1398P - Hepatotoxicity in patients (pts) with KRASG12C-mutated non-small cell lung cancer (NSCLC) treated with sotorasib after prior immunotherapy (IO)

Background

Sotorasib after prior IO may increase the risk of immune-related toxicities. We aimed to investigate the potential association between the time interval between prior IO and sotorasib and the incidence of severe hepatotoxicity. IO levels at baseline and on-treatment sotorasib levels were also evaluated.

Methods

Pts with KRAS ^G12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). On-treatment ALT/AST was collected. Severe hepatotoxicity was defined as grade ≥3 ALT or AST increase (CTCAE v5.0). Plasma samples were collected for IO and sotorasib concentrations. Sotorasib concentrations were measured by validated liquid chromatography-mass spectrometry to calculate trough concentrations (C_trough). IO concentrations will be analysed shortly.

Results

At data cut off (April 28^th 2023), 90 pts were included, of which 79 (88%) received prior IO. Median time on sotorasib was 107 days (range 28 – 799). The incidence of severe hepatotoxicity was significantly higher in pts with prior IO than those without (29% vs 0%, p=0.04). Pts receiving sotorasib <6 weeks after IO (n=18) had a significantly higher incidence of severe hepatotoxicity than those with intervals of 6-12 weeks (n=24) and ≥12 weeks (n=37) (78% vs 25% vs 8%, respectively, p<0.001) (Table). Sotorasib concentrations of 108 samples from 46 pts were evaluable. Median C_trough did not differ between those with or without severe hepatotoxicity (90 versus 126 ng/mL, p=0.10). Table: 1398P

Conclusions

IO followed by sotorasib was associated with severe hepatotoxicity, especially in pts with a short interval between treatments. No association with systemic sotorasib levels was found, further suggesting the influence of prior IO. Relation with baseline IO levels will be presented at the conference. Our results strongly suggest a minimum interval of 6 weeks between last IO course and sotorasib initiation to reduce the risk of hepatotoxicity.

Clinical trial identification

NCT05221372.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M.S. Paats: Financial Interests, Institutional, Speaker, Consultant, Advisor: AstraZeneca, Bayer, Eli Lilly, Janssen, Novartis, Pfizer, Roche, Takeda. J.G. Aerts: Financial Interests, Personal, Advisory Board: BMS, MSD, Eli Lilly; Financial Interests, Institutional, Advisory Board: AstraZeneca, Pamgene; Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Takeda; Financial Interests, Personal, Other, Inventor/medical advisor: Amphera; Financial Interests, Personal, Stocks/Shares, value is undetermined: Amphera; Financial Interests, Institutional, Royalties, and personal if granted: Amphera; Financial Interests, Institutional, Coordinating PI: Eli Lilly, BMS; Non-Financial Interests, Leadership Role: IASLC. R.H. Mathijssen: Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Cristal Therapeutics, Pfizer, Roche, Sanofi, Servier, Boehringer Ingelheim, Novartis; Financial Interests, Institutional, Coordinating PI: Pamgene. A-M.C. Dingemans: Financial Interests, Institutional, Advisory Board: Roche, Sanofi, Amgen, Bayer, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker: Takeda, Lilly, Jansen, Pfizer, AstraZeneca; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Local PI: Lilly, Amgen, Daiichi, JNJ, Mirati; Financial Interests, Institutional, Coordinating PI: Roche; Financial Interests, Institutional, Steering Committee Member: Roche; Non-Financial Interests, Other, Chair EORTC lung cancer group: EORTC; Non-Financial Interests, Member: IASCL, ASCO, AACR. All other authors have declared no conflicts of interest.