Sotorasib (Lumakras) continues to demonstrate durable efficacy in non–small-cell lung cancer (NSCLC) with KRAS p.G12C mutation at 2-year follow-up of the phase 2 CodeBreaK 100 clinical trial. At a median follow-up of 15.3 months, the 2-year overall survival (OS) was 32.5% in patients with pretreated NSCLC KRAS p.G12C mutation. These findings were presented at the 2022 American Association for Cancer Research annual meeting.
KRAS was formerly thought to be a nondruggable target in NSCLC. Sotorasib is the first KRASG12C inhibitor approved for the treatment of previously treated NSCLC with KRAS p.G12C mutation.
“This is the longest follow-up for a KRASG12C 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 historical treatment of pretreated NSCLC,” said lead investigator Grace K. Dy, MD, Chief of Thoracic Oncology and Professor of Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
“For example, the 2-year OS rate in patients with nonsquamous NSCLC treated with the chemotherapy agent docetaxel with or without the anti-VEGFR antibody therapy ramucirumab [Cyramza] as second-line therapy is expected to range between 15% and 22%,” she noted.
In May 2021, sotorasib was approved by the FDA for the treatment of previously treated NSCLC with KRAS p.G12C mutation based on the primary results of CodeBreaK 100.
Study Details
The global phase 2 CodeBreaK 100 trial enrolled patients with advanced or metastatic NSCLC with KRAS p.G12C mutation who were pretreated with ≥1 previous systemic therapies or who were ineligible/intolerant to previous therapy. Dr Dy presented a pooled analysis of 174 patients enrolled in phase 1 (N = 48) and 2 (N = 126). All patients were treated with sotorasib 960 mg orally once daily.
At baseline, 52% were male, mean age was 64.1 years, and the vast majority were current or former smokers. Sites of metastases included liver (21.8%), brain (23%), and bone (46.8%). Patients were treated with a median of 2 previous lines of therapy, including platinum-based chemotherapy (92.5%) and anti–PD-L1 therapy (90%). Eighty-three percent of patients had received both previous platinum-based chemotherapy and immunotherapy.
Median time to response was 6 weeks. Median duration of response was 12.3 months. The centrally confirmed objective response rate was 40.7%. Disease control rate was 83.7%.
Median progression-free survival was 6.3 months.
No change in median OS was observed in the updated analysis. Median OS was 12.5 months. The 1-year OS was 50.8%, and the 2-year OS was 32.5%.
“For the first time, this 2-year analysis showing OS of 32% means 1 out of 3 patients [treated with sotorasib] remain alive,” Dr Dy said. “These results are highly encouraging and set expectations for the confirmatory phase 3 CodeBreaK 200 trial [of sotorasib],” she added.
Safety Profile
Long-term treatment with sotorasib was well tolerated, with mild and manageable toxicities and no new safety concerns.
Grade 3 or 4 treatment-related adverse events occurred in 21%; only 1 of those patients had onset after 1 year (hemolytic anemia). No fatal treatment-related adverse events were reported, and no treatment-related adverse events occurred that led to discontinuation 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.
“We see benefit [of sotorasib] in patients with low levels of PD-L1 expression and STK11 co-mutations. 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,” she said.
Biomarker studies of CodeBreak 100 are ongoing.
