Posted: Tuesday, May 9, 2023
Marcelo V. Negrao, MD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues examined the molecular determinants of the efficacy of KRAS G12C inhibitors, such as adagrasib or sotorasib, in treating advanced non–small cell lung cancer (NSCLC). The researchers discovered that co-occurring mutations in three tumor suppressor genes—KEAP1, SMARCA4, and CDKN2A—are linked with poor clinical outcomes in patients with KRAS G12C–mutant NSCLC treated with either agent alone. The findings were presented at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 3431) and published in the AACR journal Cancer Discovery.
“KRAS G12C inhibitors have revolutionized the care of patients with lung cancer, but we see nonuniform clinical outcomes when these drugs are used as single agents,” said Dr. Negrao in an MD Anderson press release. “Therefore, it is important to understand biomarkers and to define subgroups of patients who will have better outcomes from single-agent therapy as well as patients who will require a different treatment strategy.”
The investigators recruited 411 patients with stage IV NSCLC who were treated with single-agent KRAS G12C inhibitors at 20 centers in the United States and Europe. The study found that co-alterations in KEAP1, SMARCA4, and CDKN2A/B were associated with significantly shorter progression-free survival and overall survival with KRAS G12C inhibitors. The impact of selected co-alterations on sotorasib efficacy was assessed in synergistic (C57BL/6) KRAS G12C inhibitor NSCLC models. On the other hand, co-mutations in DNA damage repair genes and genes encoding components of the ATRX/DAXX/EZH2 pathway were associated with improved KRAS G12C inhibitor efficacy. PI3K/AKT/MTOR/PTEN alterations and missense ROS1/ALK/BRAF/NTRK1-3 mutations resulted in inferior outcomes.
The results of this study suggest that tailoring of KRAS G12C inhibitor–anchored therapeutic strategies and patient stratification should take into account the co-mutation status of individual tumors.
Disclosure: For full disclosures of the study authors, visit abstractsonline.com.