Binimetinib + Encorafenib for Melanoma

Overseen By Isabella C Glitza, MD,PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: BRAF inhibitors

Must not be taking: CYP3A4/5 inhibitors

Disqualifiers: HIV/AIDS, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

35 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of two drugs, binimetinib (Mektovi) and encorafenib (Braftovi), to treat melanoma that has spread to the brain. These drugs may stop tumor growth by blocking certain enzymes needed for cancer cells to multiply. People with melanoma that has the BRAF V600 mutation and brain involvement, who have previously tried other treatments, might be suitable candidates. The study aims to determine if these medications can control the disease more effectively than current options. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

The trial requires a 14-day break from immunotherapy or other investigational agents before starting. If you've had systemic chemotherapy, you need a 21-day break. You cannot take other anti-cancer treatments during the trial.

Is there any evidence suggesting that binimetinib and encorafenib are likely to be safe for humans?

Research shows that using binimetinib and encorafenib together is generally safe. Studies have found that patients with certain types of skin cancer, specifically melanoma, tolerate this treatment well. Serious side effects rarely occur, and most patients manage the treatment without major issues.

In earlier studies, participants taking binimetinib and encorafenib lived longer without their cancer worsening. This suggests the treatment is not only effective but also safe for regular use. While any treatment can have side effects, evidence so far indicates that these drugs, when used together, maintain a good safety record. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for melanoma?

Researchers are excited about the combination of Binimetinib and Encorafenib for treating melanoma because these drugs specifically target the pathways that help cancer cells grow. Unlike traditional treatments that might target cancer cells broadly, Encorafenib targets the BRAF mutation, which is common in melanoma, while Binimetinib inhibits the MEK protein, working in tandem to block the cancer's growth signals more effectively. This targeted approach not only aims to be more effective but also potentially reduces the side effects compared to conventional therapies like chemotherapy. This combination offers a promising new option for patients, particularly those with BRAF-mutant melanoma.

What evidence suggests that binimetinib and encorafenib might be effective for melanoma with brain metastases?

Research has shown that the combination of binimetinib and encorafenib effectively treats melanoma. One study found that patients taking these drugs together experienced stable disease for an average of 14.9 months, significantly longer than with another treatment. Additionally, about 69.4% of patients saw their cancer shrink or disappear after treatment. On average, patients lived for 33.6 months with this treatment. This trial will evaluate the effectiveness of binimetinib and encorafenib for treating melanoma that has spread to the brain, building on these promising results. ^{2 3 6 7 8}

Who Is on the Research Team?

Isabella C. Glitza, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with metastatic melanoma that has spread to the brain, including those who have previously received FDA-approved BRAF inhibitors. Participants must have a specific BRAFV600 mutation and be in good enough health as determined by certain lab parameters. Pregnant or breastfeeding individuals are excluded, as well as those with significant heart conditions, infections, gastrointestinal impairments, or a history of certain blood clots.

Inclusion Criteria

Able to provide written informed consent

I have previously received immunotherapy or participated in a clinical trial.

My tumor has the BRAFV600 mutation.

Exclusion Criteria

I haven't had an active infection in the last week.

I do not have significant heart issues, recent serious heart events, uncontrolled heart rhythm problems, severe eye conditions, recent major blood clots, certain infections like active hepatitis B or C, and I am not pregnant or planning to become pregnant during the study.

You have tested positive for HIV or have been diagnosed with AIDS, even if you are being treated for it.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive encorafenib orally once daily and binimetinib orally twice daily on day 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 12 weeks thereafter.

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• Encorafenib

Trial Overview

The trial is testing binimetinib and encorafenib's effectiveness on melanoma that has reached the central nervous system. These drugs aim to halt tumor growth by inhibiting key enzymes. The study includes patients who've had prior treatments and those new to these medications.

How Is the Trial Designed?

Group I: Treatment (encorafenib, binimetinib) Experimental Treatment 3 Interventions

Patients receive encorafenib PO QD and binimetinib PO BID on day 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Binimetinib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in European Union as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Approved in Canada as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in Japan as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

The combination of encorafenib and binimetinib for treating BRAF-mutant advanced melanoma shows similar efficacy to existing treatments like dabrafenib+trametinib and vemurafenib+cobimetinib, based on clinical trial results.

This new combination has a lower incidence of certain side effects, such as pyrexia and photosensitivity, which can significantly improve the quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Long-term efficacy of encorafenib plus binimetinib combined treatment: case report.] Spagnolo, F.[2021]

The combination of encorafenib and binimetinib has shown a median overall survival of 33.6 months in patients with advanced BRAFV600 mutation-positive melanoma, outperforming other BRAF/MEK inhibitor combinations that achieved 22 months.

Encorafenib's unique pharmacokinetics allow for prolonged binding and greater BRAF inhibition, which may lead to improved efficacy and better tolerability, with fewer side effects like pyrexia and photosensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. Trojaniello, C., Festino, L., Vanella, V., et al.[2019]

In the COLUMBUS trial involving 577 patients with BRAFV600-mutant melanoma, the combination of encorafenib and binimetinib significantly improved overall survival (33.6 months) compared to vemurafenib (16.9 months), indicating a strong efficacy of the combination therapy.

