BRAF-MEK Inhibitor Therapy for Melanoma

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Hormonal contraceptives

Disqualifiers: Pregnancy, Uncontrolled illness, Brain metastases, others

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

Compensation: Varies

Number of Visits: 4

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of treatments for individuals with advanced melanoma that has a specific genetic mutation called BRAF V600E. It aims to assess the effectiveness of encorafenib and binimetinib, which block tumor growth, in combination with nivolumab, an immunotherapy that aids the immune system in fighting cancer. The study includes two groups: one receiving all three treatments and another receiving only nivolumab. This trial may suit those with inoperable stage IIIC-IV melanoma and a confirmed BRAF V600E mutation. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial allows patients to continue taking non-biologic disease modifying agents and low-dose corticosteroids (up to 10 mg of prednisone daily). However, hormonal contraceptives should not be used during the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of encorafenib and binimetinib is generally safe and well-tolerated for patients with BRAF-mutant melanoma. Studies have found that this treatment can be used safely over long periods, with patients often not experiencing severe side effects.

Nivolumab, also part of this treatment, is an immunotherapy drug that helps the body's immune system fight cancer. Research suggests it is safe for many patients, with most handling it well, though some might experience mild to moderate side effects.

Overall, current evidence supports the safety of these treatments for patients with melanoma. However, since this is an early-phase trial, researchers are still studying safety carefully. Participants will be closely monitored to ensure their well-being. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for melanoma because they combine targeted therapy with immunotherapy, offering a potentially more effective approach than current options. Encorafenib and Binimetinib work together as BRAF-MEK inhibitors, specifically targeting and disrupting the cancer cell growth pathway, which is not addressed by traditional therapies. Meanwhile, Nivolumab, an immunotherapy, helps the immune system recognize and attack cancer cells more efficiently. This combination aims to enhance treatment effectiveness and possibly improve outcomes for patients with melanoma compared to existing therapies.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research has shown that using the drugs encorafenib and binimetinib together may help treat melanoma, a type of skin cancer. Studies have found that this combination can significantly increase survival rates. For instance, one study reported a seven-year survival rate of 32% for melanoma patients using these drugs, which surpasses some other treatments. These drugs work by blocking certain enzymes that help cancer cells grow. In this trial, participants in Arm A will receive this combination along with nivolumab, an immunotherapy drug that helps the immune system attack cancer cells. Meanwhile, participants in Arm B will receive nivolumab alone. While detailed information about using all three treatments together isn't widely available yet, each has shown promise individually. ^{3 6 7 8 9}

Who Is on the Research Team?

Zeynep Eroglu

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute

Are You a Good Fit for This Trial?

Adults with advanced BRAF mutant melanoma (stage IIIC-IV) who have measurable disease, good organ function, and an ECOG performance status of ≤2. They must not be pregnant or nursing, agree to use non-hormonal contraception for 6 months post-treatment, and haven't had certain prior treatments like BRAF/MEK inhibitors in the metastatic setting.

Inclusion Criteria

You need to have a certain amount of a specific type of DNA in your blood when you start the study.

I will use non-hormonal birth control during and for 6 months after treatment.

Your creatinine level is less than or equal to 2 times the upper limit of normal at the study site.

Exclusion Criteria

I have had cancer before, but it's under control and I'm not currently on cancer treatment.

I do not have any serious ongoing illnesses and my heart is classified as class 2B or better.

I have HIV, am on effective treatment, and my last viral load was undetectable.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 450 mg Encorafenib daily, 45 mg Binimetinib twice daily, and 240 mg Nivolumab IV every 2 weeks

8 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Participants are monitored for time to treatment failure and tumor response

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Encorafenib; Binimetinib
• Nivolumab

Trial Overview The trial is testing a combination of encorafenib and binimetinib—drugs that block enzymes promoting tumor growth—with nivolumab, which may help the immune system fight cancer. The goal is to see if this trio can effectively kill more melanoma cells.

How Is the Trial Designed?

Group I: Arm A: BRAF-MEK Inhibitor Therapy Experimental Treatment 3 Interventions

Participants will receive 450 mg Encorafenib daily, along with 45 mg Binimetinib twice daily and 240 mg Nivolumab IV every 2 weeks.

Group II: Arm B Active Control 1 Intervention

Participants will receive 240 mg Nivolumab IV every 2 weeks

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Published Research Related to This Trial

In a phase 3 study involving 577 patients with advanced BRAFV600-mutant melanoma, the combination of encorafenib and binimetinib significantly improved median progression-free survival to 14.9 months compared to 7.3 months with vemurafenib, indicating greater efficacy of the combination therapy.

The encorafenib plus binimetinib treatment showed a better tolerability profile with fewer severe adverse events compared to encorafenib or vemurafenib alone, suggesting it could be a safer treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Dummer, R., Ascierto, PA., Gogas, HJ., et al.[2022]

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]

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]

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]

Binimetinib, an uncompetitive inhibitor of MEK1/2, has shown significant efficacy in treating metastatic melanoma, particularly in combination with encorafenib, resulting in a progression-free survival (PFS) of 14.9 months compared to 7.3 months with vemurafenib alone in Phase 3 trials.

While binimetinib has a tolerable safety profile, there is currently no long-term data on durable responses or overall survival benefits compared to other treatments, highlighting the need for individualized treatment plans for patients with BRAF-mutated metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The discovery and development of binimetinib for the treatment of melanoma. Tran, B., Cohen, MS.[2021]

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

1. asco.org asco.org/abstracts-presentations/ABSTRACT447570

Efficacy of encorafenib/binimetinib in patients with ... Background: Data on the effectiveness of encorafenib plus binimetinib in patients with melanoma brain metastases (BMs) are lacking.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0959804925002965

Efficacy of encorafenib plus binimetinib in patients with ... The median PFS in this study was 5.5 months, and the median OS was 11.9 months in unselected patients.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12416198/

COLUMBUS part 1–7-year results for encorafenib and ... Seven-year melanoma-specific survival rates were 32% with enco/bini (encorafenib plus binimetinib), 20% with vemurafenib, and almost 34% with encorafenib ...

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

Encorafenib + Binimetinib Displays Promising Safety ... Treatment with a combined BRAF/MEK–targeted approach previously demonstrated success in stage III/IV melanoma, leading Columbus-AD trial ...

5. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(25)00133-0/abstract

Combination of encorafenib and binimetinib followed by ... The primary outcome was progression-free survival in the intention-to-treat population. Safety was assessed in all patients who initiated the protocol treatment ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9916040/

A Randomized, Open-Label, Phase III Trial of Encorafenib ... In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety ...

7. 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 ...

8. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1466185/full

Real-life evidence of encorafenib plus binimetinib in ... The 5-year OS rates were 35%, 34% and 31%, and the observed median OS was 33.6, 25.9 and 22.5 months for encorafenib plus binimetinib (7), ...

9. esmo.org esmo.org/oncology-news/binimetinib-contributes-to-the-efficacy-and-safety-outcomes-observed-with-encorafenib-plus-binimetinib-combination-therapy-in-patients-with-brafv600-mutated-melanoma

Binimetinib Contributes to the Efficacy and Safety ... These data confirm and extend the evidence for the contribution of binimetinib for the treatment of BRAF-mutated, advanced, unresectable melanoma.