Divarasib, an investigational next-generation KRAS G12C inhibitor, demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) compared with approved first-generation KRAS G12C inhibitors sotorasib (Lumakras) and adagrasib (Krazati) in patients with previously treated, advanced KRAS G12C–mutant non–small cell lung cancer (NSCLC), meeting the primary and key secondary end points of the phase 3 Krascendo 1 trial (NCT06497556).1
The safety profile of the agent mirrored past reports with divarasib, and no new signals were identified. The most frequent treatment-related adverse effects were manageable and transient. Data from the trial will be filed with health authorities and disclosed at an upcoming medical meeting.
“The superior survival demonstrated in this global head-to-head comparison of KRAS G12C inhibitors confirms the potential of divarasib to improve clinical outcomes for people with KRAS G12C[–mutant] NSCLC,” Levi Garraway, MD, PhD, Roche’s chief medical officer and head of Global Product Development, stated in a news release. “These results should establish divarasib as a new standard of care for previously treated [patients with] lung cancer with this genetically defined tumor subtype.”
Of note, the FDA granted breakthrough therapy designation to divarasib in 2022, and in 2026, the agency granted orphan drug designation to divarasib for KRAS G12C–mutant NSCLC.
Krascendo 1 Knocks Out First-Generation KRAS Rivals
- Divarasib achieved statistically significant improvements in both PFS and OS vs sotorasib and adagrasib in the phase 3 Krascendo 1 trial (NCT06497556), representing the first head-to-head comparison of a KRAS G12C inhibitor against approved agents in this class.
- OS superiority was achieved at a prespecified interim analysis in a previously treated, advanced KRAS G12C–mutant NSCLC population known for poor prognosis.
- Divarasib holds FDA breakthrough therapy designation and orphan drug designation for KRAS G12C–mutant NSCLC, with regulatory submissions and full data presentation at a medical meeting planned.
How was the Krascendo 1 trial designed?
The Krascendo 1 study is a randomized, open-label, multicenter, global head-to-head trial evaluating divarasib monotherapy vs sotorasib or adagrasib in adults with previously treated KRAS G12C–mutant advanced or metastatic NSCLC.2,3 The study enrolled 338 participants and represents the only global trial to evaluate a KRAS G12C inhibitor in direct comparison with approved agents in this class.1,3
To be eligible for enrollment, patients had to have a histologically or cytologically confirmed diagnosis of metastatic or locally advanced NSCLC not fit for treatment with surgical resection or combined chemoradiation; disease progression during or after treatment with 1 to 3 lines of prior systemic therapy in the advanced or metastatic setting; measurable disease according to RECIST 1.1 criteria; documentation of a KRAS G12C mutation; an ECOG performance status of 0 or 1; and life expectancy of at least 12 weeks. The availability of a representative formalin-fixed, paraffin-embedded tumor specimen in a paraffin block or 10 to 15 unstained, freshly cut, serial slides with an associated pathology report was also required.2
Patients were randomly assigned to receive divarasib administered orally once daily, sotorasib administered orally once daily, or adagrasib administered orally twice daily.
The primary end point was blinded independent central review–assessed PFS. Secondary end points included OS, confirmed objective response rate, and duration of response.
What is on the horizon?
The phase 3 Krascendo 2 trial (NCT06793215) is evaluating divarasib in combination with pembrolizumab (Keytruda) as a chemotherapy-free regimen vs pemetrexed and either carboplatin or cisplatin plus pembrolizumab in previously untreated patients with KRAS G12C–mutant advanced NSCLC, positioning the agent in the first-line setting. The phase 3 Krascendo 3 trial (NCT07541170) is investigating adjuvant divarasib monotherapy vs investigator’s choice of immunotherapy or observation in patients with resected stage II to IIIB KRAS G12C–mutant NSCLC following standard-of-care neoadjuvant chemoimmunotherapy, extending investigation into early-stage disease.
References
- [Ad hoc announcement pursuant to Art. 53 LR] Roche's divarasib shows superiority in head-to-head phase III trial against approved KRAS G12C inhibitors in non-small cell lung cancer. News release. Roche. July 1, 2026. Accessed July 6, 2026. https://www.roche.com/media/releases/med-cor-2026-07-02
- 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. Updated June 18, 2026. Accessed July 6, 2026. https://clinicaltrials.gov/study/NCT06497556
- Gadgeel S, Rahman A, Osaghae U, et al. Divarasib versus adagrasib or sotorasib in pretreated KRAS G12C+ advanced or metastatic non-small cell lung cancer (NSCLC). J Thorac Oncol. 2024;19(10):S349. doi:10.1016/j.jtho.2024.09.629
