Sotorasib, the first KRAS G12C inhibitor approved for the treatment of KRAS G12C–mutated non–small cell lung cancer (NSCLC), continues to demonstrate meaningful and durable efficacy at 2-year follow-up in the phase II CodeBreaK 100 trial. At a median follow-up of 15.3 months, 2-year overall survival was 32.5% in patients with pretreated KRAS G12C–mutated NSCLC. These data were presented by Grace K. Dy, MD, Chief of Thoracic Oncology and Professor of Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, at the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract CT008).
“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 historical treatment of pretreated NSCLC. 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%,” said Dr. Dy.
“These results are highly encouraging and set expectations for the confirmatory CodeBreaK 200 trial [of sotorasib],” she added.
Study Details
The prognosis of KRAS G12C–mutated NSCLC remains poor following disease progression on first-line treatment with currently used therapies. Sotorasib was approved by the U.S. Food and Drug Administration for the treatment of previously treated KRAS G12C–mutated NSCLC based on the primary results of CodeBreak 100.
The global phase II CodeBreaK 100 trial enrolled patients with advanced or metastatic KRAS G12C–mutated NSCLC who were pretreated with at least one prior systemic therapy or who were ineligible/intolerant to prior therapy. The pooled analysis that Dr. Dy presented included 174 patients enrolled in phase I (n = 48) and II (n = 126) of the study who were treated with sotorasib at 960 mg orally once daily.
At baseline, 52% were male, mean age was 64.1 years, and only 6.3% of participants had never smoked. Sites of metastases included the liver (21.8%), brain (23%), and bone (46.8%). The median number of prior lines of therapy was two; 92.5% had prior platinum-based chemotherapy and 90% had prior anti–PD-L1 therapy; 83% had both prior platinum-based chemotherapy and immunotherapy.
Key Findings
The median time to response was 6 weeks, and 70% of patients had an objective response. The centrally confirmed objective response rate was 40.7%, and disease-control rate was 83.7%. The median duration of response was 12.3 months; 50.6% of responders remained in response for 12 months or more.
Median progression-free survival was 6.3 months. The updated analysis of CodeBreaK 100 showed no change in median overall survival, which remained 12.5 months. The 1-year overall survival was 50.8%, and 2-year overall survival was 32.5%.
“For the first time, this 2-year analysis showing an overall survival of 32% means one out of three patients [treated with sotorasib] remain alive,” Dr. Dy said. “This sets the bar for what to expect with CodeBreaK 200 [the phase III trial].”
Adverse Events
Seventy percent of patients experienced any treatment-related adverse event; 24% had onset of a treatment-related adverse event after 1 year. Grade 3 or 4 treatment-related adverse events occurred in 21%, and only one of those patients had onset (of hemolytic anemia) after 1 year.
No fatal treatment-related adverse events were reported, and no treatment-related adverse events occurred that led to treatment discontinuation after 1 year. Treatment-related adverse events occurring in more than 10% of patients included diarrhea (31%), elevated liver enzymes (18%), nausea (16%), and fatigue (12%).
“Most adverse events were grade 1 or 2. There was no delayed onset of adverse events, contrary to what we would expect with chemotherapy or immunotherapy,” Dr. Dy said.
“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,” she emphasized.
“We see benefit [of sotorasib] in patients with low levels of PD-L1 expression and STK11 comutations. Our findings provide a rationale for studies that investigate the incorporation of sotorasib earlier in the course of treatment to improve outcomes for [patients with NSCLC] who are less likely to benefit from immunotherapy,” Dr. Dy said. Biomarker studies are ongoing.
Comment on Study
At a press conference where this study was discussed, AACR Clinical Trials Committee Co-Chair Timothy Yap, MBBS, PhD, FRCP, of The University of Texas MD Anderson Cancer Center, said that the optimal use of sotorasib remains to be defined. “There is no simple answer, given the combinations of immunotherapies being explored in NSCLC,” Dr. Yap said.
Disclosure: For full disclosures of the study authors, visit www.abstractsonline.com.
