Understanding and harnessing immune-modulatory effects of covalent KRASG12C inhibitors in KRASG12C-mutant non-small cell lung cancer

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PROJECT SUMMARY/ABSTRACT Oncogenic KRASG12C (KG12C) mutations underpin the development of ~13% of non-squamous non-small cell lung cancer (NSCLC) and account for ~10,000 deaths annually in the U.S. The development of potent, selective and clinically active covalent inhibitors of the KG12C oncoprotein represents one of the most exciting recent advances in the field of targeted cancer therapy, yet strategies to circumvent the development of adaptive resistance and improve the durability of individual responses to KG12C inhibitors are urgently needed in order to transform clinical outcomes for patients. In addition to their tumor cell-intrinsic effects, KG12C inhibitors recondition the tumor immune microenvironment in preclinical models and synergize with anti-PD-1 therapy to promote long-term tumor regressions and immunological memory. The mechanisms that underpin KG12C inhibitor-triggered immune pathway activation in KG12C NSCLC are poorly understood. Furthermore, the optimal combinations of KG12C inhibitors with standard of care (SOC) first-line NSCLC systemic therapies including platinum-doublet chemotherapy, PD-1 inhibitor monotherapy and chemo-immunotherapy in order to maximize antitumor immunity have not been established. Furthermore, the impact of co-occurring genomic alterations in STK11/LKB1, KEAP1, TP53 and RBM10 – that shape the immune contexture of KRAS-mutant NSCLC and modify its response to PD- 1 axis blockade – on the clinical efficacy and immunological sequelae of KG12C inhibitor-based therapeutic combinations has not been systematically examined. Based on our preliminary findings and previous work we hypothesize that: 1. Induction of immunogenic cell death contributes to KG12C inhibitor-triggered immune pathway activation in KG12C NSCLC; 2. KG12C inhibitors exhibit immune-sensitizing effects that can be further enhanced with the addition of chemotherapy and/or immune checkpoint inhibitors (ICI); 3. Co-occurring genomic alterations impact both clinical and immunological responses to KG12C inhibitor mono- and combination therapy in KG12C NSCLC. In Aim 1, we will dissect mechanisms and molecular determinants of KG12C inhibitor-mediated immune sensitization in KG12C NSCLC. In Aim 2, we will evaluate synergistic KG12C inhibitor interactions with standard of care first-line systemic therapies (including platinum-doublet chemotherapy, PD-(L)1 inhibitor monotherapy and chemo-immunotherapy) in immune-competent mouse models of KG12C-mutant NSCLC. In Aim 3, we will validate treatment-induced changes in the KG12C NSCLC immune contexture at whole-tumor and single-cell resolution using clinical samples from patients with surgically resected KG12C NSCLC who were treated with neo-adjuvant AMG 510 in combination with platinum-doublet chemotherapy in an investigator-initiated phase 2 clinical trial. Clinical significance: This work will yield fresh insights into mechanisms and determinants of immune pathway activation in response to KG12C inhibitor mono- and combination therapy and will facilitate the development of personalized co-mutation-tailored combination therapeutic strategies that aim to maximize the immune- sensitizing potential and long-term clinical benefit from KG12C inhibitors.