LBA10 Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study

Sotorasib, an oral, irreversible KRASG12C inhibitor, is approved for the treatment of pre-treated adults with KRAS G12C-mutated advanced NSCLC. Here we report the primary analysis of the phase 3 CodeBreaK 200 trial comparing sotorasib vs docetaxel in KRAS G12C-mutated NSCLC. In this global, open-label phase 3 trial, 345 patients (pts) with KRAS G12C-mutated NSCLC who progressed after prior platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to oral sotorasib (960 mg daily) or intravenous docetaxel (75 mg/m2 every 3 weeks). Primary endpoint was progression-free survival (PFS) assessed by blinded independent central review 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 enrollment of 660 pts was reduced, and crossover from docetaxel to sotorasib was permitted following disease progression. At a median study follow-up of 17.7 months, the study met its primary endpoint of a statistically significant improvement in PFS with sotorasib vs docetaxel (HR, 0.66 [95% CI: 0.51, 0.86], P-value, 0.002). One-year PFS was 24.8% for sotorasib vs 10.1% for docetaxel, and PFS benefit was consistent across subgroups. ORR was significantly improved for sotorasib vs docetaxel (28.1% [95% CI 21.5–35.4%] vs 13.2% [95% CI: 8.6–19.2%], respectively; P<0.001). DCR was 82.5% for sotorasib vs 60.3% for docetaxel. Overall survival was not significantly different between treatment arms, though the study was not powered for OS. Safety findings are summarized (table).Table: LBA10TRAEs n (%)Sotorasib (N=169)Docetaxel (N=151)Any GradeGrade ≥3Any GradeGrade ≥3TRAE119 (70.4)56 (33.1)130 (86.1)61 (40.4)Serious adverse event18 (10.7)34 (22.5)TRAE leading to discontinuation16 (9.5)17 (11.3)Most common TRAEs*Diarrhea57 (33.7)20 (11.8)28 (18.5)3 (2.0)Fatigue11 (6.5)1 (0.6)38 (25.2)9 (6.0)Alopecia2 (1.2)031 (20.5)0Nausea24 (14.2)2 (1.2)30 (19.9)1 (0.7)Anemia5 (3.0)1 (0.6)27 (17.9)5 (3.3)ALT increased17 (10.1)13 (7.7)00AST increased17 (10.1)9 (5.3)00Neutropenia2 (1.2)015 (9.9)13 (8.6)Febrile neutropenia008 (5.3)8 (5.3)N represents treated patients. TRAE, treatment-related adverse event *Incidence per arm: >15%, any grade TRAE; >5%, grade ≥3 TRAEs Open table in a new tab In this first, randomized phase 3 trial for a KRASG12C inhibitor, oral sotorasib demonstrated superior PFS and ORR compared to intravenous docetaxel and had a more favorable safety profile.