Sotorasib Versus Docetaxel for Previously Treated Non-Small Cell Lung Cancer with KRASG12C Mutation:Interpretation of A Randomized,Open-Label,Phase 3 Trial
Sotorasib is a specific,irreversible inhibitor of the GTPase protein KRASG12C.CodeBreaK 200 is a multi-center,randomized,open-label,phase Ⅲ clinical trial at 148 centers in 22 countries,which compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small cell lung cancer(NSCLC)with the KRASG12C mutation.The study enrolled patients aged at least 18 years-old with KRASc12C-mu-tated advanced NSCLC,who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 in-hibitor.The key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain le-sions,previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy was available(e.g.EGFR or ALK),previous treatment with docetaxel(neoadjuvant or adjuvant docetaxel was al-lowed if the tumour did not progress within 6 months after the therapy was terminated),previous treatment with a direct KRASG12C inhibitor,systemic anticancer therapy within 28 days of study day 1,and therapeutic or pal-liative radiation therapy within 2 weeks of treatment initiation.The trial randomly assigned(1∶1)patients to oral sotorasib(960 mg,once daily)or intravenous docetaxel(75 mg/m2,once every 3 weeks)in an open-label man-ner using interactive response technology.Randomization was stratified by number of previous lines of therapy in advanced disease(1 vs 2 vs＞2),ethnicity(Asian vs non-Asian),and history of central nervous system metas-tases(present vs absent).Treatment continued until an independent central confirmation of disease progression,intolerance,initiation of another anticancer therapy,withdrawal of consent,or death,whichever occurred first.The primary endpoint was progression-free survival,which was assessed by a blinded,independent central re-view in the intention-to-treat population.Safety was assessed in all treated patients.This trial was registered at ClinicalTrials.gov,NCT04303780,and is active but no longer recruiting.Between June 4,2020 and April 26,2021,345 patients were randomly assigned to receive sotorasib(n=171)or docetaxel(n=174),169(99％)pa-tients in the sotorasib group and 151(87％)in the docetaxel group received at least one dose.After a median follow-up of 17.7 months(IQR:16.4～20.1),the study met its primary endpoint of a statistically significant in-crease in the progression-free survival for sotorasib,compared with docetaxel[median progression-free survival[5.6 months(95％CI:4.3～7.8)vs 4.5 months(95％CI:3.0～5.7),hazard ratio=0.66(95％CI:0.51～0.86);P=0.001 7].Sotorasib was well tolerated,with fewer grade 3 or worse(33％vs 40％)and serious treatment-related adverse events compared with docetaxel(11％vs 23％).For sotorasib,the most common treatment-related ad-verse events of grade 3 or worse were diarrhoea(12％),alanine aminotransferase increase(8％),and aspartate aminotransferase increase(5％).For docetaxel,the most common treatment-related adverse events of grade 3 or worse were neutropenia(9％),fatigue(6％),and febrile neutropenia(5％).Sotorasib significantly increased progression-free survival and had a more favourable safety profile,compared with docetaxel,in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs.
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