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

Abstract

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 JCO or elsewhere, for which the primary end point has already been reported.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 KRAS 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 KRAS 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 STK11 and/or KEAP1 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.

FIG 1.

Long-term benefit and outcomes with sotorasib treatment. Kaplan-Meier plot of (A) PFS and (B) OS (median OS follow-up of 24.9 months [range, 0.7-35.9 months]) by central review, and (C) swimmer plot for phase I and phase II responders by central review (one patient with an ongoing response ended treatment because of patient request). BOR, best objective response; CR, complete response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response.

FIG 2.

Association of long-term benefit and early progression with PD-L1 expression and genomic alterations: (A) PD-L1 tumor proportion score, (B) selected genomic alterations, (C) STK11 and KEAP1 mutations, and (D) Mutant versus wild-type STK11. CR, complete response; IHC, immunohistochemistry; PFS, progression-free survival; PR, partial response.