bile duct cancer, ampullary cancer, gallbladder cancer, gastric cancer, gastric adenocarcinoma, esophageal cancer, esophageal adenocarcinoma, urinary tract cancer, GI neuroendocrine tumor, or esophagogastric junction adenocarcinoma. In some embodiments, gynecological cancers are ovarian cancer, endometrial cancer, peritoneal cancer, or cervical cancer. In some embodiments, cancer is non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma.

[0089] In some embodiments, KRAS-dependent cancers include the KRAS G12C mutation and are NSCLC, lung adenocarcinoma, non-squamous NSCLC, squamous NSCLC, CRC, pancreatic cancer, PDAC, CUP, endometrial cancer, ovarian cancer, cervical cancer, gastric cancer, gastric adenocarcinoma, bile duct cancer, esophageal cancer, stomach cancer, small intestine cancer, appendiceal cancer, biliary tract cancer (BTC), ampullary cancer, gallbladder cancer, breast cancer, or metastatic neoplasms. In some embodiments, KRAS-dependent cancers include the KRAS G12C mutation and are NSCLC, CRC, or PDAC. In some embodiments, KRAS-dependent cancers include the KRAS G12C mutation and are NSCLC. In some embodiments, KRAS-dependent cancers include the KRAS G12C mutation and are CRC. In some embodiments, KRAS-dependent cancers include the KRAS G12C mutation and are PDAC. In some embodiments, KRAS-dependent cancer is an advanced solid tumor containing a KRAS G12C mutation.

[0090] In some embodiments, KRAS-dependent cancers include the KRAS G12D mutation and are pancreatic cancer, PDAC, CRC, NSCLC, non-squamous NSCLC, CUP, endometrial cancer, ovarian cancer, small intestinal adenocarcinoma, appendiceal adenocarcinoma, gastric cancer, gastric adenocarcinoma, or bile duct cancer. In some embodiments, KRAS-dependent cancers include the KRAS G12D mutation and are pancreatic cancer, PDAC, CRC, NSCLC, gastric cancer, gastric adenocarcinoma, or bile duct cancer. In some embodiments, KRAS-dependent cancers include the KRAS G12D mutation and are pancreatic cancer, PDAC, CRC, or NSCLC. In some embodiments, KRAS-dependent cancers include the KRAS G12D mutation and are PDAC. In some embodiments, KRAS-dependent cancers include the KRAS G12D mutation and are CRC. In some embodiments, KRAS-dependent cancers include the KRAS G12D mutation and are NSCLC.

[0091] In some embodiments, KRAS-dependent cancers include KRAS G12V mutations and are CRC, NSCLC, non-squamous NSCLC, PDAC, CUP, endometrial cancer, ovarian cancer, bile duct cancer, small intestinal adenocarcinoma, appendiceal adenocarcinoma, gastrointestinal cancer, esophageal cancer, and stomach cancer. In some embodiments, KRAS-dependent cancers include KRAS G12V mutations and are CRC, NSCLC, or PDAC.

[0092] In some embodiments, the KRAS-dependent cancer is pancreatic cancer, PDAC, or CUP, and includes a KRAS G12R mutation. In some embodiments, the KRAS-dependent cancer is bile duct cancer, and includes a KRAS G12R mutation. In some embodiments, the KRAS-dependent cancer is pancreatic cancer, or PDAC, and includes a KRAS G12R mutation.

[0093] In some embodiments, KRAS-dependent cancers include the KRAS G13D mutation and are CRC, non-squamous NSCLC, or endometrial cancer.

[0094] In some embodiments, KRAS-dependent cancers include more than one KRAS mutation and are NSCLC, CRC, pancreatic cancer, PDAC, or cholangiocarcinoma.

[0095] KRAS mutations account for the majority of RAS changes in PDAC, CRC, NSCLC, and lung adenocarcinoma. In some embodiments, the KRAS-dependent cancer is PDAC, CRC, NSCLC, or lung adenocarcinoma. In some embodiments, the KRAS-dependent cancer is PDAC. In some embodiments, the KRAS-dependent cancer is CRC. In some embodiments, the KRAS-dependent cancer is NSCLC. In some embodiments, the KRAS-dependent cancer is lung adenocarcinoma.

[0096] In some embodiments, KRAS-dependent cancers are KRAS-amplifying. In some embodiments, KRAS-dependent cancers are germ cell tumors, esophageal adenocarcinoma, gastric adenocarcinoma, bladder cancer, ovarian cancer, peritoneal cancer, gastric cancer, or squamous cell NSCLC.

[0097] In some embodiments, cancer may be diagnosed by a person skilled in the art, for example, by analysis of plasma or tissue biopsy from a subject, for example, a tumor tissue biopsy. In some embodiments, the cancer is in remission. In some embodiments, the cancer is early, advanced, locally advanced, recurrent, metastatic, refractory, recurrent, or a combination thereof. In some embodiments, the cancer is locally advanced or metastatic. In some embodiments, the cancer is early. In some embodiments, the cancer is metastatic or locally advanced. In some embodiments, the cancer is recurrent. In some embodiments, the cancer is refractory. In some embodiments, the cancer is metastatic.

[0098] In some embodiments, the cancer has been previously treated with first-line therapy, such as surgery, systemic therapy (e.g., chemotherapy, immunotherapy), or radiation, or a combination thereof. In some embodiments, the cancer has been previously treated with systemic therapy (e.g., chemotherapy or immunotherapy or other systemic therapy). Chemotherapy may include treatment with cisplatin or carboplatin, and may be optionally combined with paclitaxel, docetaxel, gemcitabine, etoposide, or pemetrexed. Immunotherapy may include treatment with PD-1 / PD-L1 inhibitors (e.g., nivolumab, pembrolizumab, cemiplimab, atezolizumab, or durvalumab) or CTLA-4 inhibitors (e.g., ipiltumumab or tremelimumab). In some embodiments, the cancer has been previously treated with second-line therapy, such as chemotherapy, immunotherapy, or radiation, or a combination thereof. In some embodiments, the cancer has been previously treated with immunotherapy or an EGFR signaling pathway inhibitor, e.g., an anti-EGFR monoclonal antibody, e.g., cetuximab. In some embodiments, the cancer is resistant to, refractory to, or has relapsed after treatment with immunotherapy or an EGFR signaling pathway inhibitor, e.g., an anti-EGFR monoclonal antibody, e.g., cetuximab. In some embodiments, the cancer has been previously treated with a KRAS inhibitor. In some embodiments, the prior systemic therapy is a KRAS inhibitor, which may be the same as or different from the KRAS inhibitor administered with the FTI. In some embodiments, the patient relapsed after treatment with the prior KRAS inhibitor. In some embodiments, the patient was refractory to the prior KRAS inhibitor. In some embodiments, the prior KRAS inhibitor is adagrasib, and the KRAS inhibitor to be administered with the FTI is adagrasib. In some embodiments, the prior KRAS inhibitor was sotrasib. In some embodiments, the cancer has been previously treated with local or regional disease therapies such as surgery, radiation, chemoradiation, induction chemotherapy, or a combination thereof.In some embodiments, the subject has received at least one prior treatment for cancer, and optionally, at least one prior treatment has failed to treat the cancer, failed to slow, halt or prevent the progression of the cancer, or failed to alleviate or reduce the severity of at least one cancer-related symptom. In some embodiments, at least one prior treatment is either a first-line therapy or a second-line therapy.

[0099] In some embodiments, the combination therapy methods disclosed herein provide synergistic or therapeutic benefits, for example, by improving efficacy, inhibiting tumor growth, or inducing tumor regression, better than any of the compound therapies alone. In some embodiments, the methods provided herein improve efficacy, inhibit tumor growth, or induce tumor regression better than the combined results of each single compound therapy. In some embodiments, the methods provided herein delay, halt, or prevent the progression of cancer or tumor growth. In some embodiments, the methods provided herein reduce tumor size or growth rate, delay the appearance of primary or secondary tumors, delay the occurrence of primary or secondary tumors, reduce the occurrence of primary or secondary tumors, or halt tumor growth. In some embodiments, the methods provided herein alleviate tumor-related symptoms. In some embodiments, the methods provided herein delay or reduce the severity of cancer-related secondary effects. In some embodiments, the methods provided herein increase time to progression (TTP), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), overall response rate (ORR), duration of response (DoR), disease control rate (DCR, a combination of complete response (CR), partial response (PR), and stable disease (SD)), CR rate, or SD rate, or decrease time to response (TTR), compared to no therapy or compound therapy alone. In some embodiments, the methods provided herein increase TTP, PFS, EFS, OS, ORR, DoR, DCR, CR rate, or SD rate, or decrease TTR, compared to first-line therapy, second-line therapy, chemotherapy, local or localized disease therapy, supportive care, or no therapy.

[0100] In some embodiments, the methods provided herein mitigate KRAS inhibitor resistance. In some embodiments, mitigate includes preventing the onset or emergence of resistance, slowing the progression of resistance, increasing the time to the emergence of resistance, or overcoming resistance. In some embodiments, the methods provided herein reduce the risk of recurrence, for example, delaying recurrence to KRAS inhibitor therapy. In some embodiments, the cancer has been previously treated with a KRAS inhibitor and is either refractory to such therapy or has relapsed to such therapy. In such cases, the methods mitigate resistance to KRAS inhibitors and include treatment with FTI and either the same or a different KRAS inhibitor as the previous therapy. In some embodiments, the cancer has been previously treated with two different KRAS inhibitors and is either refractory or has relapsed after such treatment.

[0101] In some embodiments, the therapeutically effective dose of compound (I), or a pharmaceutically acceptable form thereof, such as an FTI, and / or KRAS inhibitor, may depend on the absorption, tissue distribution, metabolism, and excretion rate of the active compound, the dosing schedule, the amount administered, and the specific formulation, as well as other factors known to those skilled in the art. The therapeutically effective dose is determined empirically by testing the compound in the in vitro and in vivo systems described herein, and then the dosage for humans can be estimated therefrom.

[0102] 6.3.2 Dosage and regimen In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered before, after, or concurrently with the KRAS inhibitor, optionally during one or more treatment cycles, e.g., one or more 28-day cycles. In some embodiments, the administration of the two drugs is simultaneous or sequential, or independently, sequential, intermittent, or cyclical.

[0103] In some embodiments, the methods provided herein involve administering a subject to an FTI (or a pharmaceutical composition containing the same), such as compound (I) or a pharmaceutically acceptable form thereof. In some embodiments, the combined methods provided herein involve administering to a subject (a) an FTI, such as compound (I) or a pharmaceutically acceptable form thereof, and (b) a KRAS inhibitor. In some embodiments, the methods provided herein involve administering a daily dose of one or both of the drugs to a subject. The daily dose of each drug may be administered using one or more dosage forms, for example, one, two, or three tablets or capsules. The multiple dosage forms may contain the same or different amounts of the active component, but the sum of the amounts is the desired daily dose of the active component.

