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Phase 2 Trial of Adagrasib Monotherapy and in Combination With Pembrolizumab and a Phase 3 Trial of Adagrasib in Combination in Patients With a KRAS G12C Mutation KRYSTAL-7

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Mirati Therapeutics

Status and phase

Enrolling
Phase 3
Phase 2

Conditions

Metastatic Non-Small Cell Lung Cancer
Advanced Non-Small Cell Lung Cancer

Treatments

Drug: Pembrolizumab
Drug: Adagrasib

Study type

Interventional

Funder types

Industry

Identifiers

NCT04613596
849-007
CA239-0009

Details and patient eligibility

About

The Phase 2 portion of this study evaluates the efficacy and safety of MRTX849 monotherapy and in combination with pembrolizumab in cohorts of patients with advanced NSCLC with KRAS G12C mutation and any PD-L1 TPS and who are candidates for first-line treatment.

The Phase 3 portion of the study compares the efficacy of adagrasib in combination with pembrolizumab versus pembrolizumab in patients with unresectable, locally advanced or metastatic nonsquamous NSCLC with KRAS G12C mutation and PD-L1 TPS >=50% and who are candidates for first line treatment.

Full description

The Phase 2 portion of this study will evaluate the efficacy and safety of MRTX849 as monotherapy and in combination with pembrolizumab. There will be 3 cohorts of patients, all of whom have KRAS G12C mutation, have advanced or metastatic NSCLC, and are candidates for first-line treatment. 2 cohorts have PD-L1 TPS score <1% and are randomized to MRTX849 monotherapy or MRTX849 in combination with pembrolizumab. The 3rd cohort has PD-L1 TPS score of 1% or higher and is treated with MRTX849 and pembrolizumab

The Phase 3 portion of the study will randomize patients with squamous or nonsquamous NSCLC with KRAS G12C mutation and TPS >=50% in the first-line setting to adagrasib plus pembrolizumab or pembrolizumab. Primary efficacy objective is to compare efficacy between experimental and comparator arms. Secondary and exploratory objectives include evaluation of secondary efficacy endpoints, safety and tolerability, adagrasib PK, PROs, and correlative genomic biomarkers for the combination regimen in the study population.

MRTX849 is an orally available small molecule inhibitor of KRAS G12C, and Pembrolizumab (KEYTRUDA®) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

Enrollment

806 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

  • Phase 2: Histologically confirmed diagnosis of unresectable or metastatic NSCLC with KRAS G12C mutation and any PD-L1 TPS

  • Phase 3: Histologically confirmed diagnosis of unresectable or metastatic squamous or nonsquamous NSCLC with KRAS G12C mutation and PD-L1 TPS >=50%

  • Phase 3: Presence of evaluable or measurable disease per RECIST

  • Phase 3: CNS Inclusion - Based on screening brain imaging, patients must have one of the following:

    1. No evidence of brain metastases
    2. Untreated brain metastases not needing immediate local therapy
    3. Previously treated brain metastases not needing immediate local therapy

Exclusion criteria

  • Phase 2 and Phase 3: Prior systemic treatment for locally advanced or metastatic NSCLC including chemotherapy, immune checkpoint inhibitor therapy, or a therapy targeting KRAS G12C mutation (e.g., AMG 510).

  • Phase 2: Active brain metastases

  • Phase 3: Patients with known central nervous system (CNS) lesions must not have any of the following:

    1. Any untreated brain lesions > 1.0 cm in size
    2. Any brainstem lesions
    3. Ongoing use of systemic corticosteroids for control of symptoms of brain lesions at a total daily dose of > 10 mg of prednisone (or equivalent) prior to randomization.
    4. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain lesions notwithstanding CNS-directed therapy
  • Phase 3: Radiation to the lung > 30 Gy within 6 months prior to the first dose of study treatment

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

806 participants in 5 patient groups

Phase 2 Cohort 1a: PD-L1 TPS <1%
Experimental group
Description:
Cohort 1a: Adagrasib twice daily (BID) in combination with pembrolizumab
Treatment:
Drug: Adagrasib
Drug: Adagrasib
Drug: Adagrasib
Drug: Adagrasib
Phase 2 Cohort 1b: PD-L1 TPS <1%
Experimental group
Description:
Cohort 1b: Adagrasib BID monotherapy
Treatment:
Drug: Adagrasib
Drug: Adagrasib
Drug: Adagrasib
Drug: Adagrasib
Phase 2 Cohort 2: PD-L1 TPS ≥1%
Experimental group
Description:
Cohort 2: Adagrasib BID in combination with pembrolizumab
Treatment:
Drug: Adagrasib
Drug: Adagrasib
Drug: Adagrasib
Drug: Adagrasib
Phase 3 Cohort 3 Investigational Arm
Experimental group
Description:
Adagrasib BID in combination with pembrolizumab
Treatment:
Drug: Adagrasib
Drug: Adagrasib
Drug: Adagrasib
Drug: Adagrasib
Phase 3 Cohort 4 Comparator Arm
Active Comparator group
Description:
Pembrolizumab
Treatment:
Drug: Pembrolizumab

Trial contacts and locations

335

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Central trial contact

BMS Clinical Trials Contact Center www.BMSClinicalTrials.com; First line of the email MUST contain the NCT# and Site #.

Data sourced from clinicaltrials.gov

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