Efficacy and Safety of KRAS G12C Inhibitor IBI351 Monotherapy in Patients With Advanced NSCLC: Results From a Phase 2 Pivotal Study

Introduction: KRAS glycine-to-cysteine substitution at co don 12 (G12C) mutation is a well-recognized and increasingly promising therapeutic target with huge unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study. Methods: Eligible patients with NSCLC with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. The primary endpoint was confirmed objective response rate assessed by an independent radiological review committee (IRRC) as per Response Evaluation Criteria in Solid Tumors v 1.1. Other endpoints were safety, IRRC-confirmed disease control rate, duration of response, progression-free survival (PFS), and overall survival. Results: As of December 13, 2023, 116 patients were enrolled (Eastern Cooperative Oncology Group Performance Status 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1 or anti-PD-L1 inhibitors and platinum- based chemotherapy: 84.5%). As per the IRRC assessment, the confirmed objective response rate was 49.1% (95% confidence interval [CI]: 39.7-58.6), and the disease control rate was 90.5% (95% CI: 83.7-95.2). The median duration of response was not reached whereas disease progression or death events occurred in 22 patients (38.6%), and the median PFS was 9.7 months (95% CI: 5.6-11.0). overall survival data was immature. Treatment-related adverse events (TRAEs) occurred in 107 patients (92.2%) whereas 48 patients (41.4%) had equal to or higher than grade three TRAEs. Common TRAEs were anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%) and presence of protein in urine (25.0%). TRAEs leading to treatment discontinuation occurred in nine patients (7.8%). In biomarker evaluable patients (n = 95), all patients had positive KRAS G12C in tissue whereas 72 patients were blood-positive and 23 were blood-negative for KRAS G12C. Patients with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p < 0.05) and worse PFS (p < 0.05). Tumor mutation profiling identified tumor protein p53 (45.3%), serine/threonine kinase 11 ( STK11 ) (30.5%), and kelch-like ECH-associated protein 1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency equal to or higher than 5%, mutations of six genes ( STK11, kelch-like ECH- associated protein 1, phosphatidylinositol-4,5-bisphosphate 3- kinase catalytic subunit gamma, DNA polymerase epsilon, SMAD family member 4, and BMP/retinoic acid-inducible neural-specific protein 3 ) were significantly associated with worse PFS (p < 0.05). Mutation in STK11 was also found to have a significant association with higher tumor burden at baseline and lower response rate (p < 0.05). Conclusions: IBI351 monotherapy demonstrated prom- ising and sustained efficacy with manageable safety, sup- porting its potential as a new treatment option for KRAS G12C-mutant NSCLC. (c) 2024 Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.