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

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)

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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