Divarasib Beat Sotorasib and Adagrasib Head to Head in KRAS G12C Lung Cancer. Patients Also Lived Longer.
Divarasib cut the risk of death 44 percent versus sotorasib or adagrasib in the 338-patient Krascendo 1 lung cancer trial. It is not yet approved.
Divarasib, an investigational next-generation KRAS G12C inhibitor from Roche, lengthened both progression-free and overall survival compared with sotorasib or adagrasib in previously treated KRAS G12C-mutated non-small cell lung cancer, in the phase 3 Krascendo 1 trial presented at ESMO on Oct. 25.
Roche calls it the only global head-to-head trial of a next-generation KRAS G12C inhibitor against the approved ones. Ferdinandos Skoulidis, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center presented the late-breaking abstract (LBA5) in the European Society for Medical Oncology's Presidential Symposium in Madrid, and the results were published simultaneously in the New England Journal of Medicine, according to Roche's Oct. 25 announcement. The drug is not approved anywhere; Roche says it is working with health authorities and has given no filing date.
What did Krascendo 1 test?
The open-label trial (NCT06497556) randomized 338 adults 1:1 to divarasib 400 mg once daily (n=167) or a first-generation inhibitor (n=171): sotorasib 960 mg once daily for 156 patients and adagrasib 600 mg twice daily for 15, Targeted Oncology reported from the presentation. Patients had one to three prior lines, including platinum chemotherapy and a PD-1 or PD-L1 inhibitor, had not received a KRAS G12C inhibitor and had an ECOG performance status of 0 or 1. There was no crossover. The primary endpoint was progression-free survival by blinded independent central review.
The G12C mutation is found in about 14 percent of non-small cell lung cancers, Roche said when it announced topline results in July.
What were the results?
Divarasib cut the risk of progression by 42 percent and the risk of death by 44 percent. At a median follow-up of 14.3 months, median progression-free survival was 9.8 months versus 5.7 months (HR 0.58; 95% CI, 0.44 to 0.76; P<.0001). At the first interim analysis, median overall survival was 17.7 months versus 12.0 months (HR 0.56; 95% CI, 0.41 to 0.78; P=.0005), and 12-month survival was 67.1 versus 49.2 percent, Targeted Oncology reported. Confirmed response rates were 58 versus 32 percent among 328 response-evaluable patients, with median response durations of 11.9 and 6.9 months. Roche reported consistent benefit across subgroups including PD-L1 expression and KEAP1 mutation status.
The comparison is essentially divarasib versus sotorasib, run open-label, with survival read at an interim look. The direction is clear; the size of the survival gain may move.
How does this compare with the earlier KRAS G12C trials?
The gain is larger than either approved drug showed against chemotherapy. By The Script Pad's arithmetic from the published medians, divarasib added 4.1 months of median progression-free survival over an active KRAS inhibitor. Sotorasib added 1.1 months over docetaxel in CodeBreaK 200 (5.6 versus 4.5 months; HR 0.66), and adagrasib added 1.7 months over docetaxel in KRYSTAL-12 (5.5 versus 3.8 months; HR 0.58). The control arm in Krascendo 1, 91 percent of whom received sotorasib, reached 5.7 months, close to sotorasib's 5.6 months in CodeBreaK 200, so the comparator performed as expected rather than unusually poorly. These are cross-trial comparisons with different populations and eras, not a pooled analysis.
The 12-month survival figures imply about 18 more patients alive at one year per 100 treated, or roughly one for every six, again our unadjusted arithmetic from Kaplan-Meier rates.
What about toxicity?
Divarasib was better tolerated on the measures that drive stopping treatment, though it was more emetogenic. Treatment-related grade 3 or 4 adverse events occurred in 24.6 versus 34.5 percent, serious treatment-related events in 7.8 versus 15.2 percent, and discontinuation for treatment-related events in 4.8 versus 11.7 percent, despite a median 11.3 months on divarasib versus 5.0 months in the control arm. There were no treatment-related deaths. Diarrhea (66 versus 38 percent), nausea (53 versus 20 percent) and vomiting (39 versus 8 percent) were more frequent with divarasib, mostly grade 1, while aminotransferase elevations were less frequent, Targeted Oncology reported.
What it means in clinic
For now, sotorasib and adagrasib remain the approved options after chemoimmunotherapy, and divarasib is available only in trials. Two practical points follow. First, practices should confirm that KRAS G12C is on the molecular panel ordered at diagnosis of advanced disease, as with other biomarker-gated therapies, so patients are ready if the drug is approved. Second, the GI profile argues for prophylactic antiemetic and antidiarrheal planning if divarasib reaches practice. Watch for the regulatory filing and for mature survival data; ESMO's other Presidential Symposium results, including the INTerpath-001 melanoma vaccine trial, carry similar interim caveats.
Reported, fact-checked and edited by The Script Pad's editorial staff. See How we use AI.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