[0104] In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject at a daily dose of approximately 0.1 to 2400 mg (free base equivalent) per day, according to the methods provided herein. In some embodiments, the daily dose of FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is approximately 0.1-2.5 mg, 0.5-5 mg, 0.5-10 mg, 0.5-25 mg, 0.5-50 mg, 0.5-75 mg, 0.5-100 mg, 0.5-300 mg, 0.5-600 mg, 0.5-1200 mg, 1-5 mg, 1-10 mg, 1-25 mg, 1-50 mg, 1-75 mg, 1-100 mg, 1-300 mg, 1-600 mg, 1-1200 mg, 1-2400 mg, 20-100 mg, 40-75 mg, 50-75 mg, 50-100 mg, 5 The dosage is selected from 0-150mg, 75-100mg, 100-200mg, 125-200mg, 150-300mg, 200-250mg, 200-400mg, 300-600mg, 250-500mg, 400-600mg, 500-750mg, 600-900mg, 700-100mg, 650-1000mg, 800-1200mg, 900-1500mg, 1000-1600mg, 1000-2000mg, 1200-1600mg, 1500-2000mg, 1500-2400mg, 1800-2400mg, and 2000-2400mg (free base equivalent).In some embodiments, the daily dose of FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is approximately 0.5 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, and 95 mg per day. About 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg, about 275mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400mg, about 425mg, about 450mg, about 475m g, about 500mg, about 525mg, about 550mg, about 575mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, about 950mg, about 1000mg, about 1050mg, about 1100mg, The amounts are approximately 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, and 2400 mg (free base equivalent). In some embodiments, the daily dose is administered in one, two, three, or four doses per day, for example, once or twice per day, for example, once per day. For example, in the case of twice-daily administration, the daily dose is divided into two equal or unequal doses administered to the subject during the day, such as once in the morning and once in the evening.

[0105] In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject at a daily dose of approximately 0.01 to 50 mg / kg body weight (free base equivalent) per day, according to the methods provided herein. In some embodiments, the dose of FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is selected from approximately 0.01–1 mg / kg, 0.01–2.5 mg / kg, 0.01–5 mg / kg, 0.1–5 mg / kg, 0.1–10 mg / kg, 0.1–20 mg / kg, 1–30 mg / kg, 1–40 mg / kg, 5–50 mg / kg, 10–50 mg / kg, 15–50 mg / kg, 20–50 mg / kg, 25–50 mg / kg, 30–50 mg / kg, 40–50 mg / kg, 20–40 mg / kg, and 20–25 mg / kg body weight (free base equivalent) per day. In some embodiments, the daily dose is divided into two doses administered to the subject according to the method provided herein. In some embodiments, the daily dose is administered in one, two, three, or four doses per day, for example, once or twice per day, or for example, once per day. For example, in the case of twice-daily dosing, the daily dose is divided into two equal or unequal doses administered to the subject during the day, such as once in the morning and once in the evening.

[0106] In some embodiments, the dose of the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject once a month, once a week, or once a day, according to the methods provided herein. In some embodiments, the daily dose of the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject for one or more cycles, for example, once or twice a day for one or more cycles, for example, once a day for one or more cycles. In some embodiments, the daily dose of the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject one, two, three, or four times a day consecutively for an unlimited number of days, or until remission is achieved in the subject or until a relapse occurs. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable salt thereof, is administered to the subject in a QD for one or more cycles, for example, a QD for two or more cycles, a QD for three or more cycles, or a QD for four or more cycles. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable salt thereof, is administered to the subject in BIDs for one or more cycles, for example, in BIDs for two or more cycles, in BIDs for three or more cycles, or in BIDs for four or more cycles. In some embodiments, the cycle (which may also be referred to herein as a treatment cycle or maintenance cycle) is 1 day, 7 days, 14 days, 21 days, or 28 days. In some embodiments, the treatment cycle is a 28-day cycle. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable salt thereof, is administered to the subject in QDs for one or more 28-day cycles. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable salt thereof, is administered to the subject in BIDs for one or more 28-day cycles. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable salt thereof, is administered to the subject once or twice daily every other week during the 28-day cycle, with a rest period every other week.

[0107] In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject one, two, three, or four times per day for one or more cycles, on days 1-7, 1-7 and 15-21, 1-14, 1-21, or each day (i.e., days 1-28) of a 28-day cycle, according to the methods provided herein. For example, in some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject in a QD for one or more cycles, on days 1-7, 1-7 and 15-21, 1-14, 1-21, or each day (i.e., days 1-28) of a 28-day cycle. For example, in some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject by BID for one or more cycles, on days 1-7, days 1-7 and days 15-21, days 1-14, days 1-21, or each day (i.e., days 1-28) of a 28-day cycle. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject by QD for one or more cycles, on days 1-7 of a 28-day cycle. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject by BID for one or more cycles, on days 1-7 of a 28-day cycle. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject by QD for one or more cycles, on days 1-7 and days 15-21 of a 28-day cycle. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject via BID on days 1–7 and 15–21 of a 28-day cycle for one or more cycles. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject via QD on days 1–14 of a 28-day cycle for one or more cycles. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject via BID on days 1–14 of a 28-day cycle for one or more cycles.In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject by QD on days 1 to 21 of a 28-day cycle for one or more cycles. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject by BID on days 1 to 21 of a 28-day cycle for one or more cycles. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject by QD on each day of a 28-day cycle (i.e., days 1 to 28) for one or more cycles. In some embodiments, the FTI, such as compound (I) or a pharmaceutically acceptable form thereof, is administered to the subject by BID on each day of a 28-day cycle (i.e., days 1 to 28) for one or more cycles.

[0108] In some embodiments, the KRAS inhibitor is administered to the subject at a daily dose of 10 to 2000 mg per day. In some embodiments, the daily dose of the KRAS inhibitor administered to the subject is selected from approximately 10 to 300 mg, approximately 50 to 400 mg, approximately 200 to 400 mg, approximately 500 to 1500 mg, approximately 800 to 1200 mg, or approximately 1100 to 1500 mg per day. In some embodiments, the daily dose of the KRAS inhibitor is administered to the subject in one, two, three, or four doses per day, for example, once or twice per day, for example, once per day. In some embodiments, the KRAS inhibitor is adaglasive, administered at a daily dose of approximately 1200 mg, with optional administration of approximately 600 mg twice daily. In some embodiments, the KRAS inhibitor is adaglasib, administered at a daily dose of approximately 800 mg, with optional doses of approximately 400 mg twice daily. In some embodiments, the KRAS inhibitor is sotrasib, administered at a daily dose of approximately 960 mg, with optional doses of twice daily. In some embodiments, adaglasib is administered in 200 mg tablets, for example, three 200 mg tablets twice daily. In some embodiments, sotrasib is administered in 120 mg or 320 mg tablets, for example, three 320 mg tablets or eight 120 mg tablets.

[0109] In some embodiments, the daily dose of the KRAS inhibitor is administered to the subject daily for one or more cycles according to the method provided herein. In some embodiments, the daily dose of the KRAS inhibitor is divided into two doses administered to the subject according to the method provided herein. In some embodiments, the daily dose of the KRAS inhibitor is administered one, two, three, or four times per day for one or more cycles, for example, once or twice per day for one or more cycles, for example, once per day for one or more cycles. In some embodiments, the KRAS inhibitor is administered to the subject once, two, three, or four times per day consecutively for an unlimited number of days, or until remission is achieved in the subject. In some embodiments, the KRAS inhibitor is administered to the subject once daily (QD) for one or more cycles, for example, QD for two or more cycles, QD for three or more cycles, or QD for four or more cycles. In some embodiments, the KRAS inhibitor is administered to the subject twice daily (BID) for one or more cycles, for example, BID for two or more cycles, BID for three or more cycles, or BID for four or more cycles. In some embodiments, the cycle (e.g., treatment cycle or maintenance cycle) is 1 day, 7 days, 14 days, 21 days, or 28 days. In some embodiments, the treatment cycle is a 28-day cycle. In some embodiments, the KRAS inhibitor is administered to the subject once daily for one or more 28-day cycles. In some embodiments, the KRAS inhibitor is administered to the subject twice daily for one or more 28-day cycles.

[0110] In some embodiments, compound (I), or a pharmaceutically acceptable form thereof, or an FTI, and a KRAS inhibitor are administered to the subject simultaneously or sequentially. In some embodiments, compound (I), or a pharmaceutically acceptable form thereof, or an FTI, is administered to the subject before administration of the KRAS inhibitor. In some embodiments, compound (I), or a pharmaceutically acceptable form thereof, or an FTI, is administered to the subject after administration of the KRAS inhibitor. In some embodiments, compound (I), or a pharmaceutically acceptable form thereof, or an FTI, is administered to the subject in a QD or BID on days 1-7, 1-7 and 15-21, 1-14, 1-21, or each day of a 28-day treatment cycle, and the KRAS inhibitor is administered in a QD or BID on each day of the 28-day treatment cycle.

[0111] In some embodiments, the cancer was previously treated with a KRAS inhibitor and was refractory to such treatment or relapsed after such treatment, and the subject discontinued therapy with such drug for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 6 months before initiating treatment according to the method described herein. In some embodiments, the prior KRAS inhibitor is sotrasib. In some embodiments, the prior KRAS inhibitor is adagrasib.

[0112] In some embodiments, the combination of a KRAS inhibitor with an FTI such as compound (I), or a pharmaceutically acceptable form thereof, is administered in further combination with an additional anticancer agent. In some embodiments, the additional anticancer agent is an immunotherapy agent, an anti-EGFR monoclonal antibody, an EGFR signaling pathway inhibitor, cetuximab, panitumumab, chemotherapy, a platinum-based anticancer agent (e.g., cisplatin or carboplatin), leucovorin, fluorouracil, a topoisomerase inhibitor (e.g., irinotecan or topotecan), a taxane (e.g., paclitaxel, docetaxel, or nab-paclitaxel), gemcitabine, etoposide, pemetrexed, vinorelbine, or a VEGF inhibitor (e.g., bevacizumab). The following are selected from rhamcirumab, EGFR inhibitors (e.g., osimertinib, afatinib, erlotinib, dacomitinib, gefitinib, panitumumab, cetuximab, or amivantamab), ALK inhibitors (e.g., alectinib, brigatinib, lorlatinib, ceritinib, or crizotinib), ROS1 inhibitors, BRAF inhibitors (e.g., dabrafenib, trametinib, or vemurafenib), SHP2 inhibitors (e.g., TNO155, JAB-3312), SOS1 inhibitors, and radiation, as well as combinations thereof.

