The CodeBreak 100 clinical trial is a multicenter, open-label, phase 1/2 clinical trial evaluating the use of sotorasib, a KRAS G12C inhibitor, in adults aged ≥18 years with previously treated advanced non–small cell lung cancer harboring the KRAS G12C mutation. The phase 1 primary end points were safety and tolerability, whereas the phase 2 primary end point was objective response rate (ORR); duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety were secondary end points. In the phase 2 analysis, sotorasib demonstrated an ORR of 37%. The DOR was 11.1 months, the median PFS was 6.8 months, and the median OS was 12.5 months. The safety profile was manageable.
A 2-year analysis of the CodeBreak 100 trial was recently published that assessed the long-term efficacy, safety, and biomarkers of 174 patients enrolled in the trial. The median treatment duration was 5.6 months. Safety analysis found that 121 patients experienced any-grade treatment-related adverse events (TRAEs), with the majority of TRAEs being grade ≤3. The most common TRAEs were diarrhea, increased alanine aminotransferase, and increased aspartate aminotransferase. TRAEs led to treatment reduction or interruption in 39 patients, and 11 patients discontinued treatment due to TRAEs. The median time to grade ≥3 diarrhea onset was 6.1 weeks, and for grade ≥3 hepatotoxicity the median time was 9.1 weeks. All patients with grade ≥3 diarrhea had their symptoms resolved, and all but 3 patients with grade ≥3 hepatotoxicity had resolution of hepatotoxicity. A total of 45 patients continued sotorasib treatment beyond 1 year, and 11 of these patients had any-grade TRAEs after 1 year of treatment. No grade 4 or 5 new-onset TRAEs occurred in these patients.
Efficacy analysis showed an ORR of 41% and a disease control rate of 84%. The median DOR was 12.3 months, the OS was 12.5 months, and the median PFS was 6.3 months. In all, 16 patients had brain metastases; 3 of these patients had a complete response and 11 had stable disease. Among 172 evaluable patients, 40 had PFS ≥12 months, and 62 patients had PFS ≤3 months. PD-L1 and/or biomarker data were available for 114 phase 2 patients. The most common mutations were TP53, LRP1B, KDM6A, and STK11. Long-term sotorasib use resulted in a PFS ≥12 months in 40 patients across PD-L1 expression levels. Prolonged benefit was found across KRAS G12C variant allele frequency level and in a proportion of patients who had STK11 and/or KEAP1 comutations. Patients with long-term benefit had an association with lower baseline circulating tumor DNA levels.
Source: Dy GK, Govindan R, Velcheti V, et al. Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated KRAS G12C-mutated non-small-cell lung cancer: 2-year analysis of CodeBreaK 100. J Clin Oncol. Published online April 25, 2023.