Management of sotorasib-related adverse events and hepatotoxicities following anti-PD-(L)1 therapy: Experience with sotorasib in two French anti-cancer centers and practical guidance proposal.

Introduction: Sotorasib is a first-in-class KRASG12C inhibitor that showed significant clinical activity in KRAS ^G12C -mutated non-small cell lung cancer (NSCLC). The most frequent grade 3 or 4 sotorasib-related adverse events (AEs) were diarrhea (4-12 %) and hepatotoxicity (10.1-15.1 %). Data is lacking about the management of these AEs, especially in patients receiving sequential anti-PD-(L)1 and sotorasib therapy. Our aim was to report the management of grade ≥ 2 sotorasib-related AEs in real-world setting and to propose practical guidance for the management of grade ≥ 2 sotorasib-related AEs and more generally KRASG12C inhibitors-related AEs.
Materials and Methods: Records from all consecutive patients who initiated sotorasib through expanded access program in two French anti-cancer centers from January 1st 2021 to April 1st 2023 were reviewed to identify and grade sotorasib-related AEs, according to NCI-CTCAE v5.0., and to collect AEs management data. Patients were included in the analysis if they presented a grade ≥ 2 sotorasib-related AE.
Results: From 57 patients identified, 21 met inclusion criteria including eighteen (86 %) who received sequential anti-PD-(L)1 and sotorasib therapy. Hepatotoxicity (76 %) and diarrhea (24 %) were the most common grade ≥ 2 sotorasib-related AEs. Among the 16 patients with a grade ≥ 2 hepatotoxicity, 12 (75 %) definitely discontinued sotorasib, among which 9 (56 %) after dose reductions and rechallenge, and five (32 %) received corticosteroids, allowing only one patient to resume sotorasib. Diarrhea and nausea were usually manageable and not associated with sotorasib discontinuation. We propose a step-by-step management practical guidance for sotorasib-related hepatotoxicity based on dose-reduction and careful monitoring. Liver biopsy is strongly encouraged for grade 3 and 4 hepatotoxicity to assess candidates for corticosteroids.
Discussion: The experience with sotorasib might help better prevent, screen and manage sotorasib-related and other KRASG12C inhibitors-related AEs, particularly hepatotoxicity.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Ali Chour (ali.chour@chu-lyon.fr) reported no disclosures. Clémence Basse (clemence.basse@curie.fr) reported no disclosures. Nicolas Girard (nicolas.girard2@curie.fr) reported research grants/support from AstraZeneca, Amgen, Boehringer Ingelheim, Eli Lilly, Hoffmann-La Roche, Janssen, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Sivan, and Trizell; consultative services for Bristol Myers Squibb, AstraZeneca, AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly, Hoffmann-La Roche, Janssen, Merck, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Roche, Sanofi, and Sivan; payment for expert testimony from AstraZeneca; participation on a data safety monitoring board for Roche; leadership role in the International Thymic Malignancy Interest Group; and having employment of a family member with AstraZeneca. Fanny Lebossé (fanny.lebosse@chu-lyon.fr) reported no disclosures. Pierre-Emmanuel Bonté (pierreemmanuel.bonte@curie.fr) reported no disclosures. Michael Duruisseaux (michael.duruisseaux@chu-lyon.fr) reported Membership of an advisory council or committee for BMS, GSK, Sanofi, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, Merus, Amgen, Guardant, Pfizer; consulting fees from Roche, BMS, MSD, AstraZeneca, AbbVie, Takeda, Boehringer Ingelheim, Gamamabs Pharma, Pfizer; research grants from Takeda, NanoString, Lilly, Blueprint.].
(Copyright © 2024. Published by Elsevier B.V.)