Treatment-Related Hepatotoxicity in NSCLC: Are All KRAS G12C Inhibitors Created Equal?

By: Joshua D. Madera, MD
Posted: Friday, June 28, 2024

The increased rate of hepatotoxicity associated with the KRAS G12C inhibitor sotorasib experienced by patients with non–small cell lung cancer (NSCLC) has motivated researchers to determine the efficacy and safety of another KRAS G12C inhibitor—adagrasib. The hepatotoxicity profile associated with adagrasib appears to be distinct from that of sotorasib, and these distinctions may be employed to improve clinical decision-making in this patient population, suggested Hatim Husain, MD, of Moores Cancer Center at the University of California San Diego Health, La Jolla, and colleagues in a study published in JCO Precision Oncology.

“In the present case series, most patients who discontinued sotorasib because of hepatotoxicity did not have hepatotoxicity with adagrasib,” the study authors noted. “This, together with more general reports of hepatotoxicity from CodeBreaK 200 and KRYSTAL-1, plus preliminary findings from KRYSTAL-7, indicates that adagrasib is a feasible option where hepatotoxicity is a concern.”

A retrospective analysis was performed on the medical records collected from five real-world patients with locally advanced or metastatic KRAS G12C–mutated NSCLC. All patients received adagrasib therapy after the discontinuation of sotorasib. Patients had no evidence of extracranial disease progression. A second analysis was performed on 12 patients recruited from the KRYSTAL-1 trial. These patients were also previously treated with sotorasib. All patients were closely monitored to assess the time of onset and severity of treatment-related hepatoxicity.

According to the study authors, all five real-world patients treated with sotorasib developed hepatotoxicity that required treatment discontinuation. After these patients were switched to adagrasib, they did not experience any additional treatment-related hepatotoxicity. Furthermore, based on an analysis of the patients recruited from the KRYSTAL-1 trial, three patients required a transition from sotorasib to adagrasib because of treatment-related hepatotoxicity. While on adagrasib therapy, one patient demonstrated elevated alanine transaminase levels, which resolved after treatment interruption and dose reduction.

Disclosure: For full disclosures of the study authors, visit ascopubs.org.

JCO Precision Oncology