[0113] 7. Examples method: 3D Spheroid Growth Assay Cells were seeded at a density of 2,000 cells / well in 96-well ultra-low adhesion plates. Cells were centrifuged at 1000 rpm for 2 minutes to form spheroids. The following day, spheroids were treated with adaglacib and tipifarnib or compound (I). Baseline growth was measured using a 3D Cell Titer Glo (CTG) reagent (Promega). Spheroids were incubated with the drugs for 7 days, and spheroid growth was evaluated by performing a final CTG reading.

[0114] Dox-inducible lentivirus system Cells were transduced with shScramble (shControl), shRHEB#1, and shRHEB#2 lentiviruses (Transomic), and selected with 2 μg / mL promycin for 5 days. Stable cell lines were pretreated with 1 μg / mL doxycycline for 72 hours. Cells were seeded at a density of 2,000 cells / well in 96-well ultra-low adhesion plates. Cells were centrifuged at 1000 rpm for 2 minutes to form spheroids. The following day, spheroids were treated with adagrasiv. Spheroids were treated with doxycycline every 3 days. 3D CTG readings were performed on days 0, 3, 5, 7, and 10 to evaluate spheroid growth.

[0115] siRNA transfection NCI-H2122 cells (500,000) were seeded in 60 mm dishes and transfected with Dharmacon ON-TARGETplus siRNA SMARTPool (Horizon Discovery) against RHEB using Lipofectamine RNAiMAX (ThermoFisher). After incubation for 72 hours, the cells were collected for immunoblotting to allow for RHEB expression depletion.

[0116] Immunoblotting For immunoblotting of 2D-grown cell lines, 2 million cells were plated on a 10 cm dish. For 3D immunoblotting, 10,000 cells were plated on a 96-well ultra-low adhesion plate, and the cells were centrifuged at 1000 rpm for 2 minutes to form spheroids. 24 spheroids were pooled together for each sample. Cells were washed once with PBS and resuspended in RIPA buffer supplemented with 1× cell lysis buffer (Cell Signaling Technology #9803) or Halt protease inhibitor cocktail (Thermo Scientific #78430). Cell lysates were prepared on ice by short-term sonication or vortex agitation. Tumor lysates were prepared by adding tumor fragments to a hard tissue homogenization tube (2 mL reinforced polypropylene tube) containing RIPA buffer and five 2.8 mm ceramic beads (Fisher Scientific). The tumors were then homogenized at 4.5 m / s for 30 seconds using a bead mill. The lysates were clarified by centrifugation (maximum speed, 10 minutes), and the protein concentration was determined by BCA assay (Pierce). 20–60 μg of the lysates were loaded onto 4–12% Bis-Tris gels (NuPAGE, Invitrogen) for electrophoresis and immunoblotting.

[0117] Xenotransplant model The following human patient-derived xenograft (PDX) models were used in these studies: LU2512 (non-small cell lung cancer KRAS G12C model), PA1383 (pancreatic cancer KRAS G12C model), CR6256 (colorectal cancer KRAS G12C model), CR6243 (colorectal cancer KRAS G12D model), CR3262 (colorectal cancer KRAS G12D model), CR1245 (colorectal cancer KRAS G12D model), PA0787 (pancreatic cancer KRAS G12D model) (Crown Bioscience, Beijing), and PA-07-0041 (pancreatic cancer KRAS G12V model) (WuXi, Shanghai), all in female BALB / c nude mice.

[0118] The following cell-derived xenograft (CDX) models were used in these studies: NCI-H2122 (BALB / c nude), NCI-H2030 (NOD / SCID), and NCI-H358 (NOD / SCID) KRAS G12C human non-small cell lung cancer, and MIA PaCa-2 (BALB / c nude) KRAS G12C human pancreatic cancer, SW1990 (NOD / SCID) KRAS G12D human pancreatic cancer, and SW837 (NOD / SCID) KRAS G12C human colorectal cancer (Crown Bioscience, Beijing); as well as NCI-H2030 (BALB / c nude) KRAS G12C human non-small cell lung cancer, GP2D (BALB / c nude) KRAS G12D human colorectal cancer, and Capan-1 KRAS G12V human pancreatic cancer (WuXi, Shanghai).

[0119] About the PDX model: Tumor fragments were collected from stock mice and used for inoculation into mice. A primary human tumor xenograft model tumor fragment (2-3 mm in diameter) was subcutaneously inoculated into the upper right flank of each mouse to induce tumor development. The average tumor size was approximately 300-400 mm. 3 Randomization was initiated when the patient reached a certain level. The treatment period was 4 to 8 weeks.

[0120] For NCI-H2122, NCI-H2030, and NCI-H358 CDX models, tumor cells were maintained in vitro at 37°C in an atmosphere of 5% CO2 air using RPMI-1640 supplemented with 10% fetal bovine serum. Cells in the exponential growth phase were harvested and quantified by a cell counter before tumor inoculation. 1 × 10⁶ cells per mouse were inoculated into the upper right flank region of each mouse in 0.1 mL of PBS mixed with Matrigel (1:1) for tumor development. 7 (NCI-H2122), 1-2 x 10 in 0.2-0.25 mL of PBS 7 (NCI-H2030), or 5x10 in 0.1 mL of PBS 6 Tumor cells of (NCI-H358) were subcutaneously inoculated. The average tumor size was approximately 300-400 mm. 3 (NCI-2122 and NCI-H358) or 300-500mm3 Randomization was initiated when the (NCI-H2030) threshold was reached.

[0121] For GP2D, MIA PaCa-2, SW1990, and SW837 CDX models: Tumor cells were maintained in vitro at 37°C in a 5% CO2 atmosphere in air (GP2D, MIA PaCa-2, and SW837) or in 100% air (SW1990) using DMEM (GP2D and MIA PaCa-2) or L-15 (SW1990 and SW837) supplemented with 10% fetal bovine serum. Cells were harvested during the exponential growth phase and quantified by a cell counter before tumor inoculation. Unless otherwise specified, 5 x 10⁶ cells per mouse were inoculated in 0.1 mL of PBS mixed with Matrigel (1:1) for tumor development in the upper right flank region of each mouse. 6 Tumor cells of (MIA PaCa-2 and SW837) were subcutaneously inoculated. The average tumor size was approximately 400-500 mm. 3 (MIA PaCa-2) or 300-400mm 3 Randomization was initiated when the patient reached (SW837, SW1990, and GP2D).

[0122] Randomization was performed using the "Matched distribution" method (StudyDirector® software, version 3.1.399.19). The day of randomization was designated as day 0. Treatment was initiated on the same day as randomization (day 0) according to the study design. After tumor inoculation, animals were checked daily for morbidity and mortality. During routine observation, animals were checked for tumor growth and any effects of treatment on behavior, including motility, food and water consumption, weight gain / loss (weight was measured three times a day per week after randomization), eye / hair tangles, and any other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal. After randomization, tumor volume was measured three times a week in two dimensions using calipers, and the volume was expressed in mm³ using the formula: V=(L×W×W) / 2 3The values ​​were expressed as follows: V = tumor volume, L = tumor length (longest tumor dimension), and W = tumor width (longest tumor dimension perpendicular to L). Dosage and measurement of tumors and body weight were performed in a laminar flow cabinet. Body weight and tumor volume were measured using Study Director® software (version 3.1.399.19). Tumor samples were collected for all groups 2 hours after the last dose. Each tumor was divided into two fragments. Half was rapidly frozen for protein analysis, and the other half was fixed for histological study.

[0123] In vivo drug therapy NCI-H2122, LU2512, and CR6256 xenografts were treated orally with the following: Control vehicle, QD; tipifarnib, 60 mg / kg (aqueous suspension), BID; compound (I), 15 mg / kg (aqueous suspension), BID; adaglasib, 100 mg / kg (suspension in 10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; sotrasib, 100 mg / kg (suspension in 2% HPMC and 1% Tween 80), QD; tipifarnib, 60 mg / kg, BID, plus adaglasib, 100 mg / kg, QD; tipifarnib, 60 mg / kg, BID, plus sotrasib, 100 mg / kg, QD; or compound (I), 15 mg / kg, BID, plus adaglasib, 100 mg / kg, QD.

[0124] NCI-H2030, PA1383, and CR6243 xenografts were orally treated as follows: control vehicle, BID; compound (I), 10 mg / kg (aqueous suspension), BID; adaglacib, 100 mg / kg (suspension in 10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; or compound (I), 10 mg / kg, BID, plus adaglacib, 100 mg / kg, QD.

[0125] MIA PaCa-2 and SW837 xenografts were orally treated as follows: control vehicle, BID; compound (I), 20 mg / kg (aqueous suspension), BID; adaglacib, 100 mg / kg (suspension in 10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; or compound (I), 20 mg / kg, BID, plus adaglacib, 100 mg / kg, QD.

[0126] NCI-H358 xenografts were orally treated with the following: Control vehicle (10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; tipifarnib, 60 mg / kg (aqueous suspension), BID; adaglasib, 100 mg / kg (suspension in 10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; adaglasib, 20 mg / kg (suspension in 10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; sotrasib, 30 mg / kg (suspension in 2% HPMC and 1% Tween 80), QD; sotrasib, 10 mg / kg (suspension in 2% HPMC and 1% Tween 80) (80 mg suspension), QD; tipifarnib, 60 mg / kg, BID, plus adaglasib, 100 mg / kg, QD; tipifarnib, 60 mg / kg, BID, plus adaglasib, 20 mg / kg, QD; tipifarnib, 60 mg / kg, BID, plus sotrasib, 30 mg / kg, QD; or tipifarnib, 60 mg / kg, BID, plus sotrasib, 10 mg / kg, QD.

[0127] NCI-H2030 xenografts (WuXi) were orally treated with the following: control vehicle, BID; tipifarnib, 60 mg / kg (aqueous suspension), BID; compound (I), 15 mg / kg (aqueous suspension), BID; adaglasib, 30 mg / kg (suspension in 5% DMSO + 40% PEG-400), QD; adaglasib, 100 mg / kg (suspension in 5% DMSO + 40% PEG-400), QD; sotrasib, 100 mg / kg (suspension in 5% DMSO + 40% PEG-400), QD; tipifarnib, 60 mg / kg, BID, plus adaglacib, 30 mg / kg, QD; tipifarnib, 60 mg / kg, BID, plus adaglacib, 100 mg / kg, QD; tipifarnib, 60 mg / kg, BID, plus sotrasib, 100 mg / kg, QD; compound (I), 15 mg / kg, BID, plus adaglacib, 30 mg / kg, QD; or compound (I), 15 mg / kg, BID, plus adaglacib, 100 mg / kg, QD.

[0128] PA0787 and CR3262 xenografts were treated as follows: control vehicle, PO, BID; tipifarnib, 80 mg / kg (aqueous suspension), PO, BID; compound (I), 20 mg / kg (aqueous suspension), PO, BID; MRTX1133, 30 mg / kg (aqueous suspension), IP, BID; tipifarnib, 80 mg / kg, PO, BID, plus MRTX1133, 30 mg / kg, IP, BID; or compound (I), 20 mg / kg, PO, BID, plus MRTX1133, 30 mg / kg, IP, BID.

