Encorafenib + Binimetinib for Melanoma

Overseen By Neelam Lal

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Herbal medications, supplements

Disqualifiers: Uncontrolled brain metastases, heart failure, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: Unknown

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests treatments for melanoma, a type of skin cancer, by evaluating whether a combination of the drugs encorafenib (Braftovi) and binimetinib (Mektovi) can reduce cancer recurrence after surgery. Researchers aim to understand the effectiveness of these drugs when administered before and after surgery, based on the cancer's response. Participants whose cancer does not fully respond initially might also receive a different drug, nivolumab (Opdivo). The trial seeks participants with melanoma that has a specific genetic mutation called BRAFV600, which influences cancer growth. As an Early Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the chance to contribute to groundbreaking research.

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

The trial protocol does not specify if you must stop taking your current medications, but it mentions that you cannot use certain prohibited medications, including some herbal supplements and foods, within one week before starting the study treatment. It's best to discuss your current medications with the trial team.

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

Research has shown that patients generally tolerate the combination of encorafenib and binimetinib well. In one study, only 0.5% of patients experienced a noticeable increase in heart rhythm, indicating that serious heart-related side effects are rare.

For nivolumab, studies have found that its safety remains consistent, regardless of dosage, meaning side effects are usually predictable and manageable.

In summary, both treatments have some side effects, but they are typically mild and controllable. This information is based on past studies, so discussing any concerns with a healthcare provider is always advisable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using encorafenib and binimetinib for melanoma because they target specific mutations in cancer cells, potentially offering a more precise approach than traditional chemotherapy. Encorafenib is a BRAF inhibitor, while binimetinib inhibits MEK, both of which are parts of a pathway that often contributes to melanoma growth. This dual-targeted approach aims to effectively halt cancer progression by disrupting the cancer's growth signals, which is different from standard treatments like immunotherapy with drugs such as nivolumab or traditional chemotherapy. Additionally, the combination's ability to continue treatment after surgery, based on the tumor's response, offers a tailored treatment plan that could improve outcomes for patients.

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

Research has shown that using the drugs encorafenib and binimetinib together can effectively treat melanoma, a type of skin cancer. One study found that patients taking these drugs lived for a median of 36.8 months specifically due to melanoma. Additionally, 69.4% of patients experienced tumor reduction or disappearance after treatment. In this trial, participants who achieve a pathologic complete response will continue with encorafenib and binimetinib. For those whose cancer does not completely respond, the trial offers another option: the drug nivolumab. Previous studies have shown that nivolumab can improve survival rates, with 44% of patients living for at least five years when used alone. These treatments offer promising options for managing melanoma. ^{2 3 6 7 8}

Who Is on the Research Team?

Zeynep Eroglu

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

Adults with melanoma that has a BRAFV600 mutation, either stage III or IV, can join this trial. They must have good blood counts and organ function, agree to use contraception, and not have had certain treatments or uncontrolled health issues recently. Those with specific drug allergies or who are pregnant cannot participate.

Inclusion Criteria

Your blood and liver test results must be within certain levels: Hemoglobin should be at least 8 g/dL, platelets at least 75 × 10^9/L, AST and ALT levels not more than 2.5 times the upper limit of normal, and other liver function tests should also be within specified ranges.

I am a woman who can have children, tested negative for pregnancy, and agree to use effective birth control.

My melanoma has a BRAFV600 mutation and is either stage III or IV.

Exclusion Criteria

I am not taking any medication or supplements that are not allowed in the study.

I will not consume grapefruit, pomegranates, star fruits, Seville oranges or their juices while taking encorafenib/binimetinib.

I have HIV without effective treatment and my viral load is not undetectable.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive 24 weeks of neoadjuvant encorafenib and binimetinib followed by planned resection

24 weeks

Adjuvant Treatment

Participants receive adjuvant therapy based on pathologic response status for 24 weeks

24 weeks

Follow-up

Participants are monitored for disease relapse and overall survival with imaging every 12 weeks for at least one year, and every 24 weeks for at least two years post-surgery

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• Encorafenib
• Nivolumab

Trial Overview The study is testing the effectiveness of Encorafenib and Binimetinib pills before surgery (neoadjuvant therapy) in melanoma patients with a BRAF mutation. After surgery (adjuvant therapy), Nivolumab will be used depending on the initial response to treatment.

How Is the Trial Designed?

Group I: Nivolumab after Non-Pathologic Complete Response Experimental Treatment 3 Interventions

Participants will receive 24 weeks of neoadjuvant encorafenib and binimetinib and then proceed to planned resection. If participants have non-pathologic complete response they will receive nivolumab for 24 weeks. Imaging will be conducted every 12 weeks for at least one year after surgery, and every 24 weeks for at least two years post-surgery.

Group II: Encorafenib and Binimetinib after Pathologic Complete Response Experimental Treatment 2 Interventions

Participants will receive 24 weeks of neoadjuvant encorafenib and binimetinib and then proceed to planned resection. If participants have pathologic complete response they will continue to receive encorafenib and binimetinib for 24 more weeks. Imaging will be conducted every 12 weeks for at least one year after surgery, and every 24 weeks for at least two years post-surgery.

Group III: Encorafenib and Binimetinib after Non-Pathologic Complete Response Experimental Treatment 2 Interventions

Participants will receive 24 weeks of neoadjuvant encorafenib and binimetinib and then proceed to planned resection. If participants have non-pathologic complete response they will continue to receive encorafenib and binimetinib for 24 more weeks. Imaging will be conducted every 12 weeks for at least one year after surgery, and every 24 weeks for at least two years post-surgery.

Group IV: Surveillance Active Control 2 Interventions

Participants will receive 24 weeks of neoadjuvant encorafenib and binimetinib and then proceed to planned resection. If participants have pathologic complete response they will receive adjuvant treatment for 24 weeks. Imaging will be conducted every 12 weeks for at least one year after surgery, and every 24 weeks for at least two years post-surgery.

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?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Published Research Related to This Trial

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]

A 56-year-old woman experienced transient visual symptoms, including blurry vision and colored halos, after starting Encorafenib/Binimetinib for metastatic melanoma, indicating potential retinal side effects of the treatment.

Despite the initial symptoms being linked to subretinal fluid (SRF), the patient later experienced similar visual disturbances without any detectable SRF, suggesting that Binimetinib may cause intermittent visual symptoms even after fluid resolution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Visual symptoms in a patient treated with MEK inhibitors. Tibaldi, T., Roccuzzo, G., Fazio, A., et al.[2022]

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]

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 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 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]

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 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]

Citations

1. 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 ...

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

Overall survival (OS) Review overall survival (OS) data from the COLUMBUS trial with BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib) and vemurafenib. See safety information.

3. 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 %, ...

4. 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 ...

5. 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 ...

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

COLUMBUS 5-Year Update - PubMed Central 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. 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 ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11897558/

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), ...