Study details
The French team was prompted to investigate the issue by a report of life-threatening hepatitis in a patient with NSCLC for whom sotorasib therapy was initiated 14 weeks after treatment with pembrolizumab, as well as by “the long story of adverse events ... observed with sequential use of [immune checkpoint inhibitors] and targeted therapy.”
Like Dr. Weiss, they note that severe hepatotoxicity after anti–PD-L1 therapy has not, to date, been reported for other KRASG12C inhibitors.
Patients in the study were treated outside of clinical trials at 16 medical centers in France.
Half of the patients (24/48) who were treated immediately with an anti–PD-L1 after sotorasib therapy developed grade 3 or higher sotorasib-related adverse events, including 16 (33%) with severe sotorasib-related hepatotoxicity. Severe diarrhea and fatigue were also more frequent with sequential therapy.
Severe events typically occurred within 30 days of the last anti–PD-L1 infusion and to a lesser extent within 31-60 days.
In the control arm, the rate of severe sotorasib-related adverse events was 13% (7/54). Six patients (11%) experienced severe hepatotoxicity. There was one sotorasib-related death in the sequential therapy arm, which was due to toxic epidermal necrosis. No deaths occurred in the control group.
The two groups were balanced with respect to history of daily alcohol consumption and the presence of liver metastasis. More patients in the control arm had a history of hepatobiliary disease.
The study received no outside funding. Many of the authors report ties with pharmaceutical companies, including to Amgen, the maker of sotorasib, and Mirati Therapeutics, the maker of adagrasib. Dr. Weiss was an adagrasib investigator for Mirati. Dr. West is a regular contribiutor to Medscape and is an adviser for Amgen and Mirati as well as a speaker for Amgen. Dr. Borghaei reported extensive company ties. He has received research support, travel funding, and consulting fees from Amgen as well as consulting fees from Mirati.
A version of this article first appeared on Medscape.com.