[0129] CR1245 xenografts were treated as follows on days 0-14 of the study: control vehicle, PO, BID; compound (I), 10 mg / kg (aqueous suspension), PO, BID; MRTX1133, 10 mg / kg (suspension in 10% Captisol, 50 mM citrate buffer, pH 5.0), IP, BID; or compound (I), 10 mg / kg, PO, BID, plus MRTX-1133, 10 mg / kg, IP, BID. On days 14-28 of the study, CR1245 xenografts were treated as follows: Control vehicle, PO, BID; Compound (I), 20 mg / kg (aqueous suspension), PO, BID; MRTX1133, 30 mg / kg (suspension in 10% Captisol, 50 mM citrate buffer, pH 5.0), IP, BID; or Compound (I), 20 mg / kg, PO, BID, plus MRTX-1133, 30 mg / kg, IP, BID.

[0130] SW1990 xenografts were treated as follows: control vehicle, PO, BID; compound (I), 20 mg / kg (aqueous suspension), PO, BID; MRTX1133, 10 mg / kg (suspension in 10% Captisol, 50 mM citrate buffer, pH 5.0), IP, BID; or compound (I), 20 mg / kg, PO, BID, plus MRTX-1133, 10 mg / kg, IP, BID.

[0131] In the first GP2D model experiment, GP2D xenografts (WuXi) were treated as follows: control vehicle, PO, BID; compound (I), 20 mg / kg (aqueous suspension), PO, BID; MRTX1133, 20 mg / kg (suspension in 10% Captisol, 50 mM citrate buffer, pH 5.0), IP, BID; cetuximab, 0.25 mg / dose (saline) IP, Q3D; compound (I), 20 mg / kg, PO, BID, plus MRTX1133, 20 mg / kg, IP, BID; or cetuximab, 0.25 mg / dose (saline) IP, every 3 days (Q3D), plus MRTX1133, 20 mg / kg, IP, BID.

[0132] In the second GP2D model experiment, female 6-8 week old BALB / c nude mice (GemPharmatech) were subjected to 10 × 10⁶ injections to induce tumor development. 6 The cells were subcutaneously inoculated into the right flank. The average tumor size was approximately 300 mm. 3 When the animals reached a certain level, they were randomized to 11 treatment groups of 8 animals each. GP2D tumors were treated as follows: control vehicle (10% HP-β-CD and 0.1% Tween 80), PO, BID; compound (I), 10 mg / kg (aqueous suspension), PO, BID; MRTX1133, 10 mg / kg (suspension in 10% Captisol, 50 mM citrate buffer, pH 5.0), IP, BID; RMC-6236, 10 mg / kg or 25 mg / kg (suspension in 10% Captisol, 50 mM citrate buffer, pH 5.0), PO, QD; cetuximab, 0.25 mg / dose (saline), IP, Q3D Compound (I), 10 mg / kg, plus MRTX1133, 10 mg / kg; Compound (I), 10 mg / kg, plus RMC-6236, 10 mg / kg; Compound (I), 10 mg / kg, plus RMC-6236, 25 mg / kg; Cetuximab, 0.25 mg / dose, plus MRTX1133, 10 mg / kg; or Compound (I), 10 mg / kg, plus cetuximab, 0.25 mg / dose, plus MRTX1133, 10 mg / kg.

[0133] Direct comparison of various combinations with adagrasib: NCI-H2122 KRAS G12CNSCLC xenografts were orally treated with the following: control vehicle (10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; compound (I), 10 or 20 mg / kg (aqueous suspension), BID; adaglacib, 100 mg / kg (in 10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; compound (I), 10 or 20 mg / kg, BID, in addition to adaglacib, 100 mg / kg, QD; RMC-4550 (SHP2 inhibitor), 30 mg / kg ( 50 mM citrate buffer, pH 5.0 (10% research-grade Captisol), QD; Compound (I), 10 or 20 mg / kg, BID, plus RMC-4550, 30 mg / kg, QD; BI-3406 (SOS1 inhibitor), 50 mg / kg (in 0.5% HEC), BID; Compound (I), 10 or 20 mg / kg, BID, plus BI-3406, 50 mg / kg, BID; Everolimus, 10 mg / kg (30% propylene glycol: 5% Tween 80 (in 65% ddH2O), QD; Compound (I), 10 or 20 mg / kg, BID, plus everolimus, 10 mg / kg, QD; VT103 (TEAD1 inhibitor), 10 mg / kg (in 0.5% Natrosol (HEC)), QD; or Compound (I), 10 or 20 mg / kg, BID, plus VT103, 10 mg / kg, QD.

[0134] In vivo pretreatment study: NCI-H2030 and NCI-H2122 KRAS G12CNSCLC xenografts were orally treated with the following: control vehicle (10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; compound (I), 10 mg / kg (aqueous suspension), BID; adaglasib, 60 or 100 mg / kg (in 10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; sotrasib, 100 mg / kg (2% HPMC and 1% Tween Adaglacib, 60 or 100 mg / kg, QD, plus compound (I), 10 mg / kg, BID, added before or after treatment; RMC-6236, 25 mg / kg (in 10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; or RMC-6236, 25 mg / kg, QD, plus compound (I), 10 mg / kg, BID, added before or after treatment.

[0135] Dose scheduling study: NCI-H2122 KRAS G12C NSCLC xenografts were treated orally as follows: control vehicle (10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), QD; adaglasib, 100 mg / kg (in 10% research-grade Captisol in 50 mM citrate buffer, pH 5.0), every other week QD; adaglasib, 100 mg / kg, QD, plus compound (I), 10 mg / kg aqueous suspension), BID, both continuous; adaglasib Lasib, 100 mg / kg (continuous administration), QD, plus compound (I), 10 mg / kg, BID, every other week; Adaglasib, 100 mg / kg, QD, plus compound (I), 10 mg / kg, BID, both every other week (synchronous discontinuous administration); or Adaglasib, 100 mg / kg, QD, plus compound (I), 10 mg / kg, BID, both every other week (asynchronous discontinuous administration).

[0136] NCI-H2122 KRAS G12CNSCLC xenografts were also treated orally with the following: control vehicle (0.5% methylcellulose), QD; compound (I), 10 mg / kg (aqueous suspension), BID; diasib, 25 or 100 mg / kg (in 0.5% methylcellulose), QD; or compound (I), 10 mg / kg, BID, in addition to diasib, 25 or 100 mg / kg, QD.

[0137] Capan-1 and PA-07-0041 xenografts were orally treated as follows: control vehicle (0.5% Natrosol / 5% HP-β-CD), BID; compound (I), 10 mg / kg (aqueous suspension), BID; BI-2493, 30 mg / kg (in 0.5% Natrosol / 5% HP-β-CD), BID; or compound (I), 10 mg / kg, BID, plus BI-2493, 30 mg / kg, BID.

[0138] Immunohistochemistry (IHC) All immunohistochemical staining was performed at Histowiz, Inc. (Brooklyn, New York) using a Leica Bond RX automated staining system (Leica Microsystems). Slides were dewaxed using xylene and alcohol-based dewaxing solutions. Epitope recovery was performed by heat-induced epitope retrieval (HIER) of formalin-fixed, paraffin-embedded (FFPE) tissues using a citrate-based pH 6 solution at 95°C for 20 minutes. The tissue was first incubated with peroxide block buffer (Leica Microsystems), followed by incubation for 30 minutes with primary antibodies Ki67 (ab15580), CC3 (CST9661), p-S6 (CST4858), and p-4EBP1 (CST2855) at dilutions of 1:800, 1:300, 1:200, and 1:800, respectively. Subsequently, it was incubated with DAB rabbit secondary reagent: polymer, DAB purified product, and hematoxylin (Leica Microsystems). The slides were dried, covered with coverslips, and visualized using a Leica Aperio AT2 slide scanner (Leica Microsystems).

[0139] result: The combination of tipifarnib and adagrasib caused a dose-dependent reduction in spheroid survival in NCI-H2122 (Figure 1A), NCI-1792 (Figure 1B), and NCI-H358 (Figure 1C) KRAS G12C NSCLC cell lines compared to the A549 KRAS G12S (control) NSCLC cell line (Figure 1D). The combination of compound (I) with adaglasib caused a dose-dependent decrease in spheroid viability in a certain range of KRAS G12C NSCLC cell lines (Experiment 1: NCI-H2122, Figure 1E; NCI-1792, Figure 1F; NCI-H358, Figure 1G; control A549, Figure 1H; Experiment 2: NCI-H2122, Figure 1I; NCI-2030, Figure 1J; NCI-H1792, Figure 1K; NCI-H23, Figure 1L; control A549, Figure 1M).

[0140] To evaluate the potential mechanism of action of combination therapy with FTI and a KRAS G12C inhibitor, RHEB expression was knocked down in the NCI-H2122 KRAS G12C NSCLC cell line using a doxycycline-inducible shRHEB system. Dox-inducible RHEB knockdown alone did not cause a significant change in spheroid growth, but adaglacib monotherapy slowed growth. In contrast, spheroid growth was reduced in both RHEB knockdown stable cell lines treated with adaglacib, suggesting that RHEB may play a significant role in the inhibitory effect of FTI when combined with a KRAS G12C inhibitor (Figure 2A). In control, spheroid growth in the A549 dox-inducible RHEB knockdown stable cell line showed no significant effect, regardless of whether or not it was treated with adaglacib (Figure 2B).

[0141] Key proteins involved in the mTOR and MAPK signaling pathways were evaluated by 3D and 2D immunoblotting to further determine the mechanism of action of the combination of FTI and KRAS G12C inhibitors. In the NCI-H2122 KRAS G12C NSCLC cell line, both 3D and 2D signaling showed enhanced inhibition of HER3, p-S6 (S235 / 236), p-p90 RSK (S380), p-p70 S6K (T389), and p-Rb (S807 / 811) with 48-hour combination treatment of compound (I) and either adaglasib (Figure 3A, 3B) or tipifarnib and sotrasib (Figure 3C). In addition, both combination therapies enhanced the increase of cleaved caspase-3, an apoptosis marker, compared to monotherapy. In the NCI-H2030 KRAS G12C NSCLC cell line, combination therapy with tipifarnib and adaglasib resulted in enhanced reduction of p-Rb (S807 / 811) and enhanced increase in cleaved PARP compared to adaglasib monotherapy (Figure 3D). In the NCI-H1792 KRAS G12C NSCLC cell line, combination therapy with tipifarnib and sotrasib resulted in enhanced reduction of p-S6 (S235 / 236), p-4EBP1 (S65), and p-Rb (S807 / 811) and enhanced increase in cleaved PARP compared to sotrasib monotherapy (Figure 3E). These results suggest that the combination of FTI and KRAS G12C inhibitors may potentially inhibit various nodes in the mTOR pathway that would otherwise be subjected to feedback reactivation by monotherapy with a KRAS G12C inhibitor.

