Neoadjuvant KRAS G12C Directed Therapy With Adagrasib (MRTX849) With or Without Nivolumab

Approximately 30% of patients with non-small cell lung cancer (NSCLC) present with resectable disease, but following surgery, the majority will experience relapse and death from the cancer. Despite significant advances in therapy for advanced NSCLC, no new systemic neoadjuvant therapies have been approved for resectable NSCLC without an EGFR driver mutation in over 15 years, and these patients are in critical need of new treatments to improve rates of cure. Currently, the standard approach for resectable stage II and III disease is 3-4 cycles of pre- or postoperative chemotherapy, which provides an absolute 5-year survival benefit of only 5% over surgery alone. Neoadjuvant systemic therapy provides an opportunity to improve outcomes with surgery at a similar rate to adjuvant therapy, and is a more useful platform for advancing the development of new targeted and combination therapies. Pathologic complete response (pCR) and major pathologic response (MPR, ≤10% residual viable tumor) in the resected specimen serve as surrogate endpoints for event-free and overall survival, and are useful early efficacy endpoints to accelerate drug development. In resectable NSCLC, the rates of pCR and MPR with neoadjuvant immunotherapy alone are about 10% and 45% as compared to 4% and 20% with current standard of care chemotherapy. The recent approval of osimertinib in resected EGFR-mutated NSCLC has demonstrated the efficacy of targeted therapy in resectable disease, but is only available to a small minority of NSCLC patients. KRAS is the most commonly mutated oncogene in cancer representing a vast unmet clinical need, particularly in NSCLC where it is associated with smoking history and mutated in 30% of lung adenocarcinomas. Activating KRAS mutations promote signaling pathways for growth, survival and differentiation. The most common mutant allele is KRAS G12C, present in 1 in 8 patients with NSCLC (12.5%), and represents an aggressive NSCLC phenotype with significantly higher risk of recurrence following resection in stage I-III disease. Adagrasib is a novel small molecule inhibitor of KRAS G12C producing potent inhibition of KRAS-dependent signal transduction with high selectivity. Adagrasib has shown promise in advanced NSCLC, with 45% confirmed objective response rate and 96% disease control rate in the phase 1/2 KRYSTAL study. Finally, the investigators anticipate enhanced efficacy of Adagrasib in combination with immune checkpoint blockade. Emerging clinical data suggests that Adagrasib reconditions the tumor immune microenvironment to become more immune-sensitive (e.g. in immune "cold" STK11 co-mutated tumors), and combination treatment with anti-PD-1 therapy resulted in increased durable responses compared to either agent alone in a murine model. Adagrasib is well-tolerated and has been safely combined with anti-PD1 therapy in a phase I trial. This will be the first study to bring this combination forward in resectable lung cancer. This phase 2 clinical trial investigates the role of targeted KRAS G12C inhibition with and without the anti-PD-1 agent nivolumab in resectable NSCLC