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The European Commission has granted conditional marketing authorization to sotorasib for the treatment of adult patients with KRAS G12C mutant advanced non–small cell lung cancer.
The European Commission has granted conditional marketing authorization to sotorasib (Lumykras) for the treatment of adult patients with advanced non–small cell lung cancer (NSCLC) whose tumors harbor a KRAS G12C mutation and who have progressed following at least 1 previous line of systemic treatment.1
The regulatory decision is based on data from the phase 2 CodeBreaK 100 trial (NCT03600833), which showed that when the drug was given at a once-daily dose of 960 mg, it induced an objective response rate (ORR) of 37.1% (95% CI, 28.6%-46.2%), with a median duration of response (DOR) of 11.1 months (95% CI, 6.9–not evaluable [NE]).2,3 The median time to response (TTR) was 1.35 months, and the disease control rate (DCR) was 80.6% (95% CI, 72.6%-87.2%).
At a median follow-up of 15.3 months, sotorasib resulted in a median progression-free survival (PFS) of 6.8 months (95% CI, 5.1-8.2) and a median overall survival (OS) of 12.5 months (95% CI, 10.0–NE).
Continued approval for this indication may be dependent upon verification and description of clinical benefit in a confirmatory trial, according to Amgen.
“The approval of [sotorasib], the first and only targeted therapy for KRAS G12C–mutated NSCLC with proven efficacy, has the potential to transform treatment outcomes for people in the European Union living with this notoriously difficult-to-treat cancer,” David M. Reese, MD, executive vice president of Research and Development at Amgen, stated in a press release. “Amgen’s landmark scientific discovery allowed investigators to advance the first KRAS G12C inhibitor into the clinic, and we look forward to bringing the critical innovation to more patients across the globe.”
A total of 126 patients with locally advanced or metastatic, KRAS G12C–mutated NSCLC were enrolled to CodeBreaK 100. Patients needed to have experienced disease progression on prior standard therapies.
Participants were administered oral sotorasib at a dose of 960 mg, given once daily, until progressive disease. Patients underwent radiographic scans every 6 weeks up to week 48 and once every 12 weeks thereafter.
The primary end point of the trial was independent central review–assessed ORR per RECIST v1.1 criteria. Important secondary end points included DOR, DCR, TTR, PFS, OS, and safety.
The median age of study participants was 63.5 years (range, 37-80), 30.2% had an ECOG performance status of 0, and 92.9% were either current or former smokers. Forty-two percent of patients received 1 prior line of therapy; 34.9% and 22.2% of patients, respectively, received 2 or 3 prior lines of treatment. Moreover, 89.7% of patients previously received platinum-based chemotherapy, 91.3% previously had a PD-1/PD-L1 inhibitor, and 81.0% of patients had received both approaches.
Results from an exploratory analysis of the trial indicated that tumor mutational burden (TMB) was not a predictive factor of response to treatment. Data showed that among those with TMB-high disease (defined as ≥ 10 mutations/mb), the ORR was 40.0% with sotorasib vs 42.0% in those with TMB-low disease (defined as < 10 mutations/mb).
Additional findings revealed that those with TP53 wild-type or mutated disease experienced ORRs of 40% and 39%, respectively, with the agent. The ORRs in those with STK11 wild-type or mutated disease were 39% and 40%, respectively. Lastly, those with KEAP1 wild-type disease reported an ORR of 44% with sotorasib, and those with KEAP1-mutated disease had an ORR of 20%.
Moreover, in patients with STK11-mutated, KEAP1 wild-type disease (n = 22), the agent induced an ORR of 50%, a median PFS of 11.0 months, and a median OS of 15.3 months. Among patients with STK11-mutated, KEAP1-mutated disease, the ORR was 23% with sotorasib, the median PFS was 2.6 months, and the median OS was 4.8 months.
In those with STK11 wild-type and KEAP1-mutated disease, the ORR was 14%, the median PFS was 5.5 months, and the median OS was 7.5 months. Lastly, in those with STK11 wild-type and KEAP1 wild-type disease, the ORR was 42%, the median PFS was 6.8 months, and the median OS was NE.
Regarding safety, the most common toxicities reported with sotorasib included diarrhea (34%), nausea (25%), and fatigue (21%). The most frequent grade 3 or higher adverse effects were increased alanine aminotransferase (5%), increased aspartate aminotransferase (4%), and diarrhea (4%).
In May 2021, the FDA approved sotorasib (Lumakras) as the first treatment for adult patients with NSCLC whose tumors harbor KRAS G12C mutations and who have received at least 1 prior systemic therapy.4 The approval was based on earlier findings from CodeBreaK 100.