[0142] The signaling effects of adagrasib treatment in shRHEB stable cell lines with genetic depletion of RHEB (essentially functioning as a mimic of FTI treatment) were compared to the effects observed with compound (I) and adagrasib combination in the NCI-H2122 KRAS G12C NSCLC cell line (shown in Figure 3B). First, RHEB expression was depleted in two cell samples using a doxycycline-inducible shRNA system (Figure 3F). In both dox-inducible shRHEB cell lines cultured as 3D tumor spheroids, 48 ​​hours of treatment with adagrasib reduced HER3 levels, p-p70 S6K, p-S6, p-4EBP1, and p-Rb compared to the shScramble control cell line (Figure 3F). NCI-H2122 cells cultured in 2D were also transfected with siRNA against RHEB and exposed to adagrasib. Levels of p-70 S6K, S6 ribosomal protein, and 4EBP1 phosphorylation were reduced in siRHEB-transfected cells after adagrasib exposure compared to cells transfected with a non-targeted control siRNA pool (Figure 3G). These results suggest that inhibition of RHEB contributes to the reduction in mTOR signaling observed with the combination of FTI and adagrasib.

[0143] In combination therapy groups in the KRAS G12C NSCLC models NCI-H2122 (CDX), LU2512 (PDX), and NCI-H2030 (CDX), tipifarnib combined with adaglacib and sotracib, and compound (I) combined with adaglacib, all demonstrated significant antitumor efficacy. Tumor growth inhibition (TGI) values ​​were 88.62%, 85.01%, and 88.00% in the NCI-H2122 model (Table 1), 87.87%, 86.37%, and 87.92% in the LU2512 model (Table 2), and 117.21%, 116.61%, and 117.79% in the NCI-H2030 model (Table 3) (P<0.05 compared to vehicle control).

[0144] [Table 1] Note: Bartlett's test is performed to test for uniformity and normality of variances, and nonparametric tests are performed to compare groups. P<0.05 is statistically significant compared to the vehicle control. TGI%=(1-Ti / Ci)×100, T / C%=Ti / Ci×100, where Ti and Ci are the mean tumor volumes of the treatment group and control group on a given day, respectively.

[0145] [Table 2] Note: Bartlett's test is performed to test for uniformity and normality of variances, and nonparametric tests are performed to compare groups. P<0.05 is statistically significant compared to the vehicle control.

[0146] [Table 3] Note: A one-sided t-test was performed to determine the p-value. A p-value of < 0.05 relative to the vehicle control is statistically significant.

[0147] In both the NCI-H2122 and LU2512 models, all combination therapy groups showed tumor regression, while all monotherapy groups did not (Figures 4A-C and 5A-C). In the NCI-H2030 model, the combination therapy groups achieved complete tumor regression, while the monotherapy groups of adagracib and sotracib began to recur by day 28 (Figures 6A-C). In addition, a separate study was conducted in the NCI-H2030 model to evaluate the depth and persistence of the combination of FTI and the KRAS G12C inhibitor adagracib. The combination therapy groups showed deeper tumor regression compared to the monotherapy group of adagracib (Figure 7A). By day 32, tumors in the adagracib-treated groups began to regrow, while tumors in the combination therapy groups continued to regress. Even after discontinuation of treatment, the combination-treated tumors continued to regress or stabilize by day 46 (Figure 7B). These results indicate that, in the NCI-H2030 model, the combination of FTI and adagrasib induces a deeper and more sustained antitumor response compared to monotherapy.

[0148] Intracellular hemoglobin (IHC) of NCI-H2122 endpoint tumor samples showed increased levels of cleaved caspase 3 (CC3), a marker of cell apoptosis, and decreased levels of both p-S6 (Ser235 / 236) and p-4EBP1 (Thr3746) signaling markers in combinations treated with tipifarnib and adaglacib (Figure 8A) and compound (I) and adaglacib (Figure 8B). These results suggest mTOR pathway inhibition as a potential mechanism of action for the combination of FTI and KRAS G12C inhibitors.

[0149] To further investigate the mechanism of action of the FTI / KRAS G12C inhibitor combination, pharmacodynamic studies were performed in the NCI-H2122 KRAS G12C NSCLC CDX model. Western blotting was used to evaluate key proteins involved in the mTOR and MAPK signaling pathways (Figure 9A). The combination of FTI (compound (I)) and the KRAS G12C inhibitor (adaglasiv) induced stronger inhibition of HER3 protein expression and phosphorylation of key MAPK signaling proteins (p90 RSK (S380) and S6 (S235 / 236)), as well as phosphorylation of mTOR substrates (S6 (S240 / 244) and 4EBP1 (S65 and T37 / 46)) compared to monotherapy. Phosphorylation of Rb (S807 / 811), a marker of cell cycle arrest, was also reduced by the combination compared to monotherapy. IHC performed on the same tumor samples supported these findings (Figures 9B and 9C). There was an overall trend of decreased Ki67 (a marker of proliferation) and increased cleaved caspase 3 (CC3, a marker of apoptosis) in the combination therapy tumors (overlaid on the IHC images in Figure 9B) or positive cell percentage (Table 4), as quantified by the H-score, compared to adaglacib monotherapy tumors. In addition, as shown in Figure 9B, there was a slight decrease in p-S6 and p-4EBP1 in the combination group compared to adaglacib monotherapy. While there was an observable decrease in HER3 levels in the combination group compared to adaglacib monotherapy, HER2 and EGFR levels appeared similar between the combination and adaglacib monotherapy groups (Figure 9C).

[0150] [Table 4]

[0151] The combination of compound (I) tipifarnib and the KRAS G12D inhibitor MRTX1133 was evaluated in KRAS G12D mutant PDAC models. In the combination therapy groups of KRAS G12D models PA0787 (PDX) (Figure 10A) and SW1990 (CDX) (Figure 10B), tipifarnib or compound (I) combined with MRTX1133 delayed tumor regrowth and enhanced tumor growth inhibition compared to monotherapy with MRTX1133. Specifically, in the PA0787 model, the combination of compound (I) and MRTX1133 prevented tumor regrowth. In vitro signal transduction by immunoblotting was performed to evaluate the mechanism of action of the combination of FTI and the KRAS G12D inhibitor. In the AsPC-1 KRAS G12D PDAC cell line, 48-hour combination therapy with compound (I) and MRTX1133 resulted in greater inhibition of HER3, p-ERK1 / 2 (T202 / 204), p-p90 RSK (S380), p-p70 S6K (T389), p-S6 (S235 / 236), p-S6 (S240 / 244), p-4EBP1 (S65), and p-Rb (S807 / 811) compared to MRTX1133 alone (Figure 11). These results suggest that the combination of FTI and a KRAS G12D inhibitor may potentially inhibit various nodes in the mTOR pathway that would otherwise be subjected to feedback reactivation by monotherapy with a KRAS G12D inhibitor.

[0152] The combined effects of FTI and MRTX1133 on tumor growth were also evaluated in KRAS G12D mutant CRC models. In the CR3262 PDX model, the combination of MRTX1133 with tipifarnib or compound (I) slowed tumor growth compared to monotherapy (Figure 12A). In the GP2D CDX model, in the first experiment, the combination of compound (I) and MRTX1133 induced deeper tumor regression than monotherapy with either agent (Figure 12B). The combination of compound (I) and MRTX1133 also inhibited the growth of CR1245 CRC PDX tumors better than monotherapy (Figure 12C). Samples of GP2D CDX tumors treated with MRTX1133, compound (I), or a combination thereof were collected along with vehicle controls after 28 days of treatment and lysed for immunoblot analysis. In tumors treated with combination therapy, S6 and 4EBP1 phosphorylation was lower than in tumors treated with monotherapy, suggesting more potent mTOR inhibition (Figure 13). Rb phosphorylation was lower in tumors treated with MRTX1133 and compound (I), indicating a decrease in cell cycle / proliferation. In a second experiment, the pan-RAS inhibitor RMC-6236 or KRAS G12D The antitumor effect of compound (I) in combination with the specific inhibitor MRTX1133 was demonstrated by KRAS G12DThe effects were evaluated in GP2D, a CDX model of mutant colorectal cancer. Compared to RMC-6236 alone at 10 mg / kg or 25 mg / kg, the combination of RMC-6236 and compound (I) resulted in greater inhibition of tumor growth (Figure 12D). The combination of 25 mg / kg of RMC-6236 and 10 mg / kg of compound (I) induced tumor regression. Response calls according to modified RECIST (mRECIST) criteria (BestResp and Best Avg > 10d at t, Gao et al. Nat. Med. 2015) showed 88% stable disease (mSD) and 12% partial response (mPR) for RMC-6236 alone, while the combination induced 88% mPR and 12% mSD. Treatment with MRTX1133 alone resulted in cessation of GP2D tumors, while combinations of MRTX1133 with cetuximab or compound (I) resulted in tumor regression (Figure 12E). Triple combinations of compound (I), MRTX1133, and cetuximab resulted in the deepest tumor regression. Response calls are shown in Table 5. The combination of compound (I) with 20 mg / kg of RMC-6236 also inhibited tumor growth to a greater extent in the colorectal xenograft models CO-04-0002 (PDX), LoVo (CDX), and SW620 (CDX) than either drug alone.

[0153] [Table 5] According to the modified RESCIST criteria, mPD = progressive disease, mSD = stable disease, mPR = partial response, and mCR = complete response.

[0154] These results suggest that FTI can enhance the efficacy of multiple RAS-targeted drugs in KRAS variant settings.

[0155] Additional in vivo tumor growth experiments were conducted in several additional models at the doses listed in each figure. Compound (I), adaglasib, and combinations thereof were studied in the MIA PaCa-2 KRAS G12C PDAC model (Figure 14A) and the PA1383 KRAS G12C PDAC model (Figure 14B). In the CR6256 KRAS G12C CRC model, the following two experiments were conducted: (a) tipifarnib, compound (I), sotrasib, tipifarnib and sotrasib, and compound (I) and sotrasib (Figure 15A), and (b) tipifarnib, compound (I), adaglasib, tipifarnib and adaglasib, and compound (I) and adaglasib (Figure 15B). In addition, the following additional studies were conducted. (c) In the CR6243 KRAS G12C CRC model, compound (I), adaglacib, and combinations thereof were used (Figure 15C), and (d) in the SW837 KRAS G12C CRC model, compound (I), adaglacib, and combinations thereof were used (Figure 15D). In the NCI-H358 KRAS G12C NSCLC model, the following two experiments were performed: (a) tipifarnib, adaglacib (at two dose levels), and combinations thereof (Figure 16A), and (b) tipifarnib, sotracib (at two dose levels), and combinations thereof (Figure 16B). The combination of compound (I) with 100 mg / kg of adagrasib also inhibited tumor growth to a greater extent than any of the drugs alone in LU11693 PDX, LU6405 PDX, and SW1573 CDX KRAS G12C NSCLC models.

