Researchers have discovered that co-occurring mutations in three tumor-suppressor genes—KEAP1, SMARCA4, and CDKN2A—may be linked with poor clinical outcomes in patients with KRAS G12C–mutant non–small cell lung cancer (NSCLC) who were treated with the KRAS G12C inhibitors adagrasib or sotorasib, according to new findings presented by Negrao et al at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 3431).
The study results were also published by Negrao et al in Cancer Discovery.
The novel findings—which encompass one of the largest cohorts of this patient population to date—may provide a framework for clinicians and researchers to stratify patients by predicted clinical outcomes and to develop more effective treatment strategies for those unlikely to benefit from KRAS G12C inhibitors alone.
The KRAS protein is responsible for regulating normal cell growth and proliferation, but activating mutations may contribute to abnormal cell growth and cancer development. KRAS is the most common oncogenic driver of nonsquamous NSCLC, with mutations found in 25% to 30% of patients. The KRAS G12C mutation is found in approximately 13% of cases. Both adagrasib and sotorasib are approved by the U.S. Food and Drug Administration to treat patients with advanced KRAS G12C-mutant NSCLC who did not respond to at least one prior line of standard systemic therapy.
Unfortunately, while many patients benefit from these targeted therapies, most do not achieve durable disease control from either agent as a monotherapy. The median progression-free survival for patients treated with either drug is approximately 6 to 7 months.
“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,” explained lead study author Marcelo V. Negrao, MD, Assistant Professor of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “Therefore, it is important to understand biomarkers and to define subgroups of patients that will have better outcomes from single-agent therapy as well as patients that will require a different treatment strategy,” he added.
Study Methods and Results
In the new study, the researchers evaluated the outcomes of 424 patients across 21 centers who were treated with adagrasib or sotorasib monotherapy in order to better understand the molecular factors that may be associated with response or resistance to KRAS G12C inhibitors. The researchers found that among all patients involved in the study, the overall response rate was 34% and the median progression-free survival was 5.2 months. There were no significant associations between outcomes and the specific KRAS G12C inhibitor used.
The researchers then compared patients with distinct clinical outcomes to adagrasib and sotorasib—including those with durable benefit (progression-free survival of at least 6 months) and those with early progression (progression-free survival of 3 months or less). An unbiased analysis of co-occurring mutations in each group revealed that KEAP1, SMARCA4, and CDKN2A mutations were significantly enriched in patients with early progression. Mutations in each gene were independently associated with significantly shorter progression-free survival and overall survival. In contrast, STK11 and TP53 mutations did not appear to be associated with outcomes to either drug.
When assessed together, KEAP1, SMARCA4, and CDKN2A mutations were present in about 33% of the patients involved in the study and accounted for approximately 50% of those who exhibited early disease progression with single-agent KRAS G12C inhibitors. Because these three genes are routinely sequenced with current tumor profiling panels, the researchers hope this knowledge can be used to readily stratify patients into groups with distinct clinical outcomes.
In an exploratory analysis, co-mutations in genes involved with DNA damage repair and the ATRX/DAXX pathway were associated with improved outcomes, whereas, additional alterations in RAS genes and mutations in PI3K/AKT/MTOR pathway genes were linked with inferior outcomes. However, these mutations were less prevalent in this patient population and may require additional investigation.
“This study establishes the co-mutational landscape of early disease progression with KRAS G12C inhibitor monotherapy, and it provides a blueprint for personalizing treatment approaches with distinct combination strategies,” emphasized senior study author Ferdinandos Skoulidis, MD, PhD, MRCP, Associate Professor of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “Going forward, we plan to dig deeper into these molecularly defined subgroups [to] try to identify the best individualized therapeutic strategy for each group of patients,” he highlighted.
The researchers concluded that this study may help form rational hypotheses about which treatment strategies could be the most effective in each subgroup. The researchers are actively engaged in developing new KRAS G12C inhibitor–based combination therapies as well as novel immunotherapy approaches to address unmet needs for these patients.
Disclosure: The research in this study was supported by the National Institutes of Health/National Cancer Institute, The University of Texas MD Anderson Cancer Center’s Lung Cancer Moon Shot, Rexanna’s Foundation for Fighting Lung Cancer, the Elva J. and Clayton L. McLaughlin Fund for Lung Cancer Research, Team Stuie and LUNGSTRONG, and the German Center for Lung Research. For full disclosures of the study authors, visit abstractsonline.com or aacrjournals.org.
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