Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated <i>KRAS</i> G12C-Mutated Non–Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100

Abstract

<i>Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in</i> JCO <i>or elsewhere, for which the primary end point has already been reported.</i>In the longest follow-up, to our knowledge, for a KRAS^G12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with <i>KRAS</i> G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with <i>KRAS</i> G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic <i>STK11</i> and/or <i>KEAP1</i> alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis.