Roche's divarasib cuts risk of death by 44% against Lumakras and Krazati in Phase 3

Roche presented the full Phase 3 Krascendo 1 results for its investigational KRAS G12C inhibitor divarasib at the ESMO Congress in Madrid on 25 October 2026, with simultaneous publication in The New England Journal of Medicine ¹. Divarasib beat both approved first-generation drugs in the class, Amgen's Lumakras (sotorasib) and Bristol Myers Squibb's Krazati (adagrasib), in previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC) ¹².

What the trial found

Krascendo 1 was a randomised, open-label, multicentre study of 338 adults: 167 took divarasib once daily and 171 took either sotorasib or adagrasib ¹. Patients who had already had a KRAS G12C or pan-KRAS/RAS inhibitor were excluded ². The primary endpoint was progression-free survival assessed by blinded independent central review ¹. Roche reported in July that the trial had met its primary and key secondary endpoints but held back the detailed figures until the congress ².

The main results were as follows ¹:

• Median overall survival of 17.7 months with divarasib against 12.0 months in the control arm (HR 0.56, 95% CI 0.41-0.78, p=0.0005), a 44% lower risk of death ¹.

• Median progression-free survival of 9.8 months against 5.7 months (HR 0.58, 95% CI 0.44-0.76, p<0.0001), a 42% lower risk of progression or death ¹.

• 44% of divarasib patients alive and progression-free at 12 months, against 24% ¹.

• Confirmed objective response in 58% against 32%, with median duration of response of 11.9 months against 6.9 months ¹.

Roche said the survival and progression benefit held across clinically relevant subgroups, including by PD-L1 expression and KEAP1 mutation status ¹. Tolerability also favoured divarasib. Discontinuation because of treatment-related adverse events was 4.8% against 11.7%, and serious treatment-related events were 7.8% against 15.2%, even though divarasib patients stayed on treatment for 11.3 months against 5.0 months ¹. The most common side effects were gastrointestinal toxicity and liver toxicity, in line with the drug class ¹.

What it means for the market

The trial is the only global head-to-head study of a next-generation KRAS G12C inhibitor against the approved drugs, according to Roche ¹. Direct comparisons like this are uncommon in oncology. Stefan Frings, Roche Pharma's deputy chief medical officer, said a win of this kind helps "convince payers, prescribers and patients" and called the data a package "which should be convincing to health authorities" ².

The incumbents have struggled to turn their early approvals into large franchises. Lumakras and Krazati reached the US market in 2021 and 2022, yet in the second quarter Krazati earned $55 million for Bristol Myers Squibb and Lumakras $111 million for Amgen ². Frings put Roche's peak sales ambition for divarasib at 1 billion to 2 billion Swiss francs ($1.2 billion to $2.5 billion), with most of that expected from metastatic disease ².

The second-line result is the first step in a wider programme. Krascendo 2 is testing divarasib with pembrolizumab against chemotherapy plus pembrolizumab in untreated advanced disease, and Krascendo 3 is testing it as adjuvant therapy after surgery in stage II to IIIB disease ¹. Behind divarasib, Roche has a pan-RAS inhibitor, RG6505, and a KRAS G12D inhibitor, RG6620, in Phase 1, and its partner Chugai is testing a pan-KRAS inhibitor, AUBE00 ². The FDA gave divarasib Breakthrough Therapy Designation in 2022 and Orphan Drug Designation in 2026 ¹.

Limits

The trial was open-label, and divarasib remains investigational with no approval in any market ¹². The results apply to patients who had not previously received a KRAS G12C inhibitor, since those patients were excluded ². Median overall survival is described by Roche as current at the primary analysis ¹. Frings declined to give a timeline for regulatory filings, saying only that Roche is "certainly keen to get this to as many patients as possible around the world" ².