A retrospective observational study of the natural history of advanced non–small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease. (September 2021)

• Record Type: Journal Article
• Authors: Spira, Alexander I.; Tu, Huakang; Aggarwal, Shivani; Hsu, Hil; Carrigan, Gillis; Wang, Xuena; Ngarmchamnanrith, Gataree; Chia, Victoria; Gray, Jhanelle E.
• Is Part Of: Lung cancer. Volume 159(2021)
• Page Start: 1
• Page End: 9
• Publication Date: 2021-09
• Subjects: ALK anaplastic lymphoma kinase -- BRAF B-Raf proto-oncogene -- CGDB clinico-genomic database -- CGP comprehensive genomic profiling -- EGFR epidermal growth factor receptor -- EHR electronic health records -- FH-FMI Flatiron Health-Foundation Medicine -- G12C patients with KRAS p.G12C mutated NSCLC included in study -- KEAP1 Kelch-like ECH-associated protein 1 oncogene -- KRAS Kirsten rat sarcoma viral oncogene homolog -- KRAS p.G12C codon 12 glycine-to-cysteine substitution of KRAS -- MET mesenchymal-epithelial transition -- NGS next-generation sequencing -- NSCLC non‒small-cell lung cancer -- NTRK1‒3 neurotrophic tyrosine kinases 1–3 gene -- PD-1 programmed death 1 -- PD-L1 programmed death ligand 1 -- RAS rat sarcoma viral oncogene homolog -- RECIST Response Evaluation Criteria in Solid Tumors -- RET rearranged-during-transfection gene -- ROS1 ROS proto-oncogene 1 -- rwOS real-world overall survival -- rwPFS real-world progression-free survival -- STK11/LKB1 serine/threonine kinase 11, liver kinase B1 -- TP53 tumor protein p53 -- Triple WT KRAS/EGFR/ALK wild-type -- VEGF vascular endothelial growth factor; Non–small-cell lung cancer -- KRAS p.G12C -- Retrospective; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2021.05.026
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: The KRAS p.G12C mutation is a viable therapeutic target for NSCLC. KRAS p.G12C mutated advanced NSCLC is associated with poor outcomes. Findings indicate an unmet need for more effective novel treatments in NSCLC. Abstract: Introduction: The KRAS p.G12C mutation, prevalent in non–small-cell lung cancer (NSCLC), has only recently become a viable target. Here we present results of the largest retrospective observational study analyzing KRAS p.G12C in patients with advanced NSCLC. Materials and Methods: Adults with advanced NSCLC (All Advanced NSCLC cohort) and subcohorts with different mutation profiles ( KRAS p.G12C [G12C] and KRAS/EGFR/ALK wild type [Triple WT]) diagnosed January 2011 to March 2019 were selected from a US clinico-genomic database; treatment-related characteristics, molecular profiles, real-world overall (rwOS) and progression-free survival (rwPFS) were analyzed. Results: Demographics were similar across cohorts, with more smokers and nonsquamous cell carcinoma histology in the G12C cohort. KRAS p.G12C was nearly mutually exclusive (≤1.2 %) with known actionable driver mutations, but non-driver co-mutations were common ( STK11, 21.5 %; KEAP1, 7.0 %; TP53, 48.0 %). Among G12C patients, 20 % had no documentation of receiving systemic therapy. Across treated G12C patients, 67 % received immune checkpoint inhibitors; first-line usage increased from 0% (2014) to 81 % (2019). Among G12C patients, median (95 % CI) rwOS was 12.0 (9.6–15.3), 9.5 (8.1–13.1), and 6.7 (5.9–10.7) months after first, second, and third line of therapy, respectively; median (95 % CI) rwPFS was 5.0 (4.4–5.8), 4.0 (2.8–5.3), and 3.1 (2.4–4.3) months. Outcomes for the G12C subcohort were similar to those for all patients (All Advanced NSCLC cohort). Mutations in STK11/KEAP1 were associated with poorer survival across all cohorts. Conclusion: The poor outcomes associated with KRAS p.G12C mutated advanced NSCLC indicate an unmet need for more effective novel treatments.