A Study of Encorafenib Plus Cetuximab Taken Together With Pembrolizumab Compared to Pembrolizumab Alone in People With Previously Untreated Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to learn about the effects of three study medicines (encorafenib, cetuximab, and pembrolizumab) given together for the treatment of colorectal cancer that: is metastatic (spread to other parts of the body); has the condition of genetic hypermutability (tendency to mutation) or impaired DNA mismatch repair (MMR) has a certain type of abnormal gene called BRAF and; has not received prior treatment. All participants in this study will receive pembrolizumab at the study clinic as an intravenous (IV) infusion (given directly into a vein) at the study clinic. In addition, half of the participants will take encorafenib by mouth at home every day and cetuximab by IV infusion at the study clinic. The study team will monitor how each participant is doing with the study treatment during regular visits at the study clinic.

Official Title
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A PHASE 2, RANDOMIZED, OPEN-LABEL STUDY OF ENCORAFENIB AND CETUXIMAB PLUS PEMBROLIZUMAB VERSUS PEMBROLIZUMAB ALONE IN PARTICIPANTS WITH PREVIOUSLY UNTREATED BRAF V600E-MUTANT, MSI H/DMMR METASTATIC COLORECTAL CANCER

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Encorafenib
* Biological: Cetuximab
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally confirmed microsatellite instability-high/ deficient mismatch repair (MSI-H/dMMR) stage IV colorectal carcinoma Locally confirmed BRAF V600E mutation in tumor tissue or blood Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Have not received prior systemic regimens for metastatic disease. Measurable disease per RECIST 1.1 Adequate organ function Exclusion Criteria: Colorectal adenocarcinoma that is RAS mutant or for which RAS mutation status is unknown Known active central nervous system metastases and/or carcinomatous meningitis; leptomeningeal disease Immunodeficiency or active autoimmune disease requiring systemic treatment in the past 2 years Presence of acute or chronic pancreatitis Clinically significant cardiovascular diseases (eg, thromboembolic or cerebrovascular accident events ≤ 12 wks prior) Received a live or live-attenuated vaccine within 30 days of planned start of study medication Previous treatment with any selective BRAF inhibitor (eg, encorafenib, dabrafenib, vemurafenib, XL281/BMS-908662) or any epidermal growth factor receptor (EGFR) inhibitor (eg, cetuximab, panitumumab). Previous treatment with an immune checkpoint inhibitor (eg, anti-programmed cell death [PD-1], anti-PD-L1 or anti-PD-L2 agent); or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).

Ages Eligible for Study
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Minimum Age: 16 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: This is an open-label, multicenter study of encorafenib and cetuximab plus pembrolizumab (Triplet Arm [Arm A]) versus pembrolizumab alone (Control Arm [Arm B]) as first-line treatment in participants with BRAF inhibitor (BRAF) V600E-mutant and microsatellite instability-high/ deficient mismatch repair (MSI-H/dMMR) mCRC. Randomization will be stratified by ECOG (0 vs 1)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: encorafenib, cetuximab and pembrolizumab<br>Participants receive encorafenib orally + cetuximab IV + pembrolizumab IV. | Drug: Encorafenib<br>* capsule<br>* Other names: PF-07263896 LGX818 ONO-7702 W0090;Biological: Cetuximab<br>* IV<br>* Other names: Erbitux;Biological: Pembrolizumab<br>* IV<br>* Other names: Keytruda, Lambrolizumab b MK-3475;|
| Active Comparator: Arm B: pembrolizumab<br>Participants receive pembrolizumab IV. | Biological: Pembrolizumab<br>* IV<br>* Other names: Keytruda, Lambrolizumab b MK-3475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS per investigator, defined as the time from randomization until PD based on investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurs first: | Duration of study, approximately 45 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Incidence and severity of AEs graded according to the NCI CTCAE v4.03: encorafenib and cetuximab + pembrolizumab (Arm A) vs pembrolizumab (Arm B) | Duration of study, approximately 45 months | 
| Overall Survival (OS) | OS is defined as the time from the date of randomization to the date of death due to any cause: encorafenib and cetuximab + pembrolizumab (Arm A) vs pembrolizumab (Arm B) | Duration of study, approximately 45 months | 
| Objective Response (OR) | OR is defined as a CR or PR per RECIST version 1.1 recorded from the date of randomization until date of first documentation of PD, death, or start of new anti-cancer therapy: encorafenib and cetuximab + pembrolizumab (Arm A) vs pembrolizumab (Arm B) | Duration of study, approximately 45 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Keynote-D31, BRAF V600E mutation positive, Colon cancer, Rectal cancer, Metastatic colon cancer, Colon cancer BRAF, Rectal cancer BRAF, MSI-H colorectal cancer, MSI-H colon cancer