[0156] In the NCI-H2122 KRAS G12C NSCLC CDX model, the following treatment groups were administered: adagracib, compound (I), RMC-4550 (SHP2 inhibitor), BI-3406 (SOS1 inhibitor that inhibits SOS1-KRAS interaction), everolimus (mTOR inhibitor), VT103 (TEAD1 protein palmitoylation inhibitor), compound (I) and adagracib, RMC-4550 and adagracib, BI-3406 and adagracib, everolimus and adagracib, and VT103 and adagracib (Figure 17A). Figure 17B shows extracted results from the treatment groups of adaglacib, compound (I) and adaglacib, RMC-4550 and adaglacib, BI-3406 and adaglacib, everolimus and adaglacib, and VT103 and adaglacib. Similar direct comparison studies were conducted for 28 days, comparing the combination of adaglacib and compound (I) with the combination of adaglacib and RMC-4550 (Figure 17C), BI-3406 (Figure 17D), everolimus (Figure 17E), or VT103 (Figure 17F).

[0157] In vivo pretreatment study: NCI-H2030 and NCI-H2122 KRAS G12C NSCLC CDX model, KRAS G12C Treatment was administered for varying periods with either the inhibitor adagrasib or sotrasib. Compound (I) was added to the treatment of this KRAS G12CThe antitumor activity of the compound (I)-adagrasib combination in the inhibitor-pre-treatment setting was evaluated. In particular, in the NCI-H2030 CDX model, adding compound (I) to tumors progressing on adagrasib monotherapy from day 28 onwards resulted in tumor quiescence (Figure 18A). Similar results can be obtained by adding compound (I) and adagrasib to tumors progressing on sotrasib monotherapy in this CDX model. In the NCI-H2122 CDX model, adding compound (I) to tumors treated with adagrasib monotherapy for 2 weeks resulted in tumor regression comparable to the initial combination of compound (I) and adagrasib (Figure 18B). Similar tumor regression was observed with the combination of compound (I) and adagrasib after 2 weeks of sotrasib monotherapy (Figure 18C).

[0158] Previous KRAS G12C To determine the mechanism of action of the antitumor effect observed with combination therapy of compound (I) and adagrasib after monotherapy with an inhibitor, changes in various proteins in the mTOR and MAPK signaling pathways were evaluated. NCI-H2030 KRAS G12C In the NSCLC CDX model, tumors that progressed on adagracib monotherapy and were subsequently treated with a combination of compound (I) and adagracib showed reductions in p-S6(S235 / 236) and p-S6(S240 / 244) levels comparable to those treated with initial combination therapy of compound (I) and adagracib (Figure 19A). NCI-H2122 KRAS G12C In the NSCLC CDX model, any of the KRAS G12C Tumors treated with compound (I) in combination with adagrasib after two weeks of prior treatment with an inhibitor showed reduced MAPK signaling at the levels of p-p90 RSK and p-ERK1 / 2 (T202 / 204), as well as inhibition of mTOR signaling at the levels of p-p70 S6K and p-4EBP1 (S65), compared to monotherapy (Figure 19B). G12CSwitching from one inhibitor to another did not provide further benefit. However, adding compound (I) while switching from sotrasib to adaglasib was able to eliminate p-S6 signaling at both phosphorylation sites. In addition, a decrease in p-RB levels, suggestive of cell cycle arrest, was observed only in the group treated with compound (I). These results are in KRAS G12C Adding compound (I) after prior treatment with an inhibitor suggests that inhibiting mTOR signaling may yield combination benefits comparable to those of xenograft tumors treated with initial combination therapy of compound (I) and adagrab.

[0159] A similar in vivo study was conducted in the NCI-H2122 CDX model to determine the efficacy of compound (I) in combination with the general-purpose RAS inhibitor RMC-6236 after prior KRAS inhibitor treatment. Following two weeks of adagrasib monotherapy, tumor growth was inhibited when compound (I) and RMC-6236 were added compared to tumor quiescence after switching to RMC-6236 monotherapy (Figure 18D). Adding compound (I) to tumors progressing on RMC-6236 monotherapy resulted in tumor regression comparable to the initial combination of compound (I) and RMC-6236 (Figure 18E). These results indicate that compound (I) can overcome adaptive resistance to KRAS inhibitors, such as KRAS G12C inhibitors and RAS inhibitors (e.g., pan-RAS inhibitors), even after prior treatment with such drugs.

[0160] Dose scheduling study: NCI-H2122 KRAS G12CNSCLC CDX models were treated with various schedule regimens combining compound (I) and adagrasib. The results are shown in Figure 20. The conclusion from this study is that weekly on / off dosing of compound (I) with continuous dosing of adagrasib had comparable antitumor efficacy to continuous dosing of compound (I) and adagrasib. Weekly on / off dosing of compound (I) with either continuous dosing of adagrasib or synchronous on / off dosing of adagrasib resulted in similar antitumor responses. Synchronized dosing of compound (I) and adagrasib was necessary for tumor regression, as only asynchronous dosing led to tumor stabilization. These results suggest that compound (I) requires FTI and KRAS to enhance the effect of adagrasib. G12C This suggests that it is important to treat with both inhibitors simultaneously.

[0161] Further Examples Compound (I) and another KRAS G12C The combination with the inhibitor diavalasib is NCI-H2122 KRAS G12C In the NSCLC CDX model, the combination showed enhanced antitumor activity compared to each drug alone (Figure 21). The combination of compound (I) and the pan-KRAS inhibitor BI-2493 showed enhanced antitumor activity compared to each drug alone in the KRAS G12V PDAC model (Figure 22). The addition of compound (I) and BI-2493 in the KRAS WT-amplified gastric cancer model yielded similar results. Compound (I) may enhance the activity of KRAS inhibitors in xenograft models of CRC, PDAC, and NSCLC, including G12C, G12D, and G12V variant subtypes.

[0162] Clinical trial research A Phase 1, first-in-human, open-label clinical trial will be conducted to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of compound (I) when administered in combination with a KRAS G12C inhibitor, e.g., adaglacib, in adult patients with locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation. In some embodiments, patients will have received at least one prior systemic therapy. Compound (I) will be administered once daily on days 1–7 and 15–21 of a 28-day cycle. Adaglaciv will be administered once daily in a 28-day cycle.

