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Krascendo 1: divarasib vs sotorasib or adagrasib in pre-treated locally advanced or metastatic KRAS G12C-mutated NSCLC

Despite the emergence of first-generation KRAS G12C inhibitors such as sotorasib or previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC), a clear unmet need for a KRAS G12C inhibitor that meaningfully extends survival still exists. Divarasib, an oral, next-generation KRAS G12C inhibitor, has shown increased potency and selectivity compared to sotorasib or adagrasib in vitro.1,2

The Krascendo 1 trial (NCT06497556) is the first Phase III trial to directly compare divarasib with approved next-generation KRAS-targeted treatments. 338 patients with previously treated advanced or metastatic KRAS G12C-mutated NSCLC were randomized 1:1 to divarasib or the investigator’s choice of sotorasib or adagrasib, with most control patients receiving the former. The primary endpoint was PFS per blinded independent central review, with OS and objective response rate (ORR) among the secondary endpoints.3,4

The primary analysis was presented at the European Society for Medical Oncology (ESMO) 2026 Congress. At a median follow-up of 14.3 months, divarasib significantly improved PFS (9.8 vs 5.7 months; HR 0.58; 95% CI: 0.44–0.76) and OS (17.7 vs 12.0 months; HR 0.56; 95% CI: 0.41–0.78), with a higher ORR (overall response rate) (58.4% vs 32.3%). Treatment duration was twice as long with divarasib, yet grade 3–4 treatment-related adverse events (TRAEs) (24.6% vs 34.5%) and discontinuations due to TRAEs (4.8% vs 11.7%) were lower.3

Bo Wang, MD, SCRI, Willamette Valley Cancer Institute and Research Centers, Eugene, OR, who co-authored the abstract comments:

“What we have here is a significantly improved efficacy profile with an improved safety and tolerability profile as well, which is really, I think, the gold standard for trying to move targeted therapy forward and … I think at this point, divarasib will end up being the best-in-class therapy.”

Krascendo 1 provides the first evidence of a survival advantage for a KRAS G12C inhibitor in this setting. Consequently, these results are practice-changing, positioning divarasib as a potential new standard of care for previously treated KRAS G12C-mutated NSCLC, pending regulatory approval.

References:

  1. de Langen AJ, Johnson ML, Mazieres J, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS G12C mutation: a randomised, open-label, phase 3 trial. Lancet. 2023 Mar;401(10378):733-746.
  2. Sacher A, LoRusso P, Patel MR, et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med. 2023 Aug;389(8):710-721.
  3. Skoulidis  F, Ahn MJ, Gadgeel S, et al. 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. Presented at the ESMO 2026 Congress; October 23-27, 2026; Madrid, Spain.