RM-029 / Revolution Medicines - LARVOL DELTA

Overcoming KRAS G12C inhibitor resistance by promoting immune-mediated elimination of resistant subpopulations (EACR 2026) - "Our preclinical data demonstrate that rationally designed combination strategies can stimulate anti-tumour immune responses capable of promoting immune-mediated clearance of G12Ci-resistant subpopulations. These preclinical findings provide a foundation for the development of therapeutic combinations aimed at overcoming resistance to G12Ci and improving the durability of treatment responses."

Clinical • CD8 • IFNG • KRAS

KRAS Inhibitor Induced Cancer Cell Death Enhances Sensitivity to Immune-Mediated Bystander Killing of Drug-Resistant Subclones. (PubMed, Cancer Res) - "To investigate this, we developed a preclinical model that mimics the development of resistance to KRAS-G12C inhibitors (G12Ci), such as adagrasib and RMC-4998...Mechanistically, these combination therapies led to profound remodeling of the tumor immune microenvironment, making it less immunosuppressive, and promoted cancer cell death that primed an immune response, with an influx of cytotoxic T lymphocytes recognizing tumor associated antigens shared between G12Ci resistant and sensitive cancer cells. Promotion of immune-mediated bystander elimination of drug-resistant cells may provide a paradigm for tackling the problem of drug resistance in cancer more broadly."

IO biomarker • Journal • Oncology • KRAS

Combination therapies promote immune-mediated bystander killing of KRAS-G12C inhibitor resistant cells (AACR 2026) - "KRAS G12C inhibition as monotherapy using either the RAS(ON) G12C-selective inhibitor RMC-4998 or the KRAS G12C(OFF) inhibitor adagrasib, led to a rapid outgrowth of the G12Ci-resistant subpopulation...Moreover, transcriptional profiling suggested an enhanced interferon response in the G12Ci-resistant cells caused by the effect of G12Ci on the G12Ci-sensitive cells. Loss of IFNγ receptor rendered the resistant cells less susceptible to immune-mediated bystander killing, indicating that this process was at least partly dependent on their tumour cell–intrinsic ability to respond to IFNγ.Overall, our preclinical results demonstrate that appropriate combinations can elicit anti-tumour immune responses capable of bystander elimination of G12Ci-resistant subclones, providing a paradigm for the development of therapeutic combinations with greater potential to prevent or counteract the emergence of inhibitor resistance."

Combination therapy • Oncology • CD8 • IFNG • KRAS

Combining RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitors overcomes sotorasib resistance driven byKRASG12C amplification or NRASG13R mutation (AACR 2025) - "Amplification of the KRASG12C mutant allele and acquisition of NRAS mutations have been reported as resistance mechanisms in tumors progressing on sotorasib and adagrasib...We generated five sotorasib-resistant cell lines from relapsed tumors of sotorasib-treated H358 xenografts (MR1-MR5) and two vehicle-treated tumors (MV1 and MV2). We created an additional isogenic cell line model, H358-MX1, by treating H358 cells with sotorasib and a SHP2 inhibitor, RMC-4550...In H358-MX1 mouse xenografts, RMC-7977 + RMC-4998 significantly inhibited tumor growth compared to single-agent treatments or other combination regimens. These preclinical data suggest that combination of RAS(ON) mutant-selective and RAS(ON) multi-selective inhibitors overcome resistance to KRASG12C (OFF) inhibitors driven by KRASG12C amplification and secondary NRASG13R mutation in KRASG12C mutated lung cancer models."

Lung Cancer • Oncology • Solid Tumor • KRAS • MX1 • NRAS

Investigating therapeutic strategies to promote immune rejection of KRASG12C inhibitor-resistant subpopulations in lung cancer (AACR 2024) - "KRASG12C inhibition as monotherapy, either with the active-state KRASG12C inhibitor RMC-4998 or the inactive-state inhibitor adagrasib, led to a proliferative advantage of the drug-resistant subpopulation, suggesting that any immune response to KRASG12C inhibition in the bulk tumor population was insufficient to target the resistant cell subclones...Treatment of RMC-4998 in combination with either anti-PD1 or the SHP2 inhibitor RMC-4550 was able to induce complete eradication of both KRASG12C and KRASG12D mutant lung cancer cells, despite the resistant cells being insensitive to these therapies when treated in the absence of sensitive cells...Immune profiling of treated tumors revealed that both combinations can result in a more profound remodeling of the TME and potentiate the immune responses. Overall, our preclinical results demonstrate that the anti-tumor responses generated by the combination of KRASG12C inhibitors with SHP2 inhibition and/or immune checkpoint..."

Clinical • IO biomarker • Lung Cancer • Oncology • Solid Tumor • KRAS