Sotorasib demonstrates superior PFS versus docetaxel in patients with pre-treated KRAS.G12C-mutated NSCLC
At ESMO 2022, the primary analysis of the phase III CodeBreaK 200 trial , a first, randomised phase III trial for a KRAS.G12C inhibitor, comparing sotorasib vs. docetaxel in previously treated KRAS.G12C-mutated non-small cell lung cancer were presented. Oral sotorasib demonstrated superior progression-free survival and objective response rate compared to standard of care intravenous docetaxel and had a more favourable safety profile.
Historically, docetaxel has been the preferred treatment option following progression on platinum-based chemotherapy and/or immunotherapy. Recent retrospective data suggest an improvement in outcomes when patients receive prior immunotherapy, likely due to a chemosensitisation effect post immunotherapy. Sotorasib, an oral, irreversible KRASG12C inhibitor, is approved for the treatment of pre-treated adults with KRASG12C-mutated advanced non-small cell lung cancer (NSCLC). In the first phase III study for a KRASG12C inhibitor, CodeBreaK 200 evaluated sotorasib compared with docetaxel in previously treated KRASG12C-mutated advanced NSCLC.
Study design
In this global, open-label phase III trial, 345 patients with locally advanced/unresectable or metastatic KRASG12C-mutated NSCLC who progressed after prior platinum-based chemotherapy and a checkpoint inhibitor were randomised 1:1 to oral sotorasib (960 mg daily) or intravenous docetaxel (75 mg/m2 every 3 weeks). Patients with active brain metastases were excluded from the trial. Primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST 1.1. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. After study initiation and per regulatory guidance, initial planned enrolment of 660 patients was reduced to approximately 330 patients, and crossover from docetaxel to sotorasib was permitted following disease progression.
Results
At a median study follow-up of 17.7 months, CodeBreaK 200 met its primary endpoint with sotorasib demonstrating superior PFS over docetaxel. Median PFS was 5.6 months with sotorasib and 4.5 months with docetaxel (HR[95%CI]: 0.66[0.51-0.86], p= 0.002). The 12-month PFS rate was 24.8% for sotorasib and 10.1% for docetaxel. PFS favoured sotorasib vs. docetaxel across all subgroups. The response rate was significantly higher in patients receiving sotorasib as compared to those receiving docetaxel (28.1% vs. 13.2%, p< 0.001), with a DCR of 82.5% and 60.3%, respectively. Furthermore, sotorasib was associated with both faster time to response (median 1.4 vs. 2.8 months) and longer duration of response (median 8.6 vs. 6.8 months). Overall survival was not significantly different between treatment arms (HR[95%CI]: 1.01[0.77-1.33], p= 0.53). However, the study was not powered for OS and crossover was permitted following disease progression. Respectively 4% and 34% of patients in the sotorasib and docetaxel arms received a subsequent KRASG12C inhibitor, including crossover.
Sotorasib was well tolerated with a lower incidence of grade ≥3 (33.1% vs. 40.4%) and serious treatment-related adverse events (TRAEs) vs. docetaxel (10.7% vs. 22.5%). The most common grade ≥3 TRAEs with sotorasib were diarrhoea and elevated liver enzymes, and with docetaxel were neutropenia, fatigue and febrile neutropenia. Change over time in global health status, physical functioning and dyspnoea all favoured sotorasib. However, cough and chest pain did not show significant differences in symptom improvement. Time to deterioration in global health status (6.6 vs. 9.3 weeks), physical functioning (9.4 vs. 15.1 weeks), dyspnoea (6.6 vs. 12.1 weeks) and cough (15.2 vs. 49.3 weeks) were delayed with sotorasib compared to docetaxel.
Conclusion
Sotorasib showed significant improvement in the primary endpoint of PFS versus docetaxel in previously treated KRASG12C-mutated NSCLC. Also ORR, DCR, TTR and DOR were improved for sotorasib vs. docetaxel. There was no observed difference in OS, although the study was not powered to detect a statistical difference. Sotorasib was well-tolerated with fewer grade ≥3 TRAEs than docetaxel. Finally, clinically meaningful patient-reported outcomes were superior for sotorasib vs. docetaxel. These findings support sotorasib as an important treatment option in this setting and reinforce the importance of NGS testing for KRASG12C.
Reference
Johnson M, et al. Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. Presented at ESMO 2022; Abstract LBA10.
