Sotorasib continues to demonstrate durable efficacy in non–small-cell lung cancer (NSCLC) with the KRAS G12C mutation at the 2-year follow-up of the phase 2 CodeBreaK 100 trial. At a median follow-up of 15.3 months, the 2-year overall survival (OS) rate was 32.5% in patients with pretreated NSCLC and the KRAS G12C mutation. These findings were presented at the 2022 American Association for Cancer Research meeting.
KRAS was formerly thought to be a nondruggable target in patients with NSCLC. Based on the primary results of CodeBreaK 100, on May 28, 2021, sotorasib became the first KRAS G12C inhibitor to receive FDA approval as a second-line treatment of NSCLC with KRAS G12C mutation.
“This is the longest follow-up for a KRAS G12C inhibitor, including 2-year survival, updated safety, and genomic profiles in patients with durable clinical benefit. Thirty-two percent of patients treated with sotorasib had a survival of 2 years or more. This compares favorably with the historical treatment of pretreated NSCLC,” said lead investigator Grace K. Dy, MD, Chief of Thoracic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, at the meeting.
“For example, the 2-year overall survival rate in patients with nonsquamous NSCLC treated with the chemotherapy agent docetaxel, with or without the anti-VEGFR antibody therapy ramucirumab, as second-line therapy is expected to range between 15% and 22%,” Dr Dy noted.
This international study enrolled patients with advanced or metastatic NSCLC and the KRAS G12C mutation who had received at least 1 systemic therapy or who were ineligible for or intolerant to previous therapy. Dr Dy presented a pooled analysis of 174 patients enrolled in phase 1 (N = 48) and phase 2 (N = 126) of the study. The sites of the metastases included the liver (21.8%), brain (23%), and bone (46.8%).
The patients received a median of 2 previous lines of therapy, including platinum-based chemotherapy (92.5%) and anti–PD-L1 therapy (90%); 83% of patients received previous platinum-based chemotherapy and immunotherapy. All the patients received sotorasib 960 mg orally once daily.
The median time to response was 6 weeks, the median duration of response was 12.3 months, the objective response rate was 40.7%, and the disease control rate was 83.7%.
The median progression-free survival was 6.3 months.
There was no change in median OS in the updated analysis. The median OS was 12.5 months. The 1-year OS rate was 50.8%, and the 2-year OS rate was 32.5%.
“For the first time, this 2-year analysis showing overall survival of 32% means 1 of 3 patients [treated with sotorasib] remains alive,” Dr Dy said. “These results are highly encouraging and set expectations for the confirmatory phase 3 CodeBreaK 200 trial [of sotorasib].”
“Sotorasib was well-tolerated in the long-term. Late-onset treatment-related adverse events were mild and manageable,” Dr Dy pointed out.
Grade 3 or 4 treatment-related adverse events occurred in 21% of the patients; only 1 of those patients had onset (ie, hemolytic anemia) after 1 year. No fatal treatment-related adverse events and no treatment-related adverse events that led to treatment discontinuation occurred after 1 year.
“Most adverse events were grade 1 and 2. These data support the clinical observation that adverse events [with sotorasib] are manageable. Minimal or no cumulative toxicity contrasts with what we would expect with docetaxel,” Dr Dy emphasized.
“Our findings provide a rationale for studies that investigate the incorporation of sotorasib earlier in the course of treatment to improve outcomes for NSCLC patients who are less likely to benefit from immunotherapy,” Dr Dy said.