Combination Therapies With Adagrasib in Patients With Advanced NSCLC With KRAS G12C Mutation

Study Overview
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Brief Summary
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Study 849-017 is an open-label, Phase 2 clinical trial evaluating the clinical efficacy of adagrasib in combination with pembrolizumab and chemotherapy in the first-line setting for patients with advanced NSCLC with TPS ≥ 1%, TPS <50% and KRAS G12C mutation

Official Title
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A Phase 2 Trial of Combination Therapies With Adagrasib in Patients With Advanced Non-Small Cell Lung Cancer With KRAS G12C Mutation

Conditions
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Advanced NSCLC, Metastatic Lung Cancer

Intervention / Treatment
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* Drug: Adagrasib oral dose of 400 mg twice daily tablets
* Combination Product: Pembrolizumab
* Combination Product: Chemotherapy: Pemetrexed
* Combination Product: Cisplatin/Carboplatin


Participation Criteria
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Eligibility Criteria
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Cohort A* (closed): Has an untreated and unresectable or metastatic NSCLC with histologically confirmed (squamous or nonsquamous) KRASG12C mutation and histologically confirmed PD-L1 TPS ≥1%. Cohort C: Has an untreated and unresectable or metastatic NSCLC with histologically confirmed (non-squamous only) KRASG12C mutation and histologically confirmed PD-L1 TPS < 50% AND previously completed 4 cycles of standard-of-care platinum based induction chemotherapy with pembrolizumab AND experienced stable disease, partial response, or complete response per investigator's assessment after 4 cycles OR if patients received <4 cycles of a platinum-based induction, was stopped early due to intolerable toxicity Cohort E: Has an untreated and unresectable or metastatic NSCLC with histologically confirmed (non-squamous only) KRASG12C mutation and histologically confirmed PD-L1 TPS < 50% Presence of measurable disease per RECIST v1.1 Exclusion Criteria: All Cohorts: Any prior therapy targeting KRASG12C mutation in any setting Cohorts A & E: Prior systemic therapy for locally advanced or metastatic NSCLC, including chemotherapy, immune checkpoint inhibitor therapy or chemoimmunotherapy (note: prior systemic therapy or chemoradiation given in the adjuvant or neoadjuvant setting are allowed if last dose of prior systemic treatment was >1 year prior to first dose of study treatment) Cohort C: received maintenance therapy (e.g, pembrolizumab and/or pemetrexed following completion of 4-6 cycles of a platinum-based regimen administered in the first-line setting Radiation to the lung > 30 Gy within 6 months prior to first dose of study treatment Active brain metastases

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: PD-L1 TPS≥ 1% (Closed)<br>Adagrasib 400 mg BID for 2 cycles followed by adagrasib 400 mg BID + pembrolizumab 200 mg every 3 weeks (Q3W) up to 35 cycles | Drug: Adagrasib oral dose of 400 mg twice daily tablets<br>* oral dose of 400 mg twice daily tablets<br>|
| Experimental: Cohort C<br>Adagrasib 400 mg BID + pemetrexed 500 mg/m2 Q3W + pembrolizumab 200 mg Q3W up to 31 cycles | Drug: Adagrasib oral dose of 400 mg twice daily tablets<br>* oral dose of 400 mg twice daily tablets<br>Combination Product: Pembrolizumab<br>* IV infusion once every 3 weeks<br>Combination Product: Chemotherapy: Pemetrexed<br>* IV infusion once every 3 weeks<br>Combination Product: Cisplatin/Carboplatin<br>* IV infusion once every 3 weeks<br>|
| Experimental: Cohort E<br>Adagrasib 400 mg BID + pembrolizumab 200 mg Q3W + pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 Q3W OR carboplatin AUC 5 Q3W for 4 cycles, followed by adagrasib 400 mg BID + pemetrexed 500 mg/m2 Q3W + pembrolizumab 200 mg Q3W (up to 31 cycles) | Drug: Adagrasib oral dose of 400 mg twice daily tablets<br>* oral dose of 400 mg twice daily tablets<br>Combination Product: Pembrolizumab<br>* IV infusion once every 3 weeks<br>Combination Product: Chemotherapy: Pemetrexed<br>* IV infusion once every 3 weeks<br>Combination Product: Cisplatin/Carboplatin<br>* IV infusion once every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) for Cohort A and E | Defined as the percent of patients documented to have a confirmed CR or PR | 30 months | 
| Progression-free Survival (PFS) at six months for Cohort C | PFS is defined as time from first study treatment until disease progression or death from any cause, whichever occurs first. | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Defined as number of patients with treatment emergent AEs | 30 months | 
| 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. | 30 months | 
| Overall Survival (OS) | Defined as time from date of first study treatment to date of death due to any cause | 30 months | 
| Progression-free Survival (PFS) | Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first. | 30 months | 
| Population pharmacokinetic (PK) Model Derived AUC at Steady State (AUCtau,ss). | Concentration data from this study will be pooled with other studies and exposure parameters derived using population PK methods. Data for this Outcome Measure will not be reported here since ClinicalTrials.gov is designed to report results from participants enrolled in the study and described in the Participant Flow module. | Time Frame: Pre-dose and 4-6 hours post dose; up to 6 months | 
| Cohorts C and E: DLTs during SLI (Safety Lead In) | Defined as those patients in the SLI of the study who have received at least 80% of the assigned dose of adagrasib during the first cycle on study, or interrupted or discontinued study treatment during the first cycle due to a DLT. | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS G12C, NSCLC, Non Small Cell Lung Cancer