Sotorasib vs adagrasib in the 2L+ setting: Outcomes in a large, multi-institutional, real-world database of KRAS-G12C mutated mNSCLC.

8608 Background: KRAS-G12C mutations are found in ~12% of mNSCLC. KRAS-G12C inhibitors sotorasib and adagrasib are approved treatments but have never been compared head-to-head. We report the first large, multi-institutional database analysis comparing efficacy and safety of sotarasib vs adagrasib. Methods: Flatiron Health's de-identified electronic health record US database was used to identify patients with KRAS G12C-mutated NSCLC who started treatment 12/2022-10/2025 with either sotorasib or adagrasib in 2L+. Baseline characteristics were abstracted and evaluated using chi-square tests, Wilcoxon rank-sum tests, and a multivariable logistic regression adjusting for practice type, sex, ECOG performance status, age, line of therapy, prior immunotherapy, and brain metastases. Overall survival (OS), progression-free survival (PFS), and time to treatment discontinuation (TTD) were estimated using Kaplan-Meier curves and compared using the log-rank test and Cox regression. Multivariable Cox regression model included sex, age, ECOG, line of therapy, prior immunotherapy, brain metastases, and PD-L1 expression to control for possible confounding. Results: Of the 1133 patients identified, 768 (69%) received sotorasib, and 345 (31%) received adagrasib. Sex, age, PD-L1 status and prior immunotherapy exposure did not affect choice of treatment (Table 1). In a multivariable logistic regression analysis, patients with brain metastases were more likely to be treated with adagrasib (HR =0.64; p=0.003), while patients with higher ECOG PS (2+) were more likely to be treated with sotorasib (HR =1.18; p=0.047). There was no difference in OS between sotorasib and adagrasib (HR = 1.01; p = 0.87), and there was no difference in OS on multivariable regression (adjusted HR = 0.96; p=0.02). There was no difference in PFS between sotorasib and adagrasib (HR = 0.91; p=0.15). Sotorasib had longer TTD than adagrasib (mTTD 3.8 vs 3.3m; HR = 0.82; p =0.005); this association persisted in the adjusted model (adjusted HR = 0.80; p=0.006). Conclusions: Sotorasib was associated with slightly longer TTD compared with adagrasib, which may suggest better tolerability, but no difference in PFS or OS. Sotorasib was more likely to be used in patients with poor PS while adagrasib was more likely to be used in patients with CNS metastases. Sotorasib (n = 768) Adagrasib (n = 345) p-value 2L (vs 3+) 68.6% 73.0% 0.15 ECOG PS 0-1 (vs 2-4) 64.6% 69.9% 0.13 PDL1 <1% 31.2% 38.3% 0.10 1-49% 36.4% 32.4% >=50% 32.4% 29.3% Prior immunotherapy 85.9% 89.0% 0.18 Brain metastases 28.1% 35.1% 0.02 mPFS 3.5 3.3 0.15*0.25 mTTD 3.8 3.3 0.005 *0.006 mOS 9.6 8.7 0.87*0.70 All survival data in months. Significant values in bold.