LY3499446 / Eli Lilly - LARVOL DELTA

Targeted therapy-induced chromosomal instability dictates mitotic dependency on Aurora kinase A (AACR 2026) - "We treated these models with the KRAS G12Ci LY3499446 and comprehensively assessed their DNA damage responses, CIN phenotypes, and sensitivity screening to combination therapies with agents that perturb chromosomal stability...Under conditions of combined inhibition of KRAS G12C and AURKA, in which Cyclin B1 degradation is impaired, cells fail to exit mitosis and undergo catastrophic cell death. Together, our findings identify CIN as a predictive marker of response to combined KRAS G12C and AURKA inhibition, providing mechanistic rationale to enhance the therapeutic window of AURKA inhibitors when used with targeted therapies."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKA • CCNB1 • KRAS

Aurora kinase A inhibition overcome adaptive resistance to KRAS G12C inhibitor by replication stress-induced genomic instability and mitotic cell death (AACR 2025) - "We show that the selective AURKAi (LSN3321213) induces mitotic catastrophe and subsequent cell death in NSCLC cells resistant to the G12Ci (LY3499446)...Furthermore, induction of CMYC expression in CMYC wild-type cell lines leads to mitotic catastrophe in response to G12Ci + AURKAi, suggesting that CMYC induces replication stress, thereby promoting a dependency on AURKAi. This study reveals a novel relationship between replication stress-induced genomic instability and mitotic defects in KRAS G12C NSCLC and identifies MYC amplification as a potential biomarker for guiding the selection of combined G12Ci and AURKAi therapy in patients with KRAS mutations and MYC amplification."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKA • KRAS • MYC

Targeted therapy-induced chromosomal instability dictates mitotic dependency on Aurora Kinase A. (PubMed, bioRxiv) - "Here, we show that the KRAS G12C inhibitor LY3499446 induces CIN in KRAS -mutant NSCLC cell lines...In the presence of Aurora Kinase A inhibition, cyclin B1 stabilization delays mitotic exit and diverts cell fate from mitotic slippage or division toward mitotic catastrophe. Together, our findings identify CIN as a predictive marker of response to combined KRAS G12C and Aurora Kinase A inhibition, providing mechanistic rationale to enhance the therapeutic window of AURKA inhibitors when used with targeted therapies."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKA • CCNB1 • KRAS

Aurora kinase A inhibition overcome adaptive resistance to KRAS G12C inhibitor by G1-checkpoint induced apoptosis in KRAS non-small cell lung cancer (AACR 2023) - "LY3499446 (KRAS G12Ci) and LSN3321213 (aurora kinase A inhibitor) induced apoptosis that is independent of inhibited MAPK reactivation...In summary, we provide clinical rationale for clinical testing of KRAS G12C + AURKA inhibitors. We also suggest a novel mechanism explaining the dependency of KRAS G12C resistant subpopulations on AURKA, leading to the opportunity to investigate the role of genomic instability in conferring KRAS G12Ci adaptive resistance."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKA • KRAS

A Study of LY3499446 in Participants With Advanced Solid Tumors With KRAS G12C Mutation (clinicaltrials.gov) - P1/2; N=5; Terminated; Sponsor: Eli Lilly and Company; N=230 ➔ 5; Trial completion date: Dec 2021 ➔ Oct 2020; Active, not recruiting ➔ Terminated; Trial primary completion date: Dec 2021 ➔ Oct 2020; The study was terminated due to an unexpected toxicity finding.

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

KRAS: From undruggable to a druggable Cancer Target. (PubMed, Cancer Treat Rev) - "Recently, several small molecules (AMG510, MRTX849, JNJ-74699157, and LY3499446) have been developed to specifically target K-RAS G12C. Additionally, various other approaches including, SHP2, SOS1 and eIF4 inhibition, have been utilized to abrogate tumor growth in K-RAS mutant cells, resulting in a renewed interest in this pathway. In this review article, we provide an overview on the role of K-RAS in tumorigenesis, past approaches to inhibiting Kras, and current and future prospects for targeting Kras."

Journal • Review • Oncology

[VIRTUAL] Synergy of novel KRAS G12C inhibitor LY3499446 in combination with abemaciclib or EGFR inhibitor for KRAS G12C mutant cancers (AACR-II 2020) - "EGFR inhibitors improved the degree of target engagement achieved by LY3499446 and this was also associated with enhanced anti-tumor activity in vitro and in vivo. Based on these data, LY3499446 is being tested with abemaciclib, erlotinib, and cetuximab in a Phase I clinical study (NCT94165031)."

Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • KRAS

A Study of LY3499446 in Participants With Advanced Solid Tumors With KRAS G12C Mutation (clinicaltrials.gov) - P1/2; N=230; Recruiting; Sponsor: Eli Lilly and Company; Suspended ➔ Recruiting

Clinical • Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Study of LY3499446 in Participants With Advanced Solid Tumors With KRAS G12C Mutation (clinicaltrials.gov) - P1/2; N=230; Suspended; Sponsor: Eli Lilly and Company; Recruiting ➔ Suspended

Clinical • Trial suspension • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • KRAS

A Study of LY3499446 in Participants With Advanced Solid Tumors With KRAS G12C Mutation (clinicaltrials.gov) - P1/2; N=230; Active, not recruiting; Sponsor: Eli Lilly and Company; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

"#EliLilly crashes out of #KRAS race as toxicity sees it ditch phase 1 effort #KRASInhibitor #LY3499446 https://t.co/N7LcrHz5kO" (,@1stOncology)

KRAS

KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? (PubMed, Cancer Treat Rev) - "Both AMG 510 from Amgen and MRTX849 from Mirati Therapeutics covalently binds to KRAS at the cysteine at residue 12, keeping KRAS in its inactive GDP-bound state and inhibiting KRAS-dependent signaling...In addition, two novel KRAS G12C inhibitors JNJ-74699157 and LY3499446 will have entered phase 1 studies by the end of 2019. Given the rapid clinical development of 4 direct covalent KRAS G12C inhibitors within a short period of time, understanding the similarities and differences among these will be important to determine the best treatment option based on tumor specific response (NSCLC versus colorectal carcinoma), potential resistance mechanisms (i.e. anticipated acquired mutation at the cysteine 12 residue) and central nervous system (CNS) activity. Additionally, further investigation evaluating the efficacy and safety of combination therapies with agents such as immune checkpoint inhibitors will be important next steps."

IO Biomarker • Journal • Review