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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2 Trial of Adagrasib Monotherapy and in Combination With Pembrolizumab and a Phase 3 Trial of Adagrasib in Combination With Pembrolizumab Versus Pembrolizumab in Patients With Advanced Non-Small Cell Lung Cancer With KRAS G12C Mutation

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

Intervention / Treatment
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* Drug: Adagrasib
* Drug: Adagrasib
* Drug: Adagrasib
* Drug: Adagrasib
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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: No evidence of brain metastases Untreated brain metastases not needing immediate local therapy 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: Any untreated brain lesions > 1.0 cm in size Any brainstem lesions 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. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: MRTX849 Monotherapy, MRTX849 in Combination with Pembrolizumab and Pembrolizumab alone
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: To evaluate the efficacy of Adagrasib monotherapy and in combination with pembrolizumab administered to patients having advanced/metastatic NSCLC. | Objective Response Rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) | 22 months | 
| Phase 3: To compare efficacy of Adagrasib in combination with pembrolizumab versus pembrolizumab | Progression Free Survival by blinded independent central review (BICR) | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: To characterize the safety and tolerability of study treatments in selected populations | Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities. | 22 months | 
| Phase 2: Duration of Response | Defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of either Progression of Disease (PD) or death due to any cause, whichever occurs first. | 22 months | 
| Phase 2: Progression Free Survival | Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first. | 22 months | 
| Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations | 1-Year Survival rate | 12 months | 
| Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations | Overall Survival (OS) | 22 months | 
| Phase 2: To evaluate the pharmacokinetics (PK) of study treatments by measuring blood plasma MRTX849 and potential metabolite concentrations. | Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations | 22 months | 
| Phase 3: To evaluate the safety and tolerability in the study population | Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities. | 36 months | 
| Phase 3: To evaluate the PK of adagrasib administered in the study population | Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations | 36 months | 
| Phase 3: To evaluate health-related quality of life (HRQOL) and lung cancer specific symptoms in the study population | Patient Reported Outcomes to measure quality of life | 36 months | 
| Phase 3: Overall Survival | Defined as time from date of first study treatment to date of death due to any cause | 36 months | 
| Phase 3: Progression Free Survival by Investigator | Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first. | 36 months | 
| Phase 3: Duration of Response (DOR) | Defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of either Progression of Disease (PD) or death due to any cause, whichever occurs first. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS G12C, Non-small cell lung cancer, NSCLC, Metastatic Non-Small Cell Lung Cancer, Adagrasib, Krazati, TPS