Encorafenib/Binimetinib/Nivolumab vs Ipilimumab/Nivolumab for Melanoma

Recruiting at 329 trial locations

Overseen By Dana Sparks

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: SWOG Cancer Research Network

Must not be taking: Biologic agents, Hormonal contraceptives

Disqualifiers: Prior systemic therapy, Active infection, Autoimmune 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: Varies by arm, up to 3 years

112 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial compares the effect of encorafenib, binimetinib, and nivolumab versus ipilimumab and nivolumab in treating patients with BRAF- V600 mutant melanoma that has spread to the brain (brain metastases). Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ipilimumab and nivolumab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. This trial aims to find out which approach is more effective in shrinking and controlling brain metastases from melanoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have a serious active infection requiring treatment, and you must not be planning to use hormonal contraceptives. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination of Encorafenib and Binimetinib for melanoma?

Research shows that the combination of Encorafenib and Binimetinib improves survival and quality of life in patients with a specific type of skin cancer called BRAF-mutant melanoma, compared to other treatments like vemurafenib. This combination is approved for use in patients with advanced melanoma that cannot be surgically removed or has spread to other parts of the body. ^{1 2 3 4 5}

What safety information is available for the combination of Encorafenib, Binimetinib, and Nivolumab in treating melanoma?

The combination of Encorafenib and Binimetinib has shown an acceptable safety profile in treating certain types of melanoma and non-small-cell lung cancer. However, some patients may experience skin-related side effects and visual symptoms. Always consult with a healthcare provider for personalized advice. ^{2 3 6 7 8}

What makes the drug combination of Encorafenib, Binimetinib, and Nivolumab unique for treating melanoma?

This drug combination is unique because it combines targeted therapy (Encorafenib and Binimetinib) with immunotherapy (Nivolumab), potentially offering improved outcomes for patients with BRAF-mutant melanoma. Encorafenib and Binimetinib specifically target and inhibit the BRAF and MEK proteins, which are involved in cancer cell growth, while Nivolumab helps the immune system recognize and attack cancer cells. ^{1 2 3 4 9}

Research Team

Zeynep Eroglu

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for adults with BRAF-V600 mutant melanoma that has spread to the brain. They must be able to take pills, have a certain level of physical fitness (Zubrod status <=2), and their major organs need to function within specific limits. People with HIV can join if they're on effective therapy. Those who've had other cancers may qualify if it doesn't affect this study's safety or results.

Inclusion Criteria

Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines

I had hepatitis C but have been treated and cured.

I have HIV, am on effective treatment, and my recent tests show no detectable virus.

Exclusion Criteria

I have not had radiation therapy in the last 7 days.

I am using effective birth control.

I do not have a serious infection needing treatment according to my doctor.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either encorafenib, binimetinib, and nivolumab or nivolumab and ipilimumab. Treatment cycles repeat every 21-28 days depending on the arm, in the absence of disease progression or unacceptable toxicity.

Varies by arm, up to 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 6 months for 2 years, then annually until 3 years after randomization.

3 years

Treatment Details

Interventions

• Encorafenib, Binimetinib
• Ipilimumab, Nivolumab

Trial Overview The trial compares two treatments for melanoma in the brain: one group receives Encorafenib + Binimetinib + Nivolumab, while the other gets Ipilimumab + Nivolumab. The goal is to see which combination better controls or shrinks brain metastases from melanoma.

Participant Groups

Group I: Arm II (nivolumab, ipilimumab) Experimental Treatment 2 Interventions

Patients receive nivolumab IV on day 1 of all cycles and ipilimumab IV over 30 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 4 cycles and then every 28 days in the absence of disease progression or unacceptable toxicity.

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

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

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

Approved in United States as Braftovi and Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation
• Metastatic non-small cell lung cancer with a BRAF V600E mutation

Approved in European Union as Braftovi and Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation
• Metastatic colorectal cancer with a BRAF V600E mutation

Who Is Running the Clinical Trial?

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

Southwest Oncology Group

Lead Sponsor

Trials

389

Recruited

260,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 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, 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 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]

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]

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 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]

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]

References

1. England 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). [2021]

2. England 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. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Encorafenib and Binimetinib: First Global Approvals. [2019]

4. England 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. [2019]

5. England 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. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Visual symptoms in a patient treated with MEK inhibitors. [2022]

7. United States 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. [2023]

8. England pubmed.ncbi.nlm.nih.gov

The spectrum of cutaneous adverse events during encorafenib and binimetinib treatment in B-rapidly accelerated fibrosarcoma-mutated advanced melanoma. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. [2019]