A Study of Adagrasib Plus Pembrolizumab Plus Chemotherapy vs. Placebo Plus Pembrolizumab Plus Chemotherapy in Participants With Previously Untreated Non-squamous Non-small Cell Lung Cancer With KRAS G12C Mutation (KRYSTAL-4)

Phase 3

Recruiting

• Conditions: Carcinoma, Non-Small-Cell Lung
• Interventions: Drug: Adagrasib; Drug: Pembrolizumab; Drug: Carboplatin; Drug: Pemetrexed; Drug: Placebo; Drug: Cisplatin

• Registration Number: NCT06875310
• Lead Sponsor: Mirati Therapeutics Inc.

Brief Summary

This is a trial to evaluate the efficacy, safety, and tolerability of adagrasib plus pembrolizumab plus platinum-doublet chemotherapy versus placebo plus pembrolizumab plus platinum-doublet chemotherapy in participants with previously untreated, locally advanced or metastatic NSCLC with KRAS G12C mutation

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-03-07
• Study First Submitted QC: 2025-03-07
• Study First Posted: 2025-03-13
• Study Start: 2025-04-24
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-03
• Last Update Posted: 2025-07-04
• Primary Completion: 2029-09-07
• Study Completion: 2032-04-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 630

Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of non-squamous NSCLC with evidence of KRAS G12C mutation via tumor tissue 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, known, prior documented, or suspected autoimmune or inflammatory disease.
• Uncontrolled or significant cardiovascular conditions within 6 months prior to enrollment.
• 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Adagrasib	Adagrasib	-
Adagrasib	Pembrolizumab	-
Adagrasib	Carboplatin	-
Adagrasib	Pemetrexed	-
Adagrasib	Cisplatin	-
Placebo	Pembrolizumab	-
Placebo	Carboplatin	-
Placebo	Pemetrexed	-
Placebo	Placebo	-
Placebo	Cisplatin	-

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS) as Assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by Blinded Independent Central Review (BICR)	Up to 7 years
Overall Survival (OS)	Up to 7 years

Secondary Outcome Measures

Name	Time	Method
Overall Response (OR) as Assessed per RECIST v1.1 by BICR	Up to 7 years
Duration of Response (DOR) as Assessed per RECIST 1.1 by BICR	Up to 7 years
PFS as Assessed per RECIST v1.1 by Investigator	Up to 7 years
Number of Participants With Adverse Events (AEs)	Up to 90 days from last dose
Number of Participants With Serious Adverse Events (SAEs)	Up to 90 days from last dose
Number of Participants With AEs Leading to Dose Interruption	Up to 90 days from last dose
Number of Participants With AEs Leading to Dose Reduction	Up to 90 days from last dose
Number of Participants With AEs Leading to Treatment Discontinuation	Up to 90 days from last dose
Number of Deaths	Up to 90 days from last dose
Time to Definitive Deterioration by Non-Small Cell Lung Cancer-Symptom Assessment Questionnaire (NSCLC-SAQ) Total Score	Up to 7 years
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30) Scale/item Score	Up to 90 days from last dose

Trial Locations

Locations (328)

Local Institution - 0347; 🇺🇸 Birmingham, Alabama, United States

Local Institution - 0581; 🇺🇸 Fullerton, California, United States

Local Institution - 0202; 🇺🇸 Long Beach, California, United States

Local Institution - 0643; 🇺🇸 Newport Beach, California, United States

Local Institution - 0666; 🇺🇸 Orange, California, United States

Local Institution - 0623; 🇺🇸 Santa Barbara, California, United States

Local Institution - 0442; 🇺🇸 Denver, Colorado, United States

Local Institution - 0651; 🇺🇸 Gainesville, Florida, United States

Local Institution - 0621; 🇺🇸 Palm Bay, Florida, United States

Local Institution - 0377; 🇺🇸 Tamarac, Florida, United States

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