Lilly's olomorasib shows durable first-line activity in KRAS G12C lung cancer at ESMO

Overview

Updated 2 hours ago

KRAS G12C-mutant non-small cell lung cancer has no approved first-line targeted therapy. Standard care is immunotherapy with or without chemotherapy, and because most patients never reach second-line treatment, the first choice is decisive.

At ESMO 2026 in Madrid, Eli Lilly reported that olomorasib, its investigational next-generation KRAS G12C inhibitor, paired with Merck's pembrolizumab, kept median progression-free survival beyond 21 months without reaching it. In the chemoimmunotherapy arm, the response rate was 62% with a median duration of 14.5 months. The randomized Phase 3 SUNRAY-01 results come in the first half of 2027.

Why it matters

If SUNRAY-01 confirms these results, KRAS G12C patients get their first targeted first-line option, potentially displacing chemoimmunotherapy for a significant subset.

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Key Indicators

62%

Overall response rate, olomorasib + chemoimmunotherapy

Investigator-assessed confirmed ORR in 77 first-line patients, most with PD-L1 below 50%.

14.5 months

Median duration of response, chemoimmunotherapy arm

Responses lasted a median of 14.5 months in the combination-with-chemotherapy cohort.

>21 months

Follow-up without reaching median PFS, pembrolizumab arm

Median progression-free survival was not yet reached after a median of nearly 21 months of follow-up.

13%

Share of NSCLC patients with KRAS G12C mutation

KRAS G12C is one of the most common actionable mutations in lung cancer.

31.8%

Olomorasib dose reductions, pembrolizumab arm

Liver enzyme elevations drove most reductions, a known challenge for KRAS inhibitor plus immunotherapy combinations.

Voices

Curated perspectives — historical figures and your fellow readers.

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People Involved

Marcelo V. Negrao

Associate Professor of Thoracic and Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center

Presenting author of the olomorasib data at ESMO 2026

Marina Chiara Garassino

Thoracic oncologist and lung cancer researcher, University of Chicago

Argued first-line adoption by 2026 was unlikely without mature Phase 3 data

Organizations Involved

Eli Lilly and Company

Pharmaceutical company

Developer of olomorasib; acquired Loxo Oncology in 2019

The Indianapolis-based drugmaker developing olomorasib, an investigational KRAS G12C inhibitor inherited from Loxo Oncology.

Merck & Co.

Pharmaceutical company

Supplies pembrolizumab (Keytruda) for the olomorasib combination trials

Merck's anti-PD-1 therapy pembrolizumab is the immunotherapy backbone of Lilly's SUNRAY-01 trial.

Timeline

2019 2027

6 events Latest: Today

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2027
SUNRAY-01 randomized Phase 3 data expected
Upcoming Announcement

Lilly expects first randomized Phase 3 results in the first half of 2027; Part B enrollment is already complete.
2027
October 2026
ESMO 2026: durable first-line activity reported across PD-L1 levels
Today Clinical Data

Lilly reports median PFS not reached at ~21 months for olomorasib plus pembrolizumab, 62% ORR with chemoimmunotherapy.
Today
September 2025
FDA grants olomorasib breakthrough therapy designation
Regulatory

Designation covers olomorasib plus pembrolizumab for first-line KRAS G12C-mutant NSCLC with PD-L1 above 50%.
September 4th, 2025
December 2022
FDA approves adagrasib, second KRAS G12C inhibitor
Regulatory

Mirati's Krazati gains accelerated approval, also in the second-line setting.
December 2022
May 2021
FDA approves sotorasib, first KRAS G12C inhibitor
Regulatory

Amgen's Lumakras wins accelerated approval for second-line KRAS G12C-mutant NSCLC, breaking KRAS's undruggable status.
May 2021
2019
Lilly acquires Loxo Oncology
Corporate

Lilly buys Loxo for $8 billion, inheriting the olomorasib (LY3537982) RAS program.
2019

Scenarios

Phase 3 hits, olomorasib heads to FDA for first-line approval

Likely Resolves by Q2 2027

Discussed by: Lilly trial investigators and the ESMO presenting team

If SUNRAY-01's placebo-controlled Part A (PD-L1 ≥50%) shows a progression-free survival benefit, Lilly files and the breakthrough designation from September 2025 routes the application for priority review. The trial's Part B, testing olomorasib plus chemoimmunotherapy regardless of PD-L1, has already completed enrollment, so a broad label is plausible if both parts land.

Phase 3 disappoints, mirroring earlier KRAS inhibitors

Possible Resolves by Q2 2027

Discussed by: Thoracic oncologists citing CodeBreaK 200 and KRYSTAL-12 failures on overall survival

Both sotorasib and adagrasib improved progression-free survival in second-line trials but failed to show clear overall survival benefit. If SUNRAY-01 repeats that pattern, or if liver enzyme toxicity forces dose reductions that blunt the benefit, the first-line program stalls. The 31.8% dose-reduction rate in the pembrolizumab arm is the flag to watch.

Approval limited to the high PD-L1 subset

Possible Resolves by End of 2027

Discussed by: Clinicians noting SUNRAY-01's Part A design

If the benefit concentrates in patients with PD-L1 expression of 50% or higher, the FDA may approve olomorasib only for that population, keeping low-PD-L1 patients on chemoimmunotherapy. Several trial investigators have flagged low-PD-L1 patients as a higher-risk group, and the early data there, while encouraging, come from smaller cohorts.

Historical Context

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

May 2021

Sotorasib (Lumakras) breaks the KRAS barrier (2021)

The FDA granted accelerated approval to Amgen's sotorasib, the first KRAS G12C inhibitor, for second-line non-small cell lung cancer. KRAS had been considered undruggable for four decades, and sotorasib's approval ended that assumption.

Then

Sotorasib became a standard second-line option, but the confirmatory CodeBreaK 200 trial later failed to show a clear overall survival benefit over docetaxel.

Now

The class proved KRAS was druggable, but the second-line positioning and mixed overall survival data left the first-line door open.

Why this matters now

Sotorasib's overall survival miss is the cautionary tale hanging over olomorasib. It is why researchers insist on randomized Phase 3 data before moving KRAS inhibitors to first-line.

April 2018

Osimertinib's move to first-line (2018)

The FDA approved AstraZeneca's osimertinib for first-line EGFR-mutant non-small cell lung cancer after the FLAURA trial showed superior progression-free and overall survival versus standard chemotherapy. It was an oral targeted agent displacing chemo as the first choice.

Then

Osimertinib became the standard first-line therapy for EGFR-mutant patients, a population roughly comparable in size to KRAS G12C patients.

Now

It established the playbook olomorasib now runs: a molecularly defined subset, a targeted agent, a first-line claim.

Why this matters now

Marcelo Negrao invoked exactly this precedent at ESMO, saying the field wants to 'utilize other genomically-targeted therapies in lung cancer from the outset.' Olomorasib is attempting to repeat osimertinib's trajectory for KRAS.