Selective KRASG12C inhibitor sotorasib demonstrates superior PFS and ORR compared to docetaxel in previously treated patients with NSCLC

Results from the phase 3 CodeBreaK 200 trial showed a significant improvement in progression-free survival (PFS) and overall response rate (ORR) of the selective KRAS^G12C inhibitor sotorasib versus docetaxel in previously treated patients with KRAS^G12C-mutated non-small cell lung cancer (NSCLC).

KRAS mutations are associated with poor prognosis and occur in approximately 1 in 4 patients diagnosed with NSCLC. The specific KRAS^G12C mutation is harboured in approximately 11–16% of all KRAS-mutated cases [1]. Previously, the phase 1/2 CodeBreaK 100 study (NCT03600883) showed promising PFS, ORR, and overall survival (OS) in patients with KRAS^G12C-mutated NSCLC, when treated with the (oral) selective KRAS^G12C inhibitor sotorasib [2]. The current phase 3 CodeBreaK 200 trial (NCT04303780) evaluated the efficacy and safety of sotorasib versus docetaxel in previously treated KRAS^G12C-mutated NSCLC patients. The results were presented by Dr Melissa Johnson (Sarah Cannon Research Institute, TN, USA) [3].

The CodeBreaK 200 trial enrolled a total of 345 KRAS^G12C-mutated NSCLC patients who had undergone at least 1 prior therapy, including platinum-based chemotherapy and checkpoint inhibition. Participants were 1:1 randomised to receive sotorasib (960 mg daily) or docetaxel (75 mg/m² every 3 weeks). Cross-over to sotorasib following disease progression was allowed. The primary endpoint was PFS. The secondary endpoints were OS, ORR, time to response (TTR), duration of response, and safety.

With a median follow-up of 17.7 months, the median PFS for participants in the sotorasib arm was 5.6 versus 4.5 months for participants on docetaxel (HR 0.66; P=0.002). PFS rates at 12 months were 24.8% (sotorasib) and 10.1% (docetaxel). ORR was 28.1% versus 13.2% in participants treated with sotorasib and docetaxel, respectively. The median TTR was 1.4 versus 2.8 months, and the median duration of response was 8.6 versus 6.8 months in the sotorasib and docetaxel arm, respectively. There was no difference in OS between the two treatment arms (HR 1.01). However, due to an amendment to the study protocol, the CodeBreaK 200 trial did not have enough power to detect a significant difference in OS. Of note, 34% of patients treated with docetaxel crossed over to sotorasib.

Sotorasib was well-tolerated with a lower incidence of grade ≥3 treatment-related adverse events compared with docetaxel. Time to deterioration in the global health status, physical functioning, and cancer-related symptoms were delayed with sotorasib compared with docetaxel.

“These findings support that sotorasib forms an important treatment option in this setting and reinforce the importance of testing for KRAS^G12C mutations,” resolved Dr Johnson.

1. Palma G, et al. NPJ Precis Oncol. 2021;5(1):98.
2. Dy GK, et al. AACR Annual Meeting 2022. Abstract CT008.
3. Johnson ML, et al. Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS^G12C mutation: CodeBreaK 200 phase III study. Abstract LBA10, ESMO Congress 2022, 09–13 September, Paris, France.

 



Posted on 16 November 202215 February 2024