Divarasib Improves Survival and Paves Way for New SOC in Pretreated KRAS G12C–Mutated NSCLC

Divarasib improved progression-free survival (PFS) and overall survival (OS) vs sotorasib (Lumakras) or adagrasib (Krazati) in patients with previously treated, locally advanced or metastatic KRAS G12C–mutated non–small cell lung cancer (NSCLC), according to primary findings from the phase 3 Krascendo 1 trial (NCT06497556) presented at the 2026 ESMO Congress.¹

At a median follow-up of 14.3 months, the median PFS per blinded independent central review (BICR) was 9.8 months (95% CI, 8.1-12.9) with divarasib (n = 167) vs 5.7 months (95% CI, 4.2-6.8) with sotorasib or adagrasib (n = 171; HR, 0.58; 95% CI, 0.44-0.76; P < .0001). The 12-month PFS rates were 43.9% and 24.0%, respectively.

At the first interim OS analysis, the median OS was 17.7 months (95% CI, 16.3-not evaluable [NE]) with divarasib vs 12.0 months (95% CI, 10.0-15.2) with sotorasib or adagrasib (HR, 0.56; 95% CI, 0.41-0.78; P = .0005). The 12-month OS rates were 67.1% and 49.2%, respectively.

"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 MNSCL," said lead study author Ferdinandos Skoulidis, MD, PhD, MRCP, in a presentation of the data.

Skoulidis is a professor in the Department of Thoracic-Head & Neck Med Onc in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston.

How was the phase 3 Krascendo 1 trial of divarasib in KRAS G12C–mutated NSCLC designed?

The global, open-label, randomized trial enrolled patients with advanced or metastatic KRAS G12C–mutated NSCLC who had received 1 to 3 prior lines of systemic therapy, including platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Patients were required to be KRAS G12C inhibitor–naive, have an ECOG performance status of 0 or 1, and have measurable disease per RECIST 1.1 criteria; those with active, untreated central nervous system (CNS) metastases were excluded.

Patients were randomly assigned to receive divarasib at 400 mg once daily or the investigator's choice of sotorasib at 960 mg once daily or adagrasib at 600 mg twice daily. Notably, crossover was not permitted in the trial. Patients were treated until they experienced either progression, unacceptable toxicities, or study withdrawal or termination. Randomization was stratified by history of CNS metastases, intended control-arm KRAS G12C inhibitor, and KEAP1 mutation status.

PFS per BICR served as the primary end point. Key secondary end points included OS, confirmed objective response rate (ORR) per BICR, safety and duration of response (DOR).

A total of 338 patients were randomly assigned. Most patients in the control arm received sotorasib (n = 156), with less recieving adagrasib (n = 15). Baseline characteristics revealed that patients had a median age of 66 years in both arms, and most were male (divarasib, 57%; control, 56%), current or former smokers (98%; 96%), and had adenocarcinoma histology (95%; 96%). Most patients had an ECOG performance status of 1 (61%; 60%) and had received 1 prior line of therapy (72%; 69%), and nearly all had received a prior checkpoint inhibitor (99%; 100%). KEAP1 mutations were detected in 21% vs 22% of patients, respectively, and 29% vs 30% had a history of central nervous system metastases. PD-L1 expression was below 1% in 34% vs 41% of patients and 50% or higher in 26% vs 19%.

Did divarasib improve response rates and durability vs sotorasib or adagrasib in Krascendo 1?

Among response-evaluable patients, the confirmed ORR per BICR was 58% (95% CI, 50.4%-66.1%) with divarasib (n = 161) compared with 32% (95% CI, 25.3%-40.0%) with sotorasib or adagrasib (n = 167), a statistically significant increase of 25.8% (95% CI, 15.6%-36.0%). Response rates by response in the divarasib arm broke down as 4%, 54%, 35%, 4%, and 2%, for complete responses, partial responses, stable disease, progressive disease and missing, respectively. These respective response rates for the control arm were 4%, 29%, 48%, 11%, and 8%. The median DOR was 11.9 months (95% CI, 9.7-NE) with divarasib vs 6.9 months (95% CI, 5.3-8.3) with the control arm.

