Pooled safety analysis and management of sotorasib-related adverse events in <i>KRAS</i> G12C-mutated advanced non-small cell lung cancer
Ferdinandos Skoulidis, Bob T. Li, Maximilian J. Hochmair, Ramaswamy Govindan, Mark Vincent, Anthonie J. van der Wekken, N. Reguart Aransay, Kenneth J. O’Byrne, Nicolas Girard, Frank Griesinger, Makoto Nishio, Simon Häfliger, Colin R. Lindsay, Niels Reinmuth, Astrid Paulus, Pavlos Papakotoulas, Sang‐We Kim, Carlos Gil Ferreira, Giulia Pasello, M. Duruisseaux, Spyridon Gennatas, Anastasios Dimou, Bhakti Mehta, William Kormany, Chidozie Nduka, Brooke E. Sylvester, Christine Ardito-Abraham, Yang Wang, Adrianus J. de Langen
Abstract
INTRODUCTION: We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks. METHODS: Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment. RESULTS: In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; grade ≥ 3: 147 [26.8%]). Gastrointestinal and hepatic TRAEs, including diarrhea (171 [31.1%]), nausea (80 [14.6%]), elevated alanine aminotransferase (ALT; 68 [12.4%]), and elevated aspartate aminotransferase (AST; 67 [12.2%]) were the most common (≥10%). Dose interruption and dose reduction of sotorasib resulted in the resolution of >90% of diarrhea events; median time to resolution were 18.0 days and 22.0 days, respectively. Similar trends were observed for elevated ALT and AST events. Patients who stopped immunotherapy <3 months before initiating sotorasib had a higher incidence of treatment-related hepatotoxicity (80/240 [33.3%]) than those who stopped immunotherapy ≥3 months before initiating sotorasib (26/188 [13.8%]). Treatment-related pneumonitis/interstitial lung disease (ILD) and corrected QT (QTc) prolongation were observed in 9 (1.6%) and 4 (0.7%) patients, respectively. Two (0.4%) patients died with TRAEs, 1 with ILD whose ultimate cause of death was disease progression, and the other with an unknown cause. CONCLUSIONS: Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose modification.