Next-Generation KRAS Inhibitor Divarasib Cuts Lung Cancer Death Risk by 44 Percent

The experimental targeted therapy divarasib reduced the risk of death by 44 percent compared with approved first-generation treatments in patients with advanced KRAS G12C-mutated non-small cell lung cancer. The Phase 3 Krascendo 1 trial results mark the first time a next-generation KRAS inhibitor has been directly pitted against its predecessors.[1][3][4]

Patients receiving divarasib achieved a median overall survival of 17.7 months, compared with 12.0 months for those taking either sotorasib or adagrasib. The findings were presented at the 2026 European Society for Medical Oncology Congress in Madrid and simultaneously published in The New England Journal of Medicine.[2][4][5]

"For patients with KRAS G12C-mutant lung cancer, extending survival while delaying cancer progression are the outcomes that matter most," said Ferdinandos Skoulidis, principal investigator and professor of thoracic medical oncology at The University of Texas MD Anderson Cancer Center.[4]

Skoulidis noted that the magnitude of the survival benefit establishes the experimental drug as a potential new baseline for clinical practice. He emphasized that the results offer substantial hope for patients whose treatment options have historically been limited after their cancer progresses on initial therapies.[4][5]

Divarasib is an oral medication designed to block the KRAS G12C mutation, an altered protein that drives uncontrolled cell growth in approximately 14 percent of non-small cell lung cancers. The drug works by locking the abnormal protein in an inactive state, effectively switching off a key signal that tumors depend on to survive.[4]

Efficacy and disease control

While first-generation drugs like sotorasib and adagrasib target the exact same mutation, divarasib was engineered to bind to the protein more potently and selectively. The global trial enrolled 338 patients across 26 countries to determine whether this refined molecular approach would translate into tangible clinical advantages.[2][4]

All participants had previously received systemic therapies, with 99 percent having been treated with an immune checkpoint inhibitor and platinum-based chemotherapy. Beyond the overall survival advantage, divarasib reduced the risk of disease progression or death by 42 percent compared with the control arm.[3][4]

Median progression-free survival reached 9.8 months for the divarasib group, a significant improvement over the 5.7 months observed with standard care. The durability of this disease control became particularly evident at the one-year mark, separating the two treatment trajectories.[1][3][4]

At 12 months, 43.9 percent of patients taking divarasib were alive without their disease worsening, versus just 24.0 percent of those receiving sotorasib or adagrasib. The objective response rate—the proportion of patients whose tumors significantly shrank—also nearly doubled with the newer medication.[2][4]

Confirmed responses occurred in 58.4 percent of patients taking divarasib, compared with 32.3 percent in the control group. Those responses proved highly durable, lasting a median of 11.9 months for divarasib, extending well beyond the 6.9 months observed with the older medications.[2][3]

Tolerability and side effects

Despite its higher potency and the fact that patients remained on the therapy twice as long, divarasib demonstrated a more favorable safety profile than the first-generation drugs. Severe treatment-related adverse events occurred in 24.6 percent of patients on divarasib, compared with 34.5 percent in the control arm.[1][2][3]

This improved tolerability kept more patients on their prescribed regimen, which is critical for maintaining disease control. Only 4.8 percent of patients taking divarasib discontinued treatment due to side effects, less than half the 11.7 percent discontinuation rate seen with sotorasib or adagrasib.[1][2]

The specific types of side effects differed notably between the drug classes. Divarasib caused significantly less severe hepatotoxicity—liver-related inflammation that frequently complicates targeted cancer treatments—but resulted in higher rates of gastrointestinal issues, including diarrhea and nausea.[2][3]

Skoulidis pointed out that the gastrointestinal toxicities associated with divarasib were predominantly low-grade, manageable with standard supportive measures, and reversible. In contrast, the liver toxicity seen with older drugs often forces dose reductions or permanent treatment cessation.[2]

Benjamin Besse, a medical oncologist at the Institut Gustave Roussy in France, noted during the ESMO presentation that divarasib's lower liver toxicity might make it more "immunotherapy friendly." This is a crucial factor for patients transitioning from first-line immune checkpoint inhibitors.[2][3]

Next steps for clinical practice

First-generation KRAS inhibitors like sotorasib can trigger severe liver inflammation when administered shortly after immunotherapy, complicating treatment sequencing. A drug that avoids this overlapping toxicity could allow oncologists to transition patients to targeted therapy more safely and rapidly upon disease progression.[3]

With strong results in the second-line setting, researchers are already investigating whether divarasib can move earlier in the treatment sequence. The ongoing Krascendo 2 trial is evaluating divarasib combined with pembrolizumab as a first-line therapy for treatment-naive patients with advanced disease.[3]

Divarasib remains an investigational drug and is not yet approved by regulatory agencies in any country. However, the medication previously received Breakthrough Therapy Designation from the US Food and Drug Administration, a status designed to expedite the development and review of promising therapies.[4]

The manufacturer, Roche, has not disclosed an exact timeline for regulatory filings, but the company indicated it is working closely with health authorities to bring the treatment to market. The trial's open-label design means investigators knew which drug patients received, though independent central reviewers assessed the scans.[1][2]

The 5.7-month absolute improvement in median overall survival represents a rare magnitude of benefit in previously treated, advanced lung cancer. As oncologists await regulatory action, the data provides clear evidence that refining the molecular blockade of KRAS can yield profound clinical advantages.[3][4]