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Combining adagrasib, pembrolizumab, and chemotherapy for lung cancer with a specific mutation

A Randomized, Double-Blind, Phase 3 Trial of Adagrasib Plus Pembrolizumab Plus Chemotherapy vs. Placebo Plus Pembrolizumab Plus Chemotherapy in Participants With Previously Untreated, Locally Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer With KRAS G12C Mutation (KRYSTAL-4)

Phase 3 Interventional Mirati Therapeutics Inc. · NCT06875310

This study is testing a new treatment combining adagrasib, pembrolizumab, and chemotherapy to see if it helps people with a specific type of lung cancer that has a KRAS G12C mutation.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment630 (estimated)
Ages18 Years and up
SexAll
SponsorMirati Therapeutics Inc. Industry-sponsored
Drugs / interventionspembrolizumab, chemotherapy
Locations352 sites (Birmingham, Alabama and 351 other locations)
Trial IDNCT06875310 on ClinicalTrials.gov

What this trial studies

This trial evaluates the effectiveness and safety of a combination treatment involving adagrasib, pembrolizumab, and chemotherapy in patients with previously untreated non-squamous non-small cell lung cancer (NSCLC) that has a KRAS G12C mutation. Participants will receive either the combination therapy or a placebo alongside pembrolizumab and chemotherapy. The study aims to determine if this new treatment approach can improve outcomes for patients with this specific type of lung cancer. The trial is designed for those with locally advanced or metastatic disease who have not received prior systemic therapy.

Who should consider this trial

Good fit: Ideal candidates include individuals with untreated, locally advanced or metastatic non-squamous NSCLC with a confirmed KRAS G12C mutation.

Not a fit: Patients who have received prior systemic anti-cancer therapy for advanced or metastatic disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for patients with a specific mutation in lung cancer.

How similar studies have performed: Other studies have shown promising results with similar combinations of targeted therapies and immunotherapy in lung cancer, indicating potential for success.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of non-squamous NSCLC with evidence of KRAS G12C mutation via tumor sample and/or circulating tumor deoxyribonucleic acid (ctDNA).
* Locally advanced or metastatic disease.
* Measurable disease via computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST v1.1 criteria of at least 1 lesion.
* No prior systemic anti-cancer therapy given for advanced or metastatic disease.
* Not a candidate for definitive therapy (eg, chemoradiation or complete surgical resection).
* Participants with brain metastases are eligible for enrollment, including those with untreated brain metastases. Brain metastases must be asymptomatic and not in need of immediate local therapy. Any untreated brain metastases must be ≤ 20 mm in diameter.
* Any PD-L1 expression (0 to 100%) as determined by VENTANA PD-L1 (SP263) assay, Agilent PD-L1 IHC 22C3 pharmDx, or Agilent PD-L1 IHC 28-8 pharmDx.

Exclusion Criteria:

* Participants with an active autoimmune or inflammatory disease requiring systemic treatment within 2 years.
* Uncontrolled or significant cardiovascular conditions within 6 months prior to enrollment that are ongoing or with risk of recurrence.
* Inadequate bone marrow or liver function or electrocardiogram (ECG) abnormalities.
* Ongoing treatment with concomitant medication known to cause prolonged QTc interval and that cannot be switched to alternative treatment prior to study entry.
* Treatment targeting KRAS G12C mutation (eg, sotorasib, adagrasib) in any setting.
* Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration.
* Other protocol-defined Inclusion/Exclusion criteria apply.

Where this trial is running

Birmingham, Alabama and 351 other locations

+302 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Carcinoma, Non-Small-Cell LungImmunotherapyKRASKRAS G12CTargeted therapy
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.