Roche Posts 17.7-Month Survival For Divarasib In Phase 3, After Head-To-Head KRAS Win In NSCLC

Roche has now put numbers behind the phase 3 divarasib result it first flagged in July, showing a head-to-head win against the two approved first-generation KRAS G12C inhibitors in previously treated KRAS G12C-mutated non-small cell lung cancer. At ESMO in Madrid, the company said divarasib delivered longer overall survival, longer progression-free survival, a higher response rate and fewer treatment discontinuations due to treatment-related adverse events than the control arm of Amgen’s Lumakras or Bristol Myers Squibb’s Krazati.

That matters strategically because Roche did not try to establish divarasib with an easier comparison to chemotherapy. It went directly at the drugs already defining the class, a design choice that could make the eventual regulatory and reimbursement discussion less about whether KRAS G12C inhibition works and more about whether Roche has produced a better version of it.

The Data

The open-label Krascendo 1 trial enrolled 338 people with previously treated KRAS G12C-mutated NSCLC. Patients who had already received a KRAS G12C inhibitor or pan-KRAS/RAS inhibitor were excluded. Participants received either divarasib once daily, Lumakras once daily or Krazati twice daily.

Roche said the study met its primary endpoint and key secondary endpoint, with statistically significant improvements in progression-free survival and overall survival. In the detailed ESMO presentation, median overall survival was 17.7 months for the 167 patients who received divarasib versus 12 months for the 171 patients in the Lumakras or Krazati group. Median progression-free survival was 9.8 months versus 5.7 months, respectively.

The rest of the efficacy package moved in the same direction. Roche reported that 44% of patients receiving divarasib were alive without disease progression at one year, compared with 24% in the control group. Objective response rate was 58% for divarasib versus 32% for control, while median duration of response was 11.9 months versus 6.9 months.

On safety, Roche said 4.8% of patients receiving divarasib discontinued treatment because of treatment-related adverse events, compared with 11.7% in the control arm. Serious treatment-related adverse events were reported in 7.8% of divarasib patients versus 15.2% of patients receiving Lumakras or Krazati.

The Commercial Picture

Roche is framing the dataset as a package that should travel well with health authorities. Stefan Frings, M.D., Ph.D., deputy chief medical officer at Roche Pharma, told Fierce that the results form a “very comprehensive, strong package” and argued that a head-to-head win is more persuasive if a company wants to convince payers, prescribers and patients.

That position reflects the commercial reality of the KRAS G12C market so far. Amgen and Bristol Myers Squibb reached the market first in 2021 and 2022, respectively, for KRAS G12C-mutated, locally advanced or metastatic NSCLC, but neither product has produced dominant revenue. Krazati brought in $55 million for Bristol Myers Squibb in the second quarter, while Lumakras delivered $111 million to Amgen. Roche is aiming for peak divarasib sales of 1 billion to 2 billion Swiss francs, or about $1.2 billion to $2.5 billion, according to Frings.

The signal from Krascendo 1 is that Roche is trying to enter an established targeted class by redefining the standard inside that class, not by opening a new biomarker segment. If regulators agree that the survival benefit and safety profile are strong enough, Roche would have a cleaner differentiation message than many late entrants get.

What Roche Is Building Around Divarasib

Roche is already recruiting patients into a phase 3 study comparing divarasib plus Keytruda against Keytruda plus chemotherapy in previously untreated advanced or metastatic nonsquamous KRAS G12C-mutated NSCLC. Roche has previously suggested that sales in metastatic disease would account for most of its forecast, which helps explain why the company is already pushing beyond the second-line setting.

The company is also building a broader RAS portfolio behind divarasib. Roche has started phase 1 trials of the pan-RAS inhibitor RG6505 and the KRAS G12D inhibitor RG6620 in solid tumors, while partner Chugai Pharmaceutical is testing a pan-KRAS inhibitor called AUBE00. Frings said Roche has made a “deliberate effort” to test a range of RAS drugs, a strategy that suggests divarasib is intended to be the front edge of a larger franchise rather than a standalone asset.

Frings did not give an exact regulatory filing timeline, saying only that Roche is “certainly keen to get this to as many patients as possible around the world.”