November 3rd, 2026
Summary by Mark L. Fuerst
Patients with previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC) lived longer with the oral investigational drug divarasib than with existing approved targeted therapies sotorasib and adagrasib, according to results presented at the 2026 ESMO Congress in Madrid, Spain (Abstract LBA5).
At a median follow-up of 14.3 months, divarasib improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR), with fewer severe side effects. Median OS was 17.7 months with divarasib compared with 12 months with sotorasib or adagrasib, a 44% reduction in the risk of death. Median PFS was 9.8 months with divarasib versus 5.7 months with the approved drugs, a 42% reduction in the risk of disease progression or death.
“Divarasib represents a new standard of care for previously treated KRAS G12C-mutated NSCLC,” said Ferdinandos Skoulidis, MD, of MD Anderson Cancer Center, in Houston, TX, at a press briefing during ESMO. Study results were published simultaneously in the New England Journal of Medicine.
Discussant Professor Benjamin Besse of Institut Gustave Roussy, Villejuif, France, commented, “Despite the early excitement surrounding sotorasib and then adagrasib, their efficacy is only limited and an OS benefit against chemotherapy has not been demonstrated. Results from the Krascendo 1 trial indicate that the higher potency of divarasib could translate into a new standard of care.”
Sotorasib and adagrasib are first-generation approved targeted therapies for KRAS G12C-mutated NSCLC, but neither has demonstrated a survival benefit compared with chemotherapy. Divarasib targets the same mutation and has shown greater potency and selectivity in laboratory studies.
The G12C mutation is one of the most common KRAS mutations, found in approximately one in eight people with NSCLC. NSCLC patients who have the KRAS G12C mutation may have poorer outcomes than those who have the unmutated KRAS gene (wild-type disease). Despite the approval of current, first-generation KRAS G12C-targeted treatments, there remains a significant unmet need for more effective therapy options, said Skoulidis.
Study Details
The global phase III Krascendo 1 trial is the first head-to-head comparison of divarasib with the approved drugs. The trial included 338 patients with advanced or metastatic KRAS G12C-mutated NSCLC who had received prior treatment, including chemotherapy and immunotherapy. Patients had received one to three lines of prior systemic therapy, including platinum-based chemotherapy, a PD-(L)1 inhibitor and potentially, docetaxel. In the control group, 91% received sotorasib and 9% received adagrasib. Patients were randomly assigned to divarasib 400 mg daily or to their doctor’s choice of sotorasib 960 mg daily or adagrasib 600 mg twice daily.
Baseline characteristics showed a median age of 66 years, about 57 percent male, virtually all current or former smokers (about 97%) and adenocarcinoma histology (95%). Most patients had an ECOG performance status of 1 and had received 1 prior line of therapy. Nearly all (99%) had received a prior checkpoint inhibitor.
Trial Results
Divarasib met its primary endpoint of significantly improved PFS assessed by blinded independent central review compared with control (either sotorasib or adagrasib). “Additionally, the ORR was nearly double with divarasib than that of sotorasib or adagrasib (58.4% versus 32.3%), a 25.8% improvement,” said Skoulidis.
Besse noted that “only 4% of patients had primary resistance, that is, progressive disease with divarasib, which is very encouraging.”
Patients took divarasib for more than twice as long as the approved drugs (median 11.3 versus 5 months), yet fewer stopped treatment because of treatment-related side effects (5% versus 12%).
Safety data show the most common treatment-related adverse events (TRAEs) were mainly low grade, manageable and reversible, Skoulidis said. “The rate of serious TRAEs was approximately half (divarasib 7.8%, controls 15.2%). Fewer participants discontinued treatment due to TRAEs with divarasib,” said Skoulidis.
Divarasib led to fewer grade 3–4 TRAEs than with controls (24.6% versus 34.5%), and rates of hepatotoxicity were lower with divarasib—grade 3–4 alkaline phosphatase increase was 0.6% versus 4.1%. Gastrointestinal toxicity was higher with divarasib, with grade 3–4 diarrhea (9% versus 3%).
The safety profile of divarasib was consistent with the known class effects of KRAS G12C inhibitors, he said, and no new safety signals were observed with divarasib.
Combining divarasib with immunotherapy may have a role as first-line treatment. The Krascendo 2 trial will examine divarasib plus pembrolizumab versus pembrolizumab plus chemotherapy in treatment-naive advanced/metastatic KRAS G12C-mutated NSCLC.
A large number of agents are in development, including KRAS G12C (OFF) inhibitors, KRAS G12C (ON) inhibitors, pan-RAS inhibitors and KRAS degraders. “Toxicity may be a key differentiating factor,” said Besse. “Sotorasib or adagrasib are still only available in a small number of countries and improving drug access will be crucial for any new RAS-targeting agent to ensure that patients benefit from the pharmacological advances.”