[0163] 7.1 Exemplary Embodiments One or more (including, for example, all) of the following exemplary embodiments may include each of the other embodiments or parts thereof. A1. A method of treating cancer in a subject, including administering an FTI to the subject. A2. A method for treating KRAS-dependent cancer in a subject, including administering an FTI to the subject. A3. A method for delaying the emergence of resistance to a KRAS inhibitor for cancer in a subject, or a method for overcoming resistance to a KRAS inhibitor for cancer in a subject previously treated with a KRAS inhibitor, comprising administering an FTI to the subject and, optionally, administering a KRAS inhibitor to the subject in combination with the FTI, wherein, optionally, the subject has been previously treated with the same or a different KRAS inhibitor. A4. A method for treating pancreatic cancer, pancreatic ductal adenocarcinoma, lung cancer, non-small cell lung cancer, or colorectal cancer in a subject, comprising administering compound (I) or a pharmaceutically acceptable form thereof to the subject. A5. The method according to any one of Embodiments A1 to A4, comprising administering a KRAS inhibitor as the target. A6. The method according to any one of Embodiments A1 to A5, wherein the cancer is lung cancer, pancreatic cancer, gynecological cancer, gastrointestinal cancer, breast cancer, neoplasm (metastatic neoplasm, germ cell carcinoma, plasma cell neoplasm, or myelodysplastic / myeloproliferative neoplasm), carcinoma of unknown primary origin (CUP), or leukemia. A7. The method according to Embodiment A6, wherein the lung cancer is non-small cell lung cancer (NSCLC), non-squamous NSCLC, squamous NSCLC, or lung adenocarcinoma. A8. The method according to Embodiment A6, wherein the gastrointestinal cancer is colorectal cancer (CRC), colon cancer, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer, appendiceal cancer, small intestine cancer, stomach cancer, bile duct cancer, ampullary cancer, gallbladder cancer, stomach cancer, gastric adenocarcinoma, esophageal cancer, esophageal adenocarcinoma, urinary tract cancer, GI neuroendocrine tumor, or esophagogastric junction adenocarcinoma. A9. The method according to Embodiment A6, wherein the gynecological cancer is ovarian cancer, endometrial cancer, peritoneal cancer, or cervical cancer. A10. The method according to any of the prior embodiments, wherein the cancer is lung cancer, colorectal cancer, or pancreatic cancer. A11. The method according to Embodiment A10, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma. A12. The method according to any of the prior embodiments, wherein the cancer includes a KRAS mutation or KRAS amplification, or a combination thereof. A13. The method according to any of the prior embodiments, wherein the cancer includes a KRAS mutation. A13A. The method according to any of the prior embodiments, wherein the KRAS inhibitor is a KRAS G12C inhibitor, a KRAS G12D inhibitor, a KRAS G12S inhibitor, a KRAS G12V inhibitor, a KRAS G12R inhibitor, a KRAS G13D inhibitor, a pan-KRAS inhibitor, or a pan-RAS inhibitor. A14. The method according to Embodiment A13 or Embodiment A13A, wherein the KRAS mutation is a KRAS G12C mutation, and the method comprises administering a KRAS inhibitor, wherein the KRAS inhibitor is a KRAS G12C inhibitor. A14A. The method according to Embodiment A14, wherein the cancer is NSCLC, lung adenocarcinoma, non-squamous NSCLC, squamous NSCLC, CRC, pancreatic cancer, PDAC, CUP, endometrial cancer, ovarian cancer, cervical cancer, gastric cancer, gastric adenocarcinoma, bile duct cancer, esophageal cancer, stomach cancer, small intestine cancer, appendiceal cancer, biliary tract cancer (BTC), ampullary cancer, gallbladder cancer, breast cancer, or metastatic neoplasm. A15. KRAS G12C inhibitors include adagrasib (KRAZATI®, MRTX849, Amgen), sotrasib (LUMAKRAS®, AMG-510, Amgen), divaracib (GDC-6036, Genentech), linperlisib (YL-15293), RM007, D-1553 (InvestisBio), JDQ443 (Novartis), LY3537982 (Eli Lilly), LY3499446, ERAS-601, ERAS-007, BI 1823911 (Boehringer). The method according to Embodiment A14, wherein the product is Ingelheim), JAB-21822, MK-1084, MK-1086, MK-1087, L-15293, D3S-001, RMC-6291 (Revolution), HBI-2438, FMC-376 (Frontier), BBO-8520 (BridgeBio), ZG19018 (Suzhou Zelgen), UCT-001024 (1200 Pharma), TEB-17231 (280 Bio unit of Yingli Pharma), HYP-2A (Sichuan Huiyu), ABSK071 (Abbisko), IBI351 (GFH925, Innovent / Genfleet), ARS-853, ARS-1620, or JNJ-74699157 (ARS-3248). A16. The method according to Embodiment A14 or Embodiment A15, wherein the KRAS G12C inhibitor is adagrasib or sotrasib. A17. The method according to any one of embodiments A14 to A16, wherein the cancer is non-small cell lung cancer or colorectal cancer. A18. The method according to Embodiment A17, wherein the cancer is non-small cell lung cancer. A19. The method according to Embodiment A17, wherein the cancer is colorectal cancer. A20. The method according to Embodiment A13 or Embodiment A13A, wherein the KRAS mutation is a KRAS G12D mutation, and the method comprises administering a KRAS inhibitor, wherein the KRAS inhibitor is a KRAS G12D inhibitor. A20A. The method according to Embodiment A20, wherein the cancer is pancreatic cancer, PDAC, CRC, NSCLC, non-squamous NSCLC, CUP, endometrial cancer, ovarian cancer, small intestinal adenocarcinoma, appendiceal adenocarcinoma, gastric cancer, gastric adenocarcinoma, or bile duct cancer. A21. The method according to Embodiment A20, wherein the KRAS G12D inhibitor is MRTX1133 (Mirati), TH-Z827, TH-Z835, KD-8, BI-KRAS12D1-3, BI-KRASG12D3, RMC-9805 (Revolution), ASP3082, ASP4396, LY3962673, INCB161734, HRS-4642, or QTX3046 (Quanta). A22. The method according to Embodiment A20, wherein the KRAS G12D inhibitor is MRTX1133. A23. The method according to any one of Embodiments A20 to A22, wherein the cancer is pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, or gastric cancer. A24. The method according to embodiment A23, wherein the cancer is pancreatic ductal adenocarcinoma. A25. The method according to Embodiment A23, wherein the cancer is non-small cell lung cancer. A26. The method according to embodiment A23, wherein the cancer is colorectal cancer. A27. The method according to Embodiment A23, wherein the cancer is gastric cancer. A28. The method according to Embodiment A13 or Embodiment A13A, wherein the KRAS mutation is a KRAS G12V mutation, and the method comprises administering a KRAS inhibitor, wherein the KRAS inhibitor is a KRAS G12V inhibitor. A28A. The method according to Embodiment A28, wherein the cancer is CRC, NSCLC, non-squamous NSCLC, PDAC, CUP, endometrial cancer, ovarian cancer, bile duct cancer, small intestinal adenocarcinoma, appendiceal adenocarcinoma, gastrointestinal cancer, esophageal cancer, and stomach cancer. A29. The method according to Embodiment A13 or Embodiment A13A, wherein the KRAS mutation is a KRAS G12R mutation, and the method comprises administering a KRAS inhibitor, wherein the KRAS inhibitor is a KRAS G12R inhibitor. A29A. The method according to Embodiment A29, wherein the cancer is pancreatic cancer, PDAC, or CUP. A30. The method according to Embodiment A13 or Embodiment A13A, wherein the KRAS mutation is a KRAS G12S mutation, and the method comprises administering a KRAS inhibitor, wherein the KRAS inhibitor is a KRAS G12S inhibitor. A31. The method according to Embodiment A13 or Embodiment A13A, wherein the KRAS mutation is a KRAS G13D mutation, and the method comprises administering a KRAS inhibitor, wherein the KRAS inhibitor is a KRAS G13D inhibitor. A31A. The method according to Embodiment A31, wherein the cancer is CRC, non-squamous NSCLC, or endometrial cancer. A32. The method according to Embodiment A13 or Embodiment A13A, wherein the KRAS mutation comprises at least two KRAS mutations selected from KRAS G12C, G12D, G12V, G12R, and G13D mutations, and the method comprises administering a KRAS inhibitor, wherein the KRAS inhibitor is a pan-KRAS inhibitor. A33. The method according to Embodiment A32, wherein the pan-KRAS inhibitor is BI-2852, BI-pan-KRAS1-4 (BI1701963), RSC-1255, RMC-6236, RSC-1255, QTX3034 (Quanta), JAB-23425 (Beijing Jacobio), BI-2493, LY4066434, or VRTX-153 (VRise). A34. A method according to any of the prior embodiments, comprising KRAS amplification. A35. The method according to any of the prior embodiments, wherein the cancer is in remission, early stage, advanced, locally advanced, recurrent, metastatic, refractory, recurrent, solid tumor, or a combination thereof. A36. The method according to any of the prior embodiments, wherein the cancer has been previously treated with first-line therapy and / or optional second-line therapy. A37. The method according to any of the prior embodiments, wherein the administration comprises administering an FTI before, after, or concurrently with a KRAS inhibitor, optionally during one or more treatment cycles, for example, one or more 28-day cycles. A38. A method according to any of the prior embodiments, comprising administering FTI and KRAS inhibitors simultaneously or sequentially, and independently, sequentially or in cycles. A39. Approximately 0.1-2.5mg, 0.5-5mg, 0.5-10mg, 0.5-25mg, 0.5-50mg, 0.5-75mg, 0.5-100mg, 0.5-300mg, 0.5-600mg, 0.5-1200mg, 1-5mg, 1-10mg, 1-25mg, 1-50mg, 1-75mg, 1- 100mg, 1~300mg, 1~600mg, 1~1200mg, 1~2400mg, 20~100mg, 40~75mg, 50~75mg, 50~100 mg, 50~150mg, 75~100mg, 100~200mg, 125~200mg, 150~300mg, 200~250mg, 200~400mg, This includes administering a daily dose of FTI selected from 300-600 mg, 250-500 mg, 400-600 mg, 500-750 mg, 600-900 mg, 700-100 mg, 650-1000 mg, 800-1200 mg, 900-1500 mg, 1000-1600 mg, 1000-2000 mg, 1200-1600 mg, 1500-2000 mg, 1500-2400 mg, 1800-2400 mg, and 2000-2400 mg (free base equivalent), or a daily dose of FTI of approximately 0.5 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 1 mg, 2 mg, and 2 mg per day.5mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35m g, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg About 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg, about 275mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400mg, about 425mg, about 450mg, about 475mg, about 5 00mg, approx. 525mg, approx. 550mg, approx. 575mg, approx. 600mg, approx. 650mg, approx. 700mg, approx. 750mg, approx. 800mg, approx. The method according to any of the prior embodiments, wherein the amount is 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1450 mg, approximately 1500 mg, approximately 1550 mg, approximately 1600 mg, approximately 1650 mg, approximately 1700 mg, approximately 1750 mg, approximately 1800 mg, approximately 1850 mg, approximately 1900 mg, approximately 1950 mg, approximately 2000 mg, approximately 2050 mg, approximately 2100 mg, approximately 2150 mg, approximately 2200 mg, approximately 2250 mg, approximately 2300 mg, approximately 2350 mg, or approximately 2400 mg (free base equivalent). The method according to Embodiment A39, wherein the daily dose of A40.FTI is administered in one or two doses per day. A41. The method according to any of the prior embodiments, wherein FTI is administered once or twice per day for one or more cycles, on days 1-7, 1-7 and 15-21, 1-14, 1-21, or each day (i.e., days 1-28) of a 28-day cycle. A42. The method according to any of the prior embodiments, comprising administering a KRAS inhibitor in a daily dose of 10 to 2000 mg, or approximately 10 to 300 mg, approximately 50 to 400 mg, approximately 200 to 400 mg, approximately 500 to 1500 mg, approximately 800 to 1200 mg, or approximately 1100 to 1500 mg, or approximately 1200 mg (for example, approximately 600 mg twice a day), or approximately 960 mg. A43. The method according to any of the prior embodiments, wherein FTI is tipifarnib, ronafarnib, FTI277, BMS214662, or compound (I), or a pharmaceutically acceptable form thereof. A44. The method according to any one of Embodiments A1 to A43, wherein FTI is compound (I) or a pharmaceutically acceptable form thereof. A45. The method according to Embodiment A44, wherein FTI is the free base of compound (I). A46. The method according to Embodiment A44, wherein FTI is a pharmaceutically acceptable salt of compound (I). A47. The method according to Embodiment A45 or A46, wherein FTI is a solvate of the free base or a pharmaceutically acceptable salt of compound (I). A48. The method according to Embodiment A3 or any one of A5 to A47, wherein the KRAS inhibitor administered in combination with an FTI to a subject previously treated with a KRAS inhibitor is the same KRAS inhibitor. A49. The method according to Embodiment A3 or any one of A5 to A47, wherein the KRAS inhibitor administered in combination with an FTI to a subject previously treated with a KRAS inhibitor is a different KRAS inhibitor. B1. A pharmaceutical composition comprising (a) an FTI, (b) a KRAS inhibitor, and (c) a pharmaceutically acceptable excipient. B2. A pharmaceutical composition for use in any of Embodiments A1 to A49, comprising FTI and a pharmaceutically acceptable excipient. B3. A pharmaceutical composition for use in Embodiment B2, comprising a KRAS inhibitor. B4. A pharmaceutical composition comprising (a) compound (I) or a pharmaceutically acceptable form thereof, (b) a KRAS inhibitor, and (c) a pharmaceutically acceptable excipient. B5. A pharmaceutical composition according to any of the prior embodiments, wherein the KRAS inhibitor is a KRAS G12C inhibitor, a KRAS G12D inhibitor, a KRAS G12S inhibitor, a KRAS G12V inhibitor, a KRAS G12R inhibitor, a KRAS G13D inhibitor, a pan-KRAS inhibitor, or a pan-RAS inhibitor, and optionally the KRAS inhibitor is a KRAS G12C inhibitor. B6. KRAS G12C inhibitors include adagrasib (KRAZATI®, MRTX849, Amgen), sotrasib (LUMAKRAS®, AMG-510, Amgen), divaracib (GDC-6036, Genentech), linperlisib (YL-15293), RM007, D-1553 (InvestisBio), JDQ443 (Novartis), LY3537982 (Eli Lilly), LY3499446, ERAS-601, ERAS-007, BI 1823911 (Boehringer). The pharmaceutical composition according to Embodiment B5, which is Ingelheim), JAB-21822, MK-1084, MK-1086, MK-1087, L-15293, D3S-001, RMC-6291 (Revolution), HBI-2438, FMC-376 (Frontier), BBO-8520 (BridgeBio), ZG19018 (Suzhou Zelgen), UCT-001024 (1200 Pharma), TEB-17231 (280 Bio unit of Yingli Pharma), HYP-2A (Sichuan Huiyu), ABSK071 (Abbisko), IBI351 (GFH925, Innovent / Genfleet), ARS-853, ARS-1620, or JNJ-74699157 (ARS-3248). B7. The pharmaceutical composition according to Embodiment B5, wherein the KRAS G12C inhibitor is adaglacib or sotracib. B8. A pharmaceutical composition according to any one of embodiments B1 to B4, wherein the KRAS inhibitor is a KRAS G12D inhibitor. The pharmaceutical composition according to Embodiment B8, wherein the KRAS G12D inhibitor is MRTX1133 (Mirati), TH-Z827, TH-Z835, KD-8, BI-KRAS12D1-3, BI-KRASG12D3, RMC-9805 (Revolution), ASP3082, ASP4396, LY3962673, INCB161734, HRS-4642, or QTX3046 (Quanta). The pharmaceutical composition according to Embodiment B8, wherein the B10.KRAS G12D inhibitor is MRTX1133. B11. A pharmaceutical composition according to any one of Embodiments B1 to B4, wherein the KRAS inhibitor is a KRAS G12V inhibitor, a KRAS G12R inhibitor, a KRAS G12S inhibitor, a KRAS G13D inhibitor, or a pan-KRAS inhibitor, or the KRAS inhibitor is a pan-RAS inhibitor. B12. The pharmaceutical composition according to Embodiment B11, wherein the pan-KRAS inhibitor is BI-2852, BI-pan-KRAS1-4 (BI1701963), RSC-1255, RMC-6236, RSC-1255, QTX3034 (Quanta), JAB-23425 (Beijing Jacobio), BI-2493, LY4066434, or VRTX-153 (VRise), or the pan-KRAS inhibitor is a pan-RAS inhibitor, and optionally the KRAS inhibitor is RMC-6236, or the KRAS inhibitor is RSC-1255. B13. A pharmaceutical composition according to any one of Embodiments B1 to B12, wherein FTI is tipifarnib, ronafarnib, FTI277, BMS214662, or compound (I), or a pharmaceutically acceptable form thereof. A pharmaceutical composition according to any one of Embodiments B1 to B12, wherein B14.FTI is compound (I) or a pharmaceutically acceptable form thereof. The pharmaceutical composition according to Embodiment B14, wherein B15.FTI is the free base of compound (I). The pharmaceutical composition according to Embodiment B14, wherein B16.FTI is a pharmaceutically acceptable salt of compound (I). The pharmaceutical composition according to Embodiment B15 or B16, wherein B17.FTI is a solvate of the free base or a pharmaceutically acceptable salt of compound (I). C1.(i)(a) A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient, and optionally, (b) a pharmaceutical composition comprising a KRAS inhibitor and a pharmaceutically acceptable excipient, or (ii) a pharmaceutical composition according to any of Embodiments B1 to B17.

