Updated results from the phase IB CodeBreaK 101 trial support further research of sotorasib plus platinum doublet chemotherapy for treatment-naïve KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). Data on the first-line combination demonstrated an overall response rate (ORR) of 65% with a disease control rate (DCR) of 100% and a median progression-free survival (PFS) of 10.8 months.
“In the PDL-1 negative population, which represents an unmet medical need, the median progression-free survival was 11.9 months,” reported Bob T. Li, MD, PhD, MPH, Memorial Sloan Kettering Cancer Center, New York. “Treatment related adverse events (TRAEs) were mainly hematologic, consistent with the known safety profile of platinum-based chemotherapy.”
Dr. Li reported the updated CodeBreaK 101 results during the 2024 American Society of Clinical Oncology Annual Meeting. He said these results underscore the need for international participation in the phase III CodeBreaK 202 trial, which compares sotorasib plus platinum doublet chemotherapy to the KN189 regimen in patients with PDL-1 negative KRAS G12C-mutated NSCLC.
As Dr. Li indicated, the approval of sotorasib transformed the treatment landscape for KRAS G12C-mutated lung cancers; however, KRAS mutations quickly develop resistance across multiple pathways. Sotorasib combination therapy with chemotherapy and other approaches offer the potential to evade, or at least delay, the emergence of resistant phenotypes, he said.
CodeBreaK 101 is exploring multiple sotorasib combination regimens across multiple cancer types. Patients with advanced KRAS G12C-mutated NSCLC, either treatment-naïve or previously treated, received sotorasib plus carboplatin and pemetrexed for up to 4 cycles followed by maintenance sotorasib and pemetrexed until disease progression.
Primary endpoints were safety and tolerability. Secondary endpoints included ORR, DCR, duration of response (DoR), time to response (TTR), overall survival (OS), PFS, duration of stable disease (SD), and pharmacokinetics.
The sotorasib plus platinum doublet subgroup included 37 patients in the first-line setting and 21 patients in second or later line treatment. Baseline characteristics were typical of patients with KRAS G12C-mutated lung cancers. Most of the first-line patients, 59%, were PDL-1 negative, a group felt less likely to benefit from standard therapy; most of the second-line (2L) patients, 86%, had prior anti-PD-(L)1 treatment, and the majority of the 2L patients had PDL-1 expression of 50% or greater.
Dr. Li said there were numerically fewer TRAEs in the first-line group, 49% compared to 62% in second-line and beyond; however, TRAEs were consistent regardless of line of treatment. Most TRAEs were hematologic, consistent with the suppressive effects of platinum-based chemotherapy. Liver enzyme elevations were much less frequent in the first-line setting, Dr. Li added.
DCR in the first-line setting was 100%, and 94% of all patients showed tumor shrinkage on CT scans.
Median PFS in the first-line setting was 10.8 months and 8.3 months in the second line and beyond. Notably, PFS for PDL-1 negative patients in the first-line setting was 11.9 months after a median follow-up of more than 13 months. OS data are still immature and will be reported at a later date.
“While PFS may continue to mature, the data presented support an evaluation of this regimen as a potential new first-line therapy in a larger study,” Dr. Li said. “CodeBreaK 202 is a phase III global registration study of sotorasib in combination with carboplatin/pemetrexed versus the standard of care carboplatin/pemetrexed and pembrolizumab.”
CodeBreaK 202 launched in November 2023 and aims to enroll about 750 participants worldwide.
