Sotorasib for Lung Cancers with KRAS p.G12C Mutation

Abstract

Background: Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC).

Methods: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy.

Results: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53.

Conclusions: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Figure 1.. Efficacy of Sotorasib Therapy.

Panel A shows the best percentage decrease from baseline in the tumor burden (defined as the sum of the longest diameters of all target lesions) in 121 of 124 patients with non–small-cell lung cancer who had available post-baseline measurements of target lesions. The 3 patients whose data were excluded from the graph include 2 who had missing scans and 1 who had no measurement in target lesions and had progressive disease in nontarget lesions (progressive disease as the best overall response). Panel B shows the time to response, duration of response, and patient status as of the data-cutoff date for all 46 patients who had an objective response to sotorasib therapy. Panel C shows the Kaplan–Meier curve of progression-free survival among all 124 patients who could be evaluated for a response according to central review. Panel D shows the Kaplan–Meier curve of overall survival among all 126 patients enrolled in the trial. Tick marks in Panels C and D indicate censored data.

Figure 2.. Exploratory Biomarker Analyses.

Panel A shows the percentages of patients with an objective response associated with sotorasib therapy in subgroups categorized according to programmed death ligand 1 (PD-L1) expression level. A total of 86 patients with available tissue data were evaluated. Panel B shows the percentages of patients with an objective response in subgroups categorized according to the mutational status of TP53, STK11, and KEAP1, and Panel C the percentages of patients with an objective response in subgroups categorized according to the mutational status of STK11 and KEAP1. In these analyses, 104 patients with available tissue data, plasma data, or both were evaluated. In all panels, I bars represent 95% confidence intervals.