The safety profile of encorafenib plus binimetinib was acceptable, with common grade 3 or 4 adverse events being manageable, suggesting that this combination therapy is a promising treatment option for patients with this type of melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Dummer, R., Ascierto, PA., Gogas, HJ., et al.[2019]

In a phase II study involving 98 patients with BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC), the combination of encorafenib and binimetinib achieved a confirmed objective response rate of 75% in treatment-naïve patients and 46% in previously treated patients, indicating significant efficacy.

The treatment was generally well-tolerated, with common side effects including nausea (50%) and diarrhea (43%), but it also led to dose reductions in 24% of patients and one serious adverse event of intracranial hemorrhage, highlighting the importance of monitoring safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. Riely, GJ., Smit, EF., Ahn, MJ., et al.[2023]

In the COLUMBUS study involving 577 patients with advanced BRAF-mutant melanoma, the combination treatment of encorafenib plus binimetinib significantly improved health-related quality of life (HRQoL) scores compared to vemurafenib, indicating a meaningful enhancement in patients' perceived health status.

Patients receiving the combination therapy also experienced a delay in deterioration of quality of life, suggesting that this treatment not only improves survival but also helps maintain a better quality of life during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS). Gogas, H., Dummer, R., Ascierto, PA., et al.[2021]

Encorafenib and binimetinib, a combination of a BRAF inhibitor and a MEK inhibitor, received FDA approval in June 2018 for treating patients with unresectable or metastatic melanoma that has specific BRAF mutations (V600E or V600K).

The combination therapy is also being explored in ongoing phase III clinical trials for metastatic colorectal cancer, indicating its potential broader application beyond melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib and Binimetinib: First Global Approvals. Shirley, M.[2019]

In a 5-year study of patients with advanced BRAF V600-mutant melanoma, those treated with the combination of encorafenib and binimetinib (COMBO group) had a longer duration of survival without disease progression compared to those receiving either encorafenib alone or vemurafenib.

The combination treatment also resulted in fewer patients needing additional anticancer therapies after treatment, and while side effects were similar across all groups, they decreased over time for the COMBO group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COLUMBUS 5-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF. Dummer, R., Flaherty, KT., Robert, C., et al.[2023]

Encorafenib and binimetinib are effective small-molecule inhibitors that target the BRAF and MEK proteins in the MAPK signaling pathway, significantly improving overall and progression-free survival in patients with metastatic melanoma harboring BRAF V600 mutations.

This combination therapy received FDA approval in June 2018 specifically for treating melanoma with BRAF V600E/K mutations, highlighting its clinical utility and relevance in modern cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib and binimetinib for the treatment of BRAF V600E/K-mutated melanoma. Rose, AAN.[2019]

In a study of melanoma patients treated with encorafenib and binimetinib, the most common skin-related side effects were palmoplantar hyperkeratosis (54%) and palmoplantar erythrodysesthesia (58%) when using encorafenib alone.

Encouragingly, the combination therapy of encorafenib and binimetinib was found to be well tolerated, with fewer cutaneous adverse events compared to established BRAF inhibitors, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The spectrum of cutaneous adverse events during encorafenib and binimetinib treatment in B-rapidly accelerated fibrosarcoma-mutated advanced melanoma. Graf, NP., Koelblinger, P., Galliker, N., et al.[2019]

Citations

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braftovimektovi-melanoma.com

braftovimektovi-melanoma.com/efficacy

efficacy

BRAFTOVI + MEKTOVI achieved a median PFS of 14.9 months vs 7.3 months for vemurafenib (HR=0.54 [95% CI:041-0.71] p<0.0001)

2.

braftovi.pfizerpro.com

braftovi.pfizerpro.com/mektovi-m/overall-survival

Overall survival (OS)

In the COLUMBUS trial, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI with MEKTOVI. Monitor patients who already ...

3.

sciencedirect.com

sciencedirect.com/science/article/pii/S0959804924007299

COLUMBUS 7-year update: A randomized, open-label ...

Median melanoma-specific survival (95 % CI) was 36.8 months (27.7–51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8–25.9 months) in the ...

4.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40411977/

Results from the Dutch Melanoma Treatment Registry

Encorafenib/binimetinib was the first-line treatment in 64 % of all patients, while 36 % had prior immunotherapy. Overall, the ORR was 69.4 %, ...

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curemelanoma.org

curemelanoma.org/patient-eng/melanoma-treatment/options/encorafenib-braftovi-binimetinib-mektovi

Encorafenib (Braftovi) + Binimetinib (Mektovi)

In data presented at the American Society of Clinical Oncology (ASCO) conference in June, the combination demonstrated overall survival (OS) of 33.6 months and ...

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38723373/

COLUMBUS 7-year update: A randomized, open-label ...

Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the ...

7.

braftovi.com

braftovi.com/m

BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib)

People taking BRAFTOVI + MEKTOVI lived without their cancer growing, spreading, or getting worse for a median of 14.9 months compared with a median of 7.3 ...

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dailynews.ascopubs.org

dailynews.ascopubs.org/do/encorafenib-binimetinib-displays-promising-safety-efficacy-signals-braf-v600e-k-mutated

Encorafenib + Binimetinib Displays Promising Safety ...

“We've been able to show that treatment with encorafenib/binimetinib for BRAF-mutant stage IIB/IIC melanoma is safe and tolerable—and I think ...