Impact of immunotherapy on sotorasib toxicity in NSCLC: A real-world matched analysis.

e16184 Background: Sotorasib is a standard targeted therapy for KRAS G12C-mutated advanced NSCLC. Emerging real-world evidence suggests that sequential treatment following immune checkpoint inhibitors (ICIs) potentiates severe hepatotoxicity. We sought to quantify the specific risk of prior ICI exposure and determine if extending the washout interval reduces toxicity. Methods: We conducted a retrospective cohort study of patients with NSCLC treated with sotorasib following ICI therapy. Patients were required to have baseline AST/ALT ≤120 U/L. 1:1 propensity score matching (PSM) was done for age at index, race, gender, liver metastasis, alcohol-related disorders, liver disease, obesity, and statin use. We performed 3 parallel analyses: (1) Impact of Exposure: Any ICI exposure within 1 year (n = 458) vs. ICI-naïve patients (n = 458) (2) Impact of 6-week Washout: Sotorasib initiation < 6 weeks (n = 242) vs. > 6 weeks (n = 198) post-ICI. (3) Impact of 12-week Washout: Sotorasib < 12 weeks (n = 311) vs. > 12 weeks (n = 129) post-ICI. Outcomes were Grade ≥3 hepatotoxicity (AST/ALT > 3x ULN or Total Bilirubin > 3 mg/dL) and risk of diarrhea/colitis within 90 days. Results: In matched cohorts (n = 386/arm), prior ICI exposure significantly increased the rates of Grade ≥3 hepatotoxicity compared to ICI-naïve patients [RR 3.0; p < 0.001]. No significant difference was observed in GI toxicity rate. Among ICI-exposed patients, washout duration did not significantly alter hepatotoxicity. 6-week washout (n = 171/arm) showed no significant difference in hepatotoxicity as did the 12-week analysis (n = 113/arm). Conversely, acute initiation of sotorasib ( < 6 weeks) significantly increased diarrhea/colitis rates [RR 1.78; p = 0.03]. This signal was not significant in the 12-week analysis. Conclusions: Prior immunotherapy confers a near three-fold increase in sotorasib-induced hepatotoxicity risk, which was noted to be independent of washout interval (contrasting from prior reports) suggesting that 3-month rule for liver safety may be conservative. However, initiating sotorasib within 6 weeks of ICI was associated with a two-fold increase in the risk of colitis/diarrhea clinically justifying a 6-week washout to minimize severe gastrointestinal adverse events. Sensitivity analyses with extended follow-up (6 months) showed increased hepatotoxicity only in hyper-acute (3-week) settings, likely confounded by rapid disease progression than delayed toxicity onset. Sotorasib toxicity risks by ICI exposure and timing. Comparison Event Rate (%) RR (95% CI) p-value Prior ICI in 1year vs ICI naive Hepatotoxicity 13.2% vs. 4.4% 3 (1.76 - 5.1) <0.001 GI toxicity 14.2% vs 11.1% 1.28 (0.88 – 1.86) 0.20 <6 vs ≥6wk washout Hepatotoxicity 11.7% vs 10.5% 1.11 (0.61-2.03) 0.73 GI toxicity 18.7% vs 10.5% 1.78 (1.04 - 3.04) 0.03 <12 vs ≥12wk washout Hepatotoxicity 11.5% vs 10.6% 1.08 (0.52 - 2.27) 0.83 GI toxicity 13.3% vs 12.4% 1.07 (0.54 - 2.12) 0.84