Investigator-assessed PFS was consistent with the primary analysis, with a median of 11.1 (95% CI, 8.8-14.1) months with divarasib vs 5.6 months (95% CI, 4.4-7) in the control arm. Additionally, investigator-assessed 12-month PFS rates for the divarasib and sotorasib or adagrasib arm were 47.9% and 27.4%, respectively.

The PFS benefit was generally consistent across prespecified subgroups. Among patients with KEAP1-mutated tumors, the median PFS was 4.6 months with divarasib (n = 35) vs 2.8 months with control (n = 37; HR, 0.56; 95% CI, 0.33-0.92). In patients with a history of CNS metastases, the median PFS was 6.8 months (n = 48) vs 5.7 months (n = 51; HR, 0.74; 95% CI, 0.47-1.17).

What was the safety profile of divarasib vs sotorasib or adagrasib in Krascendo 1?

The median treatment duration was 11.3 months (range, 0.0-19.8) with divarasib vs 5.0 months (range, 0.0-19.8) with sotorasib or adagrasib. Treatment-related adverse effects (TRAEs) of any grade occurred in 92.8% of patients in the divarasib arm vs 80.1% of patients in the control arm. Moreover in each the divarasib arm and control arm, grade 3/4 TRAEs occurred in 24.6% vs 34.5% of patients, and serious TRAEs occurred in 7.8% vs 15.2%; no grade 5 TRAEs were reported in either arm, respectively. TRAEs led to treatment discontinuation in 4.8% vs 11.7% of patients.

The most common TRAEs were diarrhea (divarasib, 66%; control, 38%), nausea (53%; 20%), and vomiting (39%; 8%). These TRAEs were mainly grade 1, occuring at respective grade 1 rates of 35%, 32%, and 8% with patients who received divarasib. Increased alanine aminotransferase (15%; 23%) and increased aspartate aminotransferase (14%; 21%) were less frequent with divarasib. No treatment-related QT prolongation or pneumonitis occurred with divarasib, compared with 2 and 3 patients, respectively, in the control arm.

What are the next steps for divarasib in KRAS G12C–mutated NSCLC?

The Krascendo 1 findings were published simultaneously in the New England Journal of Medicine.² The randomized phase 3 Krascendo 2 trial (NCT06793215) is comparing divarasib plus pembrolizumab (Keytruda) with pembrolizumab plus pemetrexed and carboplatin or cisplatin in patients with previously untreated, advanced or metastatic KRAS G12C–mutated NSCLC.¹

This chemotherapy-free combination previously yielded a confirmed ORR of 72.9% among the cohort of patients with PD-L1–positive tumors in the phase 1b/2 Krascendo 170 trial (NCT05789082). Cohort D of Krascendo 170 is enrolling patients who have untreated CNS metastases, and the phase 3 Krascendo 3 trial (NCT07541170) is evaluating divarasib in the adjuvant setting vs pembrolizumab or nivolumab (Opdivo) for patients with resected KRAS G12C–positive NSCLC.

Disclosures: Skoulidis reported consulting or advising for and receiving travel accomodation, honoraria, or research funding from Amgen, Astellas Pharma, AstraZeneca, BeiGene, BerGenBio BMS, Boehringer, Ingelheim, BridgeBio, EliL Lilly, Guardant Health, GenMab, HOOKIPA Pharma, Merck, Mirati Therapeutics, Sharpe & Dohme, Novartis, Novocure, Nuvalent, Pfizer, Regeneron, Revolution Medicines, Roche/Genentech, Tango Therapeutics, Turing Point Therapeutics, CURIO, DAVA Oncology, IASLC IDEOlogy Health, Intellisphere, Japanese Lung Cancer Society, MI&T, Medscape, MJH Life Sciences, PER, RV Pais Promocao Eventos, VSPO, McGill University, Universite de Montreal, or Revolution Medicines.

References

1. Skoulidis F, Ahn MJ, Gadgeel S, et al. Krascendo 1: efficacy and safety of divarasib versus sotorasib or adagrasib in previously treated locally advanced or metastatic KRAS G12C-mutated NSCLC. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA5.
2. Skoulidis F, Ahn MJ, Gadgeel S, et al. Divarasib as compared with sotorasib or adagrasib in KRAS G12C–mutated NSCLC. N Engl J Med. 2026. doi:10.1056/NEJMoa2605703