ESMO 2026: KRAS-mutated NSCLC highlights

How does divarasib compare with existing KRAS G12C inhibitors in NSCLC?

Divarasib significantly improved PFS compared with sotorasib or adagrasib. Median PFS was 9.8 months versus 5.7 months, corresponding to a 42% reduction in the risk of disease progression or death (HR, 0.58; 95% CI, 0.44–0.76; P<0.0001). A significant OS benefit was also observed, with a median OS of 17.7 months with divarasib versus 12.0 months with sotorasib or adagrasib (HR, 0.56; 95% CI, 0.41–0.78; P=0.0005).

The confirmed ORR was 58% with divarasib compared with 32% in the control group. Median treatment duration was also longer with divarasib, at 11.3 months versus 5.0 months.

What was the safety profile of divarasib in Krascendo-1?

Grade 3–4 treatment-related adverse events (TRAEs) occurred in 24.6% of patients receiving divarasib and in 34.5% receiving sotorasib or adagrasib, and serious TRAEs occurred in 7.8% versus 15.2% in the divarasib and sotorasib or adagrasib groups, respectively. TRAEs led to discontinuation in 4.8% of the divarasib group compared with 11.7% of the sotorasib or adagrasib group, and no grade 5 TRAEs were reported.

What did the Krascendo-1 trial show in KRAS G12C–mutated NSCLC?

Krascendo-1 provides phase 3 head-to-head evidence comparing divarasib with existing KRAS G12C-targeted therapies in previously treated NSCLC. Divarasib significantly improved PFS, OS, and ORR versus sotorasib or adagrasib, while treatment-related discontinuations were less frequent with divarasib. Skoulidis concluded, “Based on the results of the Krascendo-1 clinical trial, divarasib represents a new standard of care for patients with previously treated KRAS G12C–mutant advanced or metastatic non–small-cell lung cancer.”

Looking ahead, Skoulidis highlighted that divarasib is also being evaluated in the first-line setting in the phase 3 Krascendo-2 trial, as monotherapy in untreated brain metastases in cohort D of Krascendo-170, and in the adjuvant setting in Krascendo-3.

What progress is being made in targeting KRAS G12D–mutated NSCLC?

While several targeted therapies are now available for KRAS G12C–mutated NSCLC, treatment options remain limited for other KRAS subtypes, including KRAS G12D, which represents a significant unmet need. Alongside the Krascendo-1 findings, Ferdinandos Skoulidis presented the design of an ongoing randomized, open-label phase 3 study evaluating setidegrasib, a novel KRAS G12D–targeted protein degrader, in patients with locally advanced unresectable or metastatic NSCLC. The study will enroll 356 adults whose disease has progressed on or after platinum-based chemotherapy and checkpoint inhibitor therapy. Participants will receive setidegrasib or docetaxel, with crossover to setidegrasib permitted following disease progression. The dual primary endpoints are PFS and OS. Recruitment is ongoing.

Frequently asked questions

What is the Krascendo-1 trial in KRAS G12C–mutated NSCLC?

Krascendo-1 is a global, randomized, open-label phase 3 trial evaluating the efficacy and safety of divarasib compared with approved KRAS G12C inhibitors (sotorasib or adagrasib) in previously treated advanced or metastatic KRAS G12C–mutated NSCLC. The primary endpoint was PFS.

Why is Krascendo-1 important for KRAS G12C–mutated NSCLC?

Unlike earlier phase 3 studies that compared individual KRAS G12C inhibitors with chemotherapy, Krascendo-1 directly compares divarasib with currently available KRAS G12C–targeted therapies. It is the first global randomized phase 3 trial to compare a next-generation KRAS G12C inhibitor head-to-head with first-generation inhibitors, and it demonstrated significant improvements in PFS, OS, and ORR with divarasib.

How does divarasib differ from other KRAS G12C inhibitors?

Divarasib is an oral, next-generation KRAS G12C inhibitor that has demonstrated greater potency and selectivity for KRAS G12C than sotorasib or adagrasib in preclinical studies. In Krascendo-1, direct comparison with sotorasib or adagrasib showed significant improvements in PFS, OS, and ORR with divarasib.

What is setidegrasib for KRAS G12D–mutated NSCLC?

Setidegrasib is a KRAS G12D-targeted protein degrader that demonstrated encouraging antitumor activity and a manageable safety profile in early-phase clinical studies of previously treated KRAS G12D-mutated NSCLC. It is now being evaluated in an ongoing phase 3 study of patients with KRAS G12D-mutated locally advanced unresectable or metastatic NSCLC.

Why is KRAS G12D an important therapeutic target in NSCLC?

KRAS G12D mutations occur in approximately 5% of NSCLC tumors. Although targeted therapies are available for KRAS G12C-mutated NSCLC, there are currently no approved targeted therapies for KRAS G12D-mutated disease, highlighting an important unmet need. The ongoing phase 3 setidegrasib study aims to address this unmet need in KRAS G12D-mutated disease.