Next-generation KRAS drug extends survival in head-to-head lung cancer trial

Overview

Updated 1 hour ago

Five years after the first KRAS inhibitor reached the market, a next-generation drug just beat the existing ones head-to-head. The Phase III Krascendo 1 trial found divarasib cut the risk of death by 44% and nearly doubled response rates in patients with previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC).

Researchers at Tennessee Oncology's Greco-Hainsworth Centers for Research in Nashville served as investigators, and the results were presented at the ESMO 2026 Congress and published in the New England Journal of Medicine. If the FDA approves divarasib, it would become the new standard for the 14% of NSCLC patients whose tumors carry the G12C mutation and who progress on current drugs.

Why it matters

For KRAS G12C-mutated lung cancer patients who relapse on current drugs, divarasib could add nearly six months of survival with fewer severe side effects.

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Key Indicators

44%

Reduction in risk of death vs. standard KRAS inhibitors

Divarasib lowered mortality risk compared to sotorasib or adagrasib in previously treated KRAS G12C-mutated NSCLC.

17.7 months

Median overall survival with divarasib

Compared to 12.0 months in patients receiving sotorasib or adagrasib.

58.4%

Objective response rate with divarasib

Nearly double the 32.3% response rate in the sotorasib/adagrasib control group.

338

Patients enrolled in Krascendo 1

Phase III trial across 151 sites in 26 countries.

Voices

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People Involved

Wade Iams, MD, MSCI

Medical oncologist and principal investigator at Tennessee Oncology's Greco-Hainsworth Centers for Research

Principal investigator for the Krascendo 1 trial

Ferdinandos Skoulidis, MD, PhD

Professor of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center

Lead principal investigator for the Krascendo 1 trial

Organizations Involved

Tennessee Oncology

Community oncology practice

Led U.S. community-based enrollment for the Krascendo 1 trial

A community oncology practice with 35 clinical sites across Tennessee and northwest Georgia.

Genentech

Biotechnology company

Sponsor of Krascendo 1; developer of divarasib

A member of the Roche Group and the sponsor of the Krascendo 1 trial.

MD Anderson Cancer Center

Academic cancer center

Academic lead institution for Krascendo 1

The academic home of lead principal investigator Ferdinandos Skoulidis.

Timeline

May 2021 October 2026

5 events Latest: Today

Tap a bar to jump to that date

October 2026
Krascendo 1 results presented at ESMO, published in NEJM
Today Research

Divarasib cuts death risk 44% vs. sotorasib or adagrasib in KRAS G12C-mutated NSCLC; results hit Presidential Symposium.
Today
2026
FDA grants divarasib Orphan Drug Designation
Regulatory

Orphan designation for KRAS G12C-mutated NSCLC brings incentives including tax credits and exclusivity upon approval.
2026
December 2022
FDA approves adagrasib, second KRAS G12C inhibitor
Regulatory

Adagrasib (Krazati) won approval for KRAS G12C-mutated NSCLC, giving patients a second first-generation option.
December 12th, 2022
2022
FDA grants divarasib Breakthrough Therapy Designation
Regulatory

The designation signals FDA recognition of divarasib's potential to address a serious unmet need and can speed review.
2022
May 2021
FDA approves sotorasib, first KRAS inhibitor
Regulatory

Sotorasib (Lumakras) became the first approved drug for KRAS G12C-mutated NSCLC, ending decades of KRAS being deemed undruggable.
May 28th, 2021

Scenarios

FDA approves divarasib for previously treated KRAS G12C-mutated NSCLC

Likely Resolves by End of 2027

Discussed by: Genentech press release; trial investigators

Genentech holds Breakthrough Therapy Designation for divarasib, which can shorten FDA review timelines. A regulatory filing based on Krascendo 1 could yield an approval decision within months, making divarasib the new standard of care for patients who failed a first-generation KRAS inhibitor.

Divarasib wins first-line or combination approvals beyond relapsed disease

Possible Resolves by End of 2028

Discussed by: Genentech (company phase III development program)

Genentech is running a phase III program testing divarasib as a monotherapy and in chemo-free combinations across earlier lines of therapy. If first-line or adjuvant data also read out positive, divarasib's addressable population would expand well beyond the relapsed-disease setting studied in Krascendo 1.

FDA issues Complete Response Letter or delays divarasib approval

Unlikely Resolves by Q2 2028

Discussed by: Routine regulatory risk

The FDA could issue a Complete Response Letter over manufacturing, trial-design, or safety questions, or request additional data before ruling on approval. That would push a decision past 2027 despite the strong efficacy signal.

Historical Context

2 moments from history that rhyme with this story — and how they unfolded.

2015-2018

Osimertinib replaces first-generation EGFR inhibitors (2015-2018)

Osimertinib, a next-generation EGFR inhibitor engineered for better selectivity and brain penetration, was approved for T790M-positive NSCLC in 2015, then moved to first-line therapy in 2018 after beating gefitinib and erlotinib head-to-head.

Then

Osimertinib showed superior efficacy and central nervous system activity versus the older drugs in clinical trials.

Now

It became the standard first-line EGFR inhibitor, displacing first-generation drugs for most patients.

Why this matters now

The same pattern — a better-engineered next-generation inhibitor displacing its older class — is now playing out with divarasib versus sotorasib and adagrasib.

May 2021 - December 2022

Sotorasib and adagrasib open the KRAS drug class (2021-2022)

The FDA approved sotorasib in May 2021 and adagrasib in December 2022, the first drugs to target KRAS after four decades of failed attempts to drug it.

Then

Both produced meaningful but limited responses; most patients eventually progressed on treatment.

Now

They proved KRAS was druggable and established biomarker-testing infrastructure that now supports next-generation inhibitors.

Why this matters now

These first-generation drugs are the exact comparators divarasib beat in the Krascendo 1 control arm.