What side effects are associated with this type of intervention?

The combination of Encorafenib (BRAF Inhibitor) and Binimetinib (MEK Inhibitor) for treating melanoma is associated with several side effects, including cutaneous reactions, gastrointestinal issues, ocular problems, cardiac events, and musculoskeletal pain. Specific adverse events include fever, photosensitivity, and alopecia. Pembrolizumab (PD-1 Inhibitor) can cause immune-related adverse events such as skin reactions, endocrine disorders, and less commonly, vitiligo and alopecia. These side effects are generally manageable and reversible, but they can sometimes lead to treatment discontinuation.

What prior FDA approvals exist?

The FDA has approved several treatments for melanoma, particularly targeting the BRAF V600 mutation and immune checkpoint pathways. Encorafenib, a second-generation BRAF inhibitor, has shown improved efficacy and tolerability. It is often used in combination with Binimetinib, a MEK inhibitor, to enhance treatment outcomes. Pembrolizumab, a PD-1 inhibitor, has been approved for its effectiveness in improving overall survival and progression-free survival in melanoma patients. These drugs, either as monotherapies or in combination, represent significant advancements in the treatment of advanced or metastatic melanoma.

What other types of research exist?

Promising alternatives for melanoma treatment in 2024 include: 1) Dabrafenib (BRAF inhibitor) plus Trametinib (MEK inhibitor), which has shown improved relapse-free survival and overall survival in clinical trials. 2) Nivolumab (PD-1 inhibitor) plus Ipilimumab (CTLA-4 inhibitor), which has demonstrated significant progression-free survival benefits. 3) Atezolizumab (PD-L1 inhibitor) combined with chemotherapy, which has been FDA approved for certain cancer types and shows potential in melanoma. These alternatives offer different mechanisms of action and have shown efficacy in clinical studies.

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Kinase Inhibitor

Triple Drug Therapy for Advanced Melanoma

Phase 3

Waitlist Available

Research Sponsored by Pfizer

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Documented evidence of a BRAF V600E or V600K mutation in melanoma tumor tissue as previously determined by either PCR or NGS-based local laboratory assay obtained during the course of normal clinical care, in a CLIA- or similarly certified laboratory

Have not received prior first-line systemic therapy for metastatic or unresectable locally advanced melanoma

Must not have

Known history of a positive test for HIV or known AIDS

Participants who previously received and subsequently discontinued encorafenib and/or binimetinib and/or anti-PD-1/-L1 due to severe toxicity

Timeline

Screening 3 weeks

Treatment Varies

Follow Up day 1 of every 3 cycles: c4d1, c7d1, c10d1, etc. for the first 24 months and then day 1 of every 4 cycles after 24 months

Awards & highlights

Pivotal Trial

No Placebo-Only Group

Summary

This trial is testing a combination of three drugs to treat advanced skin cancer in patients with a specific genetic mutation. One drug helps the immune system fight cancer, while the other two stop cancer cells from growing. The study aims to see if this combination is safe and effective.

Who is the study for?

Adults with advanced or metastatic melanoma that has a specific BRAF gene mutation and no prior treatment for their condition. They must be able to follow the study plan, have at least one measurable lesion, proper organ function, and an ECOG status of 0 or 1. Exclusions include significant heart disease history, recent serious blood clots or strokes, active infections requiring treatment, brain metastases involvement, certain medication use within specified timeframes before the trial starts.

What is being tested?

The trial is testing a combination of three drugs: Encorafenib and Binimetinib taken orally daily at home along with Pembrolizumab given via IV every three weeks in the clinic. The goal is to assess their effectiveness when used together against melanoma that hasn't been treated before.

What are the potential side effects?

Potential side effects may include fatigue, skin reactions, liver problems (like hepatitis), muscle pain or weakness (myopathy), allergic reactions including swelling under the skin (angioedema) and infusion-related reactions from Pembrolizumab.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My melanoma has a BRAF V600 mutation confirmed by a certified test.

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I haven't had systemic therapy for advanced melanoma.

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I am 18 years old or older.

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My skin cancer is at an advanced stage and cannot be surgically removed.

Select...

I am fully active or can carry out light work.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have tested positive for HIV/AIDS.

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I stopped taking encorafenib, binimetinib, or anti-PD-1/-L1 due to severe side effects.

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I have or had lung inflammation not caused by infection, treated with steroids.

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I have or had brain metastases or cancer spread to the lining of the brain.

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I cannot swallow or absorb pills.

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I have not been treated for an infection with medication in the last 2 weeks.

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My melanoma is located in the mucosal or ocular area.

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I am not allergic to encorafenib, binimetinib, pembrolizumab, or their ingredients.

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I have a muscle disorder that could increase my CK levels.

