Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti-Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRASG12C-Mutant Lung Cancer.

INTRODUCTION: 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. METHODS: This is a multicenter, retrospective study of consecutive advanced KRASG12C-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. RESULTS: 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. CONCLUSIONS: 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.

Prognostic and Predictive Biomarkers in the Era of Immunotherapy for Lung Cancer.

The therapeutic algorithm of lung cancer has recently been revolutionized by the emergence of immune checkpoint inhibitors. However, an objective and durable response rate remains low with those recent therapies and some patients even experience severe adverse events. Prognostic and predictive biomarkers are therefore needed in order to select patients who will respond. Nowadays, the only validated biomarker is the PD-L1 expression, but its predictive value remains imperfect, and it does not offer any certainty of a sustained response to treatment. With recent progresses in molecular biology, genome sequencing techniques, and the understanding of the immune microenvironment of the tumor and its host, new molecular features have been highlighted. There are evidence in favor of the positive predictive value of the tumor mutational burden, as an example. From the expression of molecular interactions within tumor cells to biomarkers circulating in peripheral blood, many markers have been identified as associated with the response to immunotherapy. In this review, we would like to summarize the latest knowledge about predictive and prognostic biomarkers of immune checkpoint inhibitors efficacy in order to go further in the field of precision immuno-oncology.