Alexander I Spira1, Huakang Tu2, Shivani Aggarwal3, Hil Hsu4, Gillis Carrigan5, Xuena Wang6, Gataree Ngarmchamnanrith7, Victoria Chia8, Jhanelle E Gray9. 1. Virginia Cancer Specialists, 8503 Arlington Blvd Suite 400, Fairfax, VA, 22031, USA; US Oncology Research, The Woodlands, TX, USA; Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address: Alexander.Spira@USOncology.com. 2. Center for Observational Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: htu01@amgen.com. 3. Center for Observational Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: shivania@amgen.com. 4. Center for Observational Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: hhsu02@amgen.com. 5. Center for Observational Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: gcarriga@amgen.com. 6. Global Biostatistical Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA. Electronic address: xuenaw@amgen.com. 7. Clinical Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA. Electronic address: gatareen@amgen.com. 8. Center for Observational Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: vchia@amgen.com. 9. Department of Thoracic Oncology, Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL, 33612, USA. Electronic address: Jhanelle.gray@moffitt.org.
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.
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 G12Cpatients, 20 % had no documentation of receiving systemic therapy. Across treated G12Cpatients, 67 % received immune checkpoint inhibitors; first-line usage increased from 0% (2014) to 81 % (2019). Among G12Cpatients, 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.