•In our study, the vast majority of grade ≥ 2 adverse events (AEs) occurred in patients receiving sequential anti-PD-(L)1 and sotorasib therapy and are mostly represented by hepatotoxicity.•Dose reduction is generally insufficient to allow treatment continuation in case of grade ≥ 2 hepatotoxicity.•As corticosteroids impact on hepatotoxicity is unclear, liver biopsy can help discriminate candidates for corticosteroids in grade 3 or 4 hepatotoxicity.•Nausea and diarrhea are usually manageable with symptomatic treatment and do not lead to sotorasib discontinuation.•We propose practical guidance for sotorasib-related AEs prevention and hepatotoxicity management based on our experience and other available data that may be also useful for the new KRASG12C inhibitors in development. Sotorasib is a first-in-class KRASG12C inhibitor that showed significant clinical activity in KRASG12C-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. 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. 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. The experience with sotorasib might help better prevent, screen and manage sotorasib-related and other KRASG12C inhibitors-related AEs, particularly hepatotoxicity.