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I have a serious heart condition.

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I have an immune system disorder that needed treatment in the last 2 years.

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I have a digestive issue that affects how my body absorbs medication.

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I have or am at risk for retinal vein occlusion.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ time from the date of randomization to the date of death due to any cause.

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~time from the date of randomization to the date of death due to any cause.

This trial's timeline: 3 weeks for screening, Varies for treatment, and time from the date of randomization to the date of death due to any cause. for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Phase 3: Objective Response (OR) by Blinded Independent Central Review (BICR)

Safety Lead In (SLI): Incidence of Dose Limiting Toxicities (DLTs)

Secondary study objectives

Phase 3: Change from baseline in 5-level EuroQol-5D (EQ-5D-5L) index score and visual analog scale (VAS)

Melanoma

Phase 3: Change from baseline in Patient Global Impression of Severity (PGIS) score

+11 more

Side effects data

From 2024 Phase 3 trial • 804 Patients • NCT03040999

64%

Radiation skin injury

63%

Stomatitis

58%

Anaemia

56%

Nausea

48%

Dry mouth

45%

Constipation

45%

Weight decreased

44%

Dysphagia

42%

Neutrophil count decreased

33%

Dysgeusia

33%

Vomiting

32%

Fatigue

31%

White blood cell count decreased

28%

Hypomagnesaemia

26%

Decreased appetite

25%

Hypothyroidism

25%

Hypokalaemia

24%

Lymphocyte count decreased

24%

Platelet count decreased

23%

Oropharyngeal pain

23%

Blood creatinine increased

22%

Diarrhoea

22%

Odynophagia

20%

Hypoacusis

20%

Alanine aminotransferase increased

20%

Hyponatraemia

19%

Tinnitus

19%

Oral candidiasis

19%

Asthenia

16%

Pyrexia

16%

Cough

15%

Aspartate aminotransferase increased

15%

Rash

14%

Insomnia

13%

Acute kidney injury

13%

Pharyngeal inflammation

13%

Pruritus

12%

Dysphonia

12%

Gamma-glutamyltransferase increased

11%

Pneumonia

11%

Dehydration

10%

Hyperthyroidism

10%

Hypoalbuminaemia

10%

Hypocalcaemia

10%

Headache

10%

Productive cough

Neck pain

Peripheral sensory neuropathy

Gastrooesophageal reflux disease

Hiccups

Hyperglycaemia

Hyperuricaemia

Dizziness

Hypophosphataemia

Urinary tract infection

Ear pain

Localised oedema

Hyperkalaemia

Erythema

Oral pain

Abdominal pain upper

Arthralgia

Anxiety

Febrile neutropenia

Dyspepsia

Saliva altered

Back pain

Oedema peripheral

Hypertension

Dyspnoea

Nasopharyngitis

Alopecia

Dry skin

Sepsis

Pneumonia aspiration

Trismus

Pneumonitis

Laryngeal oedema

Malnutrition

Pharyngeal haemorrhage

Cellulitis

Septic shock

Systemic infection

Clostridium difficile colitis

Cardiac arrest

Death

Bronchitis

Hepatitis

Immune-mediated hepatitis

Oesophagitis

General physical health deterioration

Hypophagia

Tumour haemorrhage

Cerebrovascular accident

Syncope

Acute respiratory failure

Aspiration

Colitis

Mouth haemorrhage

Hypersensitivity

Acute myocardial infarction

Abscess neck

Device related infection

Stoma site infection

Vascular device infection

Wound infection

Hypercalcaemia

Pulmonary embolism

Respiratory failure

100%

80%

60%

40%

20%

Study treatment Arm

Pembrolizumab + CRT Followed by Pembrolizumab

Placebo + CRT Followed by Placebo

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: Triplet ArmExperimental Treatment3 Interventions

Encorafenib and Binimetinib in combination with Pembrolizumab

Group II: Control ArmActive Control1 Intervention

Pembrolizumab

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Binimetinib

2018

Completed Phase 3

~1250

Pembrolizumab

2017

Completed Phase 3

~3150

Encorafenib

2022

Completed Phase 3

~970

0 / 18Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Encorafenib, a BRAF inhibitor, targets and inhibits the activity of the mutated BRAF protein, which is involved in cell growth and proliferation in melanoma cells. Binimetinib, a MEK inhibitor, works downstream of BRAF in the same pathway, further blocking cell growth signals. Pembrolizumab, a PD-1 inhibitor, enhances the immune system's ability to detect and destroy cancer cells by blocking the PD-1 pathway, which tumors use to evade immune detection. These mechanisms are crucial for melanoma patients as they directly target the genetic mutations and immune evasion strategies that drive melanoma progression, offering a more personalized and effective treatment approach.

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