[0164] The embodiments described herein are intended to be illustrative only, and those skilled in the art can recognize or confirm numerous equivalents of particular compounds, materials, and procedures using only routine experiments. All such equivalents are considered to fall within the scope of the present invention and are encompassed within the appended claims.

[0165] Embedding by reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated herein by reference in whole. In case of any conflict, the application containing any definition herein shall prevail.

Claims

1. A method for treating KRAS-dependent cancer in a subject, comprising administering an FTI and a KRAS inhibitor to the subject.

2. The method according to claim 1, wherein the cancer is lung cancer, pancreatic cancer, gynecological cancer, gastrointestinal cancer, breast cancer, neoplasm (metastatic neoplasm, germ cell cancer, plasma cell neoplasm, or myelodysplastic / myeloproliferative neoplasm), carcinoma of unknown primary origin (CUP), or leukemia.

3. The method according to claim 2, wherein the lung cancer is non-small cell lung cancer (NSCLC), non-squamous NSCLC, squamous NSCLC, or lung adenocarcinoma.

4. The method according to claim 1, wherein the gastrointestinal cancer is colorectal cancer (CRC), colon cancer, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer, appendiceal cancer, small intestine cancer, stomach cancer, bile duct cancer, ampullary cancer, gallbladder cancer, stomach cancer, gastric adenocarcinoma, esophageal cancer, esophageal adenocarcinoma, urinary tract cancer, GI neuroendocrine tumor, or esophagogastric junction adenocarcinoma.

5. The method according to claim 2, wherein the gynecological cancer is ovarian cancer, endometrial cancer, peritoneal cancer, or cervical cancer.

6. The method according to claim 2, wherein the cancer is lung cancer, colorectal cancer, or pancreatic cancer.

7. The method according to claim 6, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma.

8. The method according to any one of claims 1 to 7, wherein the cancer comprises a KRAS mutation or KRAS amplification, or a combination thereof.

9. The method according to claim 8, wherein the cancer includes a KRAS mutation.

10. The method according to claim 9, wherein the KRAS mutation is a KRAS G12C mutation, and the KRAS inhibitor is a KRAS G12C inhibitor.

11. The aforementioned KRAS G12C inhibitors include adagrasib (KRAZATI®, MRTX849, Amgen), sotrasib (LUMAKRAS®, AMG-510, Amgen), divaracib (GDC-6036, Genentech), limperlisib (YL-15293), RM007, D-1553 (InvestisBio), JDQ443 (Novartis), LY3537982 (Eli Lilly), LY3499446, ERAS-601, ERAS-007, BI 1823911 (Boehringer) Ingelheim), JAB-21822, MK-1084, MK-1086, MK-1087, L-15293, D3S-001, RMC-6291 (R evolution), HBI-2438, FMC-376 (Frontier), BBO-8520 (BridgeBio), ZG19018 (Suzhou Zelgen), UCT-001024 (1200 Pharma), TEB-17231 (Yingli Pharma's 280Bio unit), HYP-2A (Sichuan The method according to claim 10, wherein the material is Huiyu), ABSK071 (Abbisko), IBI351 (GFH925, Innovent / Genfleet), ARS-853, ARS-1620, or JNJ-74699157 (ARS-3248).

12. The method according to claim 11, wherein the KRAS G12C inhibitor is adaglasib or sotrasib.

13. The method according to any one of claims 10 to 12, wherein the cancer is non-small cell lung cancer or colorectal cancer.

14. The method according to claim 9, wherein the KRAS mutation is a KRAS G12D mutation, and the KRAS inhibitor is a KRAS G12D inhibitor, a pan-KRAS inhibitor, or a pan-RAS inhibitor.

15. The method according to claim 14, wherein the KRAS G12D inhibitor is MRTX1133 (Mirati), TH-Z827, TH-Z835, KD-8, BI-KRAS12D1-3, BI-KRAS G12D3, RMC-9805 (Revolution), ASP3082, ASP4396, LY3962673, INCB161734, HRS-4642, or QTX3046 (Quanta).

16. The method according to claim 14, wherein the KRAS G12D inhibitor is MRTX1133.

17. The method according to any one of claims 14 to 16, wherein the cancer is pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, or gastric cancer.

18. (a) The KRAS mutation is a KRAS G12V mutation, and the KRAS inhibitor is a KRAS G12V inhibitor, or (b) The KRAS mutation is a KRAS G12R mutation, and the KRAS inhibitor is a KRAS G12R inhibitor, or (c) The KRAS mutation is a KRAS G12S mutation, and the KRAS inhibitor is a KRAS G12S inhibitor, or (d) The method according to claim 9, wherein the KRAS mutation is a KRAS G13D mutation and the KRAS inhibitor is a KRAS G13D inhibitor.

19. The method according to claim 9, wherein the KRAS mutation comprises at least two KRAS mutations selected from KRAS G12C, G12D, G12V, G12R, and G13D mutations, and the KRAS inhibitor is a pan-KRAS inhibitor.

20. The method according to claim 19, wherein the pan-KRAS inhibitor is BI-2852, BI-pan-KRAS1-4 (BI1701963), RSC-1255, RMC-6236, RSC-1255, QTX3034 (Quanta), JAB-23425 (Beijing Jacobio), BI-2493, LY4066434, or VRTX-153 (VRise), or the pan-KRAS inhibitor is a pan-RAS inhibitor, and optionally the KRAS inhibitor is RMC-6236, or optionally the KRAS inhibitor is RSC-1255.

21. The method according to any one of claims 1 to 20, wherein the cancer includes KRAS amplification.

22. The method according to any one of claims 1 to 21, wherein the FTI is tipifarnib, ronafarnib, FTI277, BMS214662, or compound (I), or a pharmaceutically acceptable form thereof.

23. The method according to claim 22, wherein the FTI is compound (I) or a pharmaceutically acceptable form thereof.

24. A method for delaying the emergence of resistance to a KRAS inhibitor for cancer in a subject, or a method for overcoming resistance to a KRAS inhibitor for cancer in a subject previously treated with a KRAS inhibitor, comprising the method according to any one of claims 1 to 23.

25. A method for treating pancreatic cancer, pancreatic ductal adenocarcinoma, lung cancer, non-small cell lung cancer, or colorectal cancer in a subject, comprising administering to the subject (a) compound (I) or a pharmaceutically acceptable form thereof, and (b) a KRAS inhibitor.

26. The method according to claim 24 or 25, wherein the cancer comprises a KRAS G12C mutation or a KRAS G12D mutation.

27. The treatment includes administering additional anticancer agents to the subject, wherein the additional anticancer agents are optionally immunotherapies, anti-EGFR monoclonal antibodies, EGFR signaling pathway inhibitors, cetuximab, panitumumab, chemotherapy, platinum-based anticancer agents (e.g., cisplatin or carboplatin), leucovorin, fluorouracil, topoisomerase inhibitors (e.g., irinotecan or topotecan), taxanes (e.g., paclitaxel, docetaxel, or nab-paclitaxel), gemcitabine, etoposide, pemetrexed, vinorelbine, V The method according to any one of claims 1 to 26, wherein an EGF inhibitor (e.g., bevacizumab or ramucirumab), an EGFR inhibitor (e.g., osimertinib, afatinib, erlotinib, dacomitinib, gefitinib, or amivantamab), an ALK inhibitor (e.g., alectinib, brigatinib, lorlatinib, ceritinib, or crizotinib), a ROS1 inhibitor, and a BRAF inhibitor (e.g., dabrafenib, trametinib, or vemurafenib), and combinations thereof are selected and each is optionally combined with radiation.

28. A pharmaceutical composition comprising (a) compound (I) or a pharmaceutically acceptable form thereof, (b) a KRAS inhibitor, and (c) a pharmaceutically acceptable excipient.

29. (i) (a) a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable excipient, and (b) a pharmaceutical composition comprising a KRAS inhibitor and a pharmaceutically acceptable excipient, or (ii) A pharmaceutical kit or packaging comprising the pharmaceutical composition described in claim 27.

Images