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.
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
Primary outcome:
1. Phase 2: To evaluate the efficacy of Adagrasib monotherapy and in combination with pembrolizumab administered to patients having advanced/metastatic NSCLC. (Time Frame - 22 months):
Objective Response Rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
2. Phase 3: To compare efficacy of Adagrasib in combination with pembrolizumab versus pembrolizumab (Time Frame - 36 months):
Progression Free Survival per RECIST 1.1 by Blinded Independent Central Review (BICR) and Overall Survival
Secondary outcome:
1. Phase 2: To characterize the safety and tolerability of study treatments in selected populations (Time Frame - 22 months):
Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities.
2. Phase 2: Duration of Response (Time Frame - 22 months):
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.
3. Phase 2: Progression Free Survival (Time Frame - 22 months):
Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first.
4. Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations (Time Frame - 12 months):
1-Year Survival rate
5. Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations (Time Frame - 22 months):
Overall Survival (OS)
6. Phase 2: To evaluate the pharmacokinetics (PK) of study treatments by measuring blood plasma MRTX849 and potential metabolite concentrations. (Time Frame - 22 months):
Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations
7. Phase 3: To evaluate the safety and tolerability in the study population (Time Frame - 36 months):
Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities.
8. Phase 3: To evaluate the PK of adagrasib administered in the study population (Time Frame - 36 months):
Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations
9. Phase 3: To evaluate health-related quality of life (HRQOL) and lung cancer specific symptoms in the study population (Time Frame - 36 months):
Patient Reported Outcomes to measure quality of life
10. Phase 3: Progression Free Survival per RECIST 1.1 by Investigator (Time Frame - 36 months):
Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first.
11. Phase 3: Duration of Response (DOR) per RECIST 1.1 by Investigator and BICR (Time Frame - 36 months):
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.
12. Phase 3: Objective Response Rate (ORR) per RECIST 1.1 by Investigator and BICR (Time Frame - 36 months):
Defined as the percent of patients documented to have a confirmed CR or PR.
- Experimental: Phase 2 Cohort 1a: PD-L1 TPS <1%
Cohort 1a: Adagrasib twice daily (BID) in combination with pembrolizumab - Experimental: Phase 2 Cohort 1b: PD-L1 TPS <1%
Cohort 1b: Adagrasib BID monotherapy - Experimental: Phase 2 Cohort 2: PD-L1 TPS ≥1%
Cohort 2: Adagrasib BID in combination with pembrolizumab - Experimental: Phase 3 Cohort 3 Investigational Arm
Adagrasib BID in combination with pembrolizumab - Active Comparator: Phase 3 Cohort 4 Comparator Arm
Pembrolizumab
- Adagrasib (Pembrolizumab):
Adagrasib 400 mg twice daily (BID) in combination with pembrolizumab (Cohort 1a) - Adagrasib:
Adagrasib 600 mg BID monotherapy (Cohort 1b) - Adagrasib (Pembrolizumab):
adagrasib 400 mg BID in combination with pembrolizumab - Adagrasib (Pemrolizumab):
Adagrasib 400 mg BID + pembrolizumab 200 mg every Q3W - Pembrolizumab:
Pembrolizumab 200 mg IV Q3W
Quelle: ClinicalTrials.gov
