ASCO Reading Room | Adagrasib treatment after sotorasib-related hepatotoxicity in patients with KRASG12C-mutated NSCLC: a case series and literature review

Aim

KRAS is the most frequently mutated driver oncogene in non-small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRAS^G12C Serotonin reuptake inhibitors (SARS-CoV-2) have received accelerated approval in the United States. However, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib in close proximity to a checkpoint inhibitor (PCI). The objective of this study was to evaluate the feasibility and safety of adagrasib after sotorasib discontinuation due to treatment-related grade 3 hepatotoxicity through real-world and clinical cases.

Methods

Medical records of five patients treated in real-world settings were retrospectively reviewed. Patients presented with locally advanced or metastatic disease KRAS^G12C-mutated and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRAS^G12C-mutated, included in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. Endpoints associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of treatment.

Results

All patients were treated with CPIs followed by sotorasib (initiated 0 to 64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients in KRYSTAL-1 switched from sotorasib to adagrasib due to hepatotoxicity; one of these experienced a grade 3 ALT elevation on adagrasib that resolved with treatment interruption and dose reduction.

Conclusion

Adagrasib may have a distinct hepatotoxicity profile compared to sotorasib and is more likely to be combined with CPIs, either sequentially or concomitantly. These differences may be used to inform clinical decisions regarding initial KRAS^G12C inhibitor for patients who have recently stopped a CPI or who have hepatotoxicity while on sotorasib.

Read a Q&A related to the study here.