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

Purpose

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 squamous or nonsquamous NSCLC with KRAS G12C mutation and PD-L1 TPS >=50% and who are candidates for first line treatment.

Conditions

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

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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

Study Design

Phase
Phase 2/Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
MRTX849 Monotherapy, MRTX849 in Combination with Pembrolizumab and Pembrolizumab alone
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Phase 2 Cohort 1a: PD-L1 TPS <1% 		Cohort 1a: Adagrasib twice daily (BID) in combination with pembrolizumab
  • Drug: Adagrasib
    Adagrasib 400 mg twice daily (BID) in combination with pembrolizumab (Cohort 1a)
    Other names:
    • Pembrolizumab
Experimental
Phase 2 Cohort 1b: PD-L1 TPS <1% 		Cohort 1b: Adagrasib BID monotherapy
  • Drug: Adagrasib
    Adagrasib 600 mg BID monotherapy (Cohort 1b)
Experimental
Phase 2 Cohort 2: PD-L1 TPS ≥1% 		Cohort 2: Adagrasib BID in combination with pembrolizumab
  • Drug: Adagrasib
    adagrasib 400 mg BID in combination with pembrolizumab
    Other names:
    • Pembrolizumab
Experimental
Phase 3 Cohort 3 Investigational Arm 		Adagrasib BID in combination with pembrolizumab
  • Drug: Adagrasib
    Adagrasib 400 mg BID + pembrolizumab 200 mg every Q3W
    Other names:
    • Pemrolizumab
Active Comparator
Phase 3 Cohort 4 Comparator Arm 		Pembrolizumab
  • Drug: Pembrolizumab
    Pembrolizumab 200 mg IV Q3W

Recruiting Locations

Brigham and Womens/Mass General Health Care Center at Foxborough
Foxboro, Massachusetts 02035
Contact:
Naeem Tahir, Site 007-5480
5085431700

Dana-Farber Brigham and Womens Cancer Center at Milford Regional
Milford, Massachusetts 01757
Contact:
Alexandra Bailey, Site 007-5479
7813379091

More Details

Status
Recruiting
Sponsor
Mirati Therapeutics Inc.

Study Contact

BMS Clinical Trials Contact Center www.BMSClinicalTrials.com
855-907-3286
Clinical.Trials@bms.com

Detailed 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.