Krascendo 1: Efficacy and safety of divarasib (diva) vs sotorasib (soto) or adagrasib (ada) in previously treated locally advanced or metastatic KRAS G12C-mutated NSCLC

doi:10.1056/nejmoa2605703

Krascendo 1

Paciente / Población Intervención / Exposición Comparación Desenlace

In patients with previously treated advanced or metastatic KRAS G12C-mutated NSCLC, divarasib improved progression-free and overall survival compared with investigator's choice of sotorasib or adagrasib.

N

338pacientes

Diseño

Phase 3, global, open-label trial randomising adults with ECOG PS 0/1 and advanced or metastatic KRAS G12C-mutated NSCLC after at least one prior systemic treatment (including anti-PD-1/PD-L1 and platinum-based chemotherapy) 1:1 to divarasib or investigator's choice of sotorasib or adagrasib, stratified by KEAP1 status, history of CNS metastases and intended KRAS G12C inhibitor (NCT06497556).

Desenlace

Progression-free survival per blinded independent committee review (BICR).

ResultadoMedian PFS per BICR 9.8 months (95% CI 8.1-12.9) with divarasib vs 5.7 months (95% CI 4.2-6.8) with control (sotorasib or adagrasib), stratified HR 0.58 (95% CI 0.44-0.76; P <0.0001). Median OS 17.7 months (95% CI 16.3-NE) vs 12.0 months (95% CI 10.0-15.2), stratified HR 0.56 (95% CI 0.41-0.78; P = 0.0005). Confirmed ORR per BICR 58.4% (94/161; 95% CI 50.4-66.1) vs 32.3% (54/167; 95% CI 25.3-40.0). Median treatment duration 11.3 vs 5.0 months. Grade 3-4 TRAEs 24.6% vs 34.5%, serious TRAEs 7.8% vs 15.2%, and TRAEs leading to discontinuation 4.8% vs 11.7%. There were no Grade 5 TRAEs.

Skoulidis F, Ahn M, Gadgeel S, et al. N Engl J Med. 2026; published online 25 October. 10.1056/nejmoa2605703

Discusión y crítica

This open-label phase 3 trial shows that divarasib significantly improved PFS and OS over an active KRAS G12C inhibitor control, and the primary endpoint was assessed by blinded independent review. Median follow-up was only 14.3 months and the upper confidence limit for median OS with divarasib was not estimable, so the survival data are still maturing. The control arm was mostly sotorasib (156 of 171) and had only 15 adagrasib patients, so the abstract says little about divarasib against adagrasib specifically, and treatment lasted twice as long with divarasib, which makes the adverse event comparison harder to read. Patient-reported outcomes, duration of response and results by stratification subgroup such as KEAP1 status or CNS metastases are not reported, and the study was funded by F. Hoffmann-La Roche Ltd.