OBJECTIVES: Two KRAS^G12C inhibitors are approved for aNSCLC patients: adagrasib and sotorasib. Emerging evidence suggests an increased risk of high-grade, treatment-related hepatotoxicity with sotorasib when initiated within 90 days post-IO; however, the same has not been observed for adagrasib, hypothesized to result from differences in pharmacokinetic/pharmacodynamic profiles. This study explores the potential economic and clinical consequences of treatment-related hepatotoxicity with these two KRAS^G12C inhibitors.

METHODS: KRAS^G12C-mutated patients with aNSCLC enrolled in the KRYSTAL-1/CodeBreaK200 trials, whose most recent therapy was IO, informed the analysis. A model was developed for a hypothetical patient cohort where the index date was last administration of IO. Survival until initiation of adagrasib/sotorasib was approximated using published data, with grade≥3 hepatotoxicity rates/long-term survival from the clinical trials applied to the proportion of patients alive at various initiation points. Three scenarios for sotorasib initiation times were evaluated: 28 days, 2.6 months, and 4.41 months; adagrasib initiation was fixed at 28 days. A primary analysis compared hepatotoxicity-related management costs (US payer perspective), while a secondary analysis estimated life-years gained (LYG).

RESULTS: After a 28-day washout-period for both, adagrasib was associated with lower hepatotoxicity management costs versus sotorasib ($2,102 versus $5,263; net savings of $3,161). This cost-saving lessened with increasing time since prior-IO relative to the initiation of sotorasib. In the secondary analysis, LYG for adagrasib versus sotorasib were positive in all scenarios. Differences remained consistent across time points under conservative pre-treatment survival assumptions (LYG=0.47-0.51) and increased when using less optimistic pre-treatment survival (LYG=0.47 [28 days], 0.82 [2.6 months], and 1.10 [4.41 months]).

CONCLUSIONS: When adagrasib and sotorasib are initiated at the same time relative to prior-IO, adagrasib may offer economic benefits due to lower hepatotoxicity management costs. Furthermore, for patients who initiate adagrasib sooner, given lower hepatotoxicity risk, additional clinical benefit may be realized from extended survival.