Roche’s Phase III KRASCENDO 1 trial found improved overall and progression-free survival with divarasib versus sotorasib or adagrasib in KRAS G12C-mutated lung cancer.
Written By: Sravani Pamanji, PharmD
Reviewed By: Pharmacally Editorial Team
Roche reported positive results from the Phase III KRASCENDO 1 trial, in which divarasib improved overall survival (OS) and progression-free survival (PFS) compared with the approved KRAS G12C inhibitors sotorasib and adagrasib. The findings, announced on 25 October 2026, a median OS of 17.7 months with divarasib versus 12.0 months with the comparator treatments.
Divarasib reduced the relative hazard of death by 44% and the hazard of disease progression or death by 42%. The results suggest that next-generation KRAS G12C inhibition could improve outcomes for patients whose cancer has progressed following previous treatment.
Targeting KRAS G12C in Advanced Lung Cancer
NSCLC is the most common type of lung cancer. In a subset of patients, mutations in the KRAS gene, particularly KRAS G12C, drive signalling pathways involved in tumour growth. Although targeted therapies have expanded treatment options, disease progression remains a clinical challenge.
Divarasib is an investigational oral KRAS G12C inhibitor developed by Roche. It selectively targets the mutated protein, locking it in an inactive state and suppressing tumour-driving signalling.
KRASCENDO 1 Demonstrates Improved Survival Outcomes
The randomised, open-label, multicentre Phase III KRASCENDO 1 trial (NCT06497556) enrolled 338 adults with previously treated KRAS G12C-mutated advanced or metastatic NSCLC. Participants received divarasib (167 patients) or a comparator treatment, sotorasib or adagrasib (171 patients).
Blinded independent central review assessed PFS, the primary endpoint. OS and tumour response were among the secondary endpoints. At a median follow-up of 14.3 months, the trial met its primary endpoint and key secondary OS endpoint.
Key efficacy findings were
- Overall survival: Median OS was 17.7 months with divarasib versus 12.0 months with comparator treatment (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.41–0.78; p=0.0005).
- Progression-free survival: Median PFS was 9.8 versus 5.7 months (HR, 0.58; 95% CI, 0.44–0.76; p<0.0001).
- 12-month PFS rate: 44% versus 24%.
- Confirmed objective response rate: 58% versus 32%.
- Median duration of response: 11.9 versus 6.9 months.
Response outcomes were assessed in 328 evaluable participants; 10 patients were excluded from this analysis because they lacked measurable disease at baseline. Duration of response was assessed among patients who responded to treatment.
The findings indicate benefits across survival, disease control and tumour response, rather than an improvement confined to a single efficacy measure.
Safety Findings and Treatment Tolerability
Roche reported no new safety signals. The safety profile was consistent with the known effects of KRAS G12C inhibitors, with gastrointestinal adverse events, including diarrhoea, nausea and vomiting, and hepatotoxicity among the common treatment-related events.
Treatment-related adverse events led to discontinuation in 4.8% of participants receiving divarasib versus 11.7% receiving comparator treatment. Serious treatment-related adverse events occurred in 7.8% versus 15.2%, respectively.
Median treatment duration was 11.3 months with divarasib compared with 5.0 months in the comparator group. The lower reported rates of treatment-related discontinuation and serious adverse events despite longer exposure are encouraging, although longer treatment duration should be considered when interpreting safety comparisons.
Regulatory Status and Ongoing Development
Divarasib remains investigational, and the Phase III findings do not constitute marketing authorisation. The US Food and Drug Administration granted divarasib Breakthrough Therapy Designation in 2022 and Orphan Drug Designation for KRAS G12C-mutated NSCLC in 2026.
Roche is also evaluating divarasib in Phase III studies of previously untreated advanced NSCLC and adjuvant treatment for earlier-stage disease. These studies will help establish whether its potential benefits extend to other treatment settings.
Clinical Interpretation
The improvement in OS is an important finding because it suggests that divarasib’s benefit extends beyond delaying disease progression. The accompanying PFS and response results strengthen the evidence of antitumour activity. However, the 5.7-month difference between median OS values is a comparison between study groups, not a prediction of additional survival for an individual patient. Similarly, a 44% relative reduction in the hazard of death does not mean that 44% more patients will survive.
The findings were reported at the first interim OS analysis and should be interpreted alongside the study’s follow-up duration and population. The open-label design and limited representation of patients with untreated brain metastases are relevant limitations. Although benefits were reported across clinically relevant subgroups, including those defined by PD-L1 expression and KEAP1 mutation status, subgroup findings do not establish identical benefits for every patient group.
Overall, KRASCENDO 1 supports further evaluation of divarasib as a potential treatment option for previously treated KRAS G12C-mutated advanced or metastatic NSCLC. Its eventual role in clinical practice will depend on regulatory review and the broader assessment of clinical evidence.
References
Roche’s divarasib demonstrated best-in-class efficacy, advancing the standard of care in previously treated KRAS G12C-mutated lung cancer. Roche, 25 October 2026. https://www.roche.com/investors/updates/inv-update-2026-10-25
A Study Evaluating the Efficacy and Safety of Divarasib Versus Sotorasib or Adagrasib in Participants with Previously Treated KRAS G12C-positive Advanced or Metastatic Non-Small Cell Lung Cancer (Krascendo 1), ClinicalTrials.gov ID NCT06497556
Skoulidis F, et al. Divarasib as Compared with Sotorasib or Adagrasib in KRAS G12C-Mutated NSCLC. The New England Journal of Medicine. Published online 25 October 2026. doi:10.1056/NEJMoa2605703
About the Writer
Sravani Pamanji is a PharmD (LinkedIn) professional with experience in scientific writing, medical literature review, drug profile preparation, and clinical case documentation. She has contributed to scientific publication and presented at the 74th Indian Pharmaceutical Congress. Her training includes ICH GCP E6(R3), scientific research, and medication safety. She is passionate about evidence-based medical communication and accurate dissemination of clinical and pharmaceutical information.