Advanced Non-Small Cell Lung Cancer, Metastatic Non-Small Cell Lung Cancer
Conditions
Keywords
KRAS G12C, Non-small cell lung cancer, NSCLC, Metastatic Non-Small Cell Lung Cancer, Adagrasib, Krazati, TPS
Brief summary
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.
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.
Interventions
DRUGAdagrasib
Adagrasib 400 mg twice daily (BID) in combination with pembrolizumab (Cohort 1a)
DRUGPembrolizumab
Pembrolizumab 200 mg IV Q3W
Sponsors
Mirati Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
MRTX849 Monotherapy, MRTX849 in Combination with Pembrolizumab and Pembrolizumab alone
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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 measurable disease per RECIST1.1 * 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 \> 2.0 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: To evaluate the efficacy of Adagrasib monotherapy and in combination with pembrolizumab administered to patients having advanced/metastatic NSCLC. | 22 months | Objective Response Rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) |
| Phase 3: To compare efficacy of Adagrasib in combination with pembrolizumab versus pembrolizumab | 36 months | Progression Free Survival per RECIST 1.1 by Blinded Independent Central Review (BICR) and Overall Survival |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: To characterize the safety and tolerability of study treatments in selected populations | 22 months | Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities. |
| Phase 2: Duration of Response | 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. |
| Phase 2: Progression Free Survival | 22 months | Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first. |
| Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations | 12 months | 1-Year Survival rate |
| Phase 2: To evaluate the pharmacokinetics (PK) of study treatments by measuring blood plasma MRTX849 and potential metabolite concentrations. | 22 months | Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations |
| Phase 3: To evaluate the safety and tolerability in the study population | 36 months | Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities. |
| Phase 3: To evaluate health-related quality of life (HRQOL) and lung cancer specific symptoms in the study population | 36 months | Patient Reported Outcomes to measure quality of life |
| Phase 3: Progression Free Survival per RECIST 1.1 by Investigator | 36 months | Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first. |
| Phase 3: Duration of Response (DOR) per RECIST 1.1 by Investigator and BICR | 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. |
| Phase 3: Objective Response Rate (ORR) per RECIST 1.1 by Investigator and BICR | 36 months | Defined as the percent of patients documented to have a confirmed CR or PR. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czechia, Denmark, Finland, France, Georgia, Germany, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, New Zealand, Norway, Peru, Philippines, Poland, Portugal, Romania, Serbia, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTBMS Clinical Trials Contact Center www.BMSClinicalTrials.com
CONTACTFirst line of the email MUST contain NCT # and Site #.
STUDY_DIRECTORBristol-Myers Squibb
Bristol-Myers Squibb
Outcome results
None listed