Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti-Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRAS G12C -Mutant Lung Cancer

• Published in: Journal of thoracic oncology
• Main Authors: Chour, Ali, Denis, Julie, Mascaux, Céline, Zysman, Maeva, Bigay-Game, Laurence, Swalduz, Aurélie, Gounant, Valérie, Cortot, Alexis, Darrason, Marie, Fallet, Vincent, Auclin, Edouard, Basse, Clémence, Tissot, Claire, Decroisette, Chantal, Bombaron, Pierre, Giroux-Leprieur, Etienne, Odier, Luc, Brosseau, Solenn, Creusot, Quentin, Gueçamburu, Marina, Meersseman, Corentin, Rochand, Adrien, Costantini, Adrien, Gaillard, Claire Marine, Wasielewski, Eric, Girard, Nicolas, Cadranel, Jacques, Lafitte, Claire, Lebossé, Fanny, Duruisseaux, Michaël
• Format: Journal Article
• Language: English
• Published: United States 20.05.2023
• Subjects: Anti–PD-(L)1; Non–small cell lung cancer; Sotorasib; Sequence; Hepatotoxicity; KRAS(G12C) mutation
• ISSN: 1556-1380

Sequential anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti-PD-(L)1. This study was designed to address whether sequential anti-PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs. This is a multicenter, retrospective study of consecutive advanced KRAS -mutant NSCLC treated with sotorasib outside clinical trials in 16 French medical centers. Patient records were reviewed to identify sotorasib-related AEs (National Cancer Institute Common Classification Criteria for Adverse Events-Version 5.0). Grade 3 and higher AE was considered as severe. Sequence group was defined as patients who received an anti-PD-(L)1 as last line of treatment before sotorasib initiation and control group as patients who did not receive an anti-PD-(L)1 as last line of treatment before sotorasib initiation. We identified 102 patients who received sotorasib, including 48 (47%) in the sequence group and 54 (53%) in the control group. Patients in the control group received an anti-PD-(L)1 followed by at least one treatment regimen before sotorasib in 87% of the cases or did not receive an anti-PD-(L)1 at any time before sotorasib in 13% of the cases. Severe sotorasib-related AEs were significantly more frequent in the sequence group compared with those in the control group (50% versus 13%, p < 0.001). Severe sotorasib-related AEs occurred in 24 patients (24 of 48, 50%) in the sequence group, and among them 16 (67%) experienced a severe sotorasib-related hepatotoxicity. Severe sotorasib-related hepatotoxicity was threefold more frequent in the sequence group compared with that in the control group (33% versus 11%, p = 0.006). No fatal sotorasib-related hepatotoxicity was reported. Non-liver severe sotorasib-related AEs were significantly more frequent in the sequence group (27% versus 4%, p < 0.001). Severe sotorasib-related AEs typically occurred in patients who received last anti-PD-(L)1 infusion within 30 days before sotorasib initiation. Sequential anti-PD-(L)1 and sotorasib therapy are associated with a significantly increased risk of severe sotorasib-related hepatotoxicity and severe non-liver AEs. We suggest avoiding starting sotorasib within 30 days from the last anti-PD-(L)1 infusion.