Abstract B029: Immune checkpoint mediated resistance to KRASG12D inhibition

Abstract Non-small cell lung cancer (NSCLC) remains a leading cause of cancer deaths in the U.S. KRAS mutations are among the most common oncogenic drivers, with two distinct mutations (G12C and G12D) being the most prevalent in smokers and non-smokers, respectively. This distinct expression has been linked to therapeutic responses, especially to immune checkpoint inhibitors (ICIs). Importantly, CD274/PD-L1 expression varies in the two subtypes, likely explaining different responses to ICI, which shows little efficacy in KRASG12D-mutant tumors. A deeper understanding of how KRASG12D shapes the tumor microenvironment (TME) and how KRAS inhibition interfaces with ICI therapy is needed to guide more effective treatment strategies. Using a KRASG12D genetically engineered mouse model, we have shown that genetic KRASG12D inhibition modulates immunosuppression and immune checkpoint expression in myeloid cells (Lasse-Opsahl & Barravecchia et al., JCI Insight 2025). Here, we tested the pan-RAS inhibitor RMC-7977 for 5 days at 10 mg/kg/day in this L-iKRASG12D model. Single-cell RNA sequencing revealed that RMC-7977 significantly increased the percentage (∼36%) of neutrophils expressing PD-L1 but did not affect neutrophil abundance, indicating strong adaptive PD-L1–mediated resistance, and providing rationale for combining RMC-7977 with anti–PD-L1 ICI. Interestingly, when we tested co-targeted therapy (RMC-7977 + anti-PD-L1 [6.7 mg/kg]), we observed no significant change in the percentage of neutrophils expressing PD-L1, but did see a reduction in neutrophil abundance, suggesting additional alterations in the TME. To assess therapeutic efficacy of this combination, we used an orthotopic KRASG12D lung cancer model derived from the L-iKRASG12D model. Consistent with our prior observations, genetic KRASG12D inhibition combined with anti–PD-L1 significantly extended survival. In contrast, pharmacological KRAS inhibition (RMC-7977) combined with anti–PD-L1 did not show a survival benefit. These results suggest that RMC-7977 may activate a distinct resistance mechanism from genetic KRAS inhibition that limits therapeutic durability. However, longer pharmacological intervention may be needed to achieve survival benefit with ICI. Unlike genetic inhibition, which maintains stable pathway suppression, pharmacologic intervention is temporary, allowing persister cells to regain KRAS signaling after discontinuing treatment. Future studies will assess whether sequential dosing with a KRAS inhibitor plus anti–PD-L1 prevents tumor recurrence. In conclusion, our findings show that KRASG12D inhibition reshapes the TME by increasing the percentage of PD-L1+ neutrophils and reducing overall neutrophil abundance when combined with anti–PD-L1 therapy. Our survival study further suggests that achieving sustained KRAS inhibition may be necessary for combination with ICI to achieve clinical benefit, though we acknowledge that prolonged dosing may be limited by toxicities. These insights may potentially inform optimized or sequential KRASi–ICI strategies to prevent tumor recurrence. Citation Format: Niloofar Khairkhah, Ali Namvar, Mostafa M H. Ibrahim, Emily L. Lasse-Opsahl, Carlos E. Espinoza, Megan Faunce, Lily Rober, Marina Pasca di Magliano, Stefanie Galban. Immune checkpoint mediated resistance to KRASG12D inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B029.