Binimetinib + Encorafenib for Solid Cancers

(BEAVER Trial)

Overseen By Celeste Yu, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: BRAF inhibitors, MEK inhibitors

Disqualifiers: BRAF V600E, Melanoma V600K, Brain metastasis, Cardiovascular diseases, 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: 2

Duration: Until disease progression or unacceptable toxicity

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two investigational drugs, binimetinib (Mektovi) and encorafenib (Braftovi), to evaluate their effectiveness in treating advanced or metastatic solid tumors when no other standard treatment is available. Researchers aim to determine if these drugs can slow cancer growth in patients with specific BRAF gene mutations. Individuals with solid cancer that has not responded to standard treatments and have certain BRAF mutations might be suitable candidates. Participants will take the medications orally every day and continue unless side effects become too severe or the cancer progresses. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had any systemic chemotherapy, immunotherapy, or targeted therapy within 4 weeks before starting the study treatment. You can continue taking bisphosphonates or denosumab for bone metastases if they were started at least 4 weeks prior to treatment.

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

Research has shown that using the drugs binimetinib and encorafenib together can be safe for treating certain types of cancer. These drugs have been used in combination before, and their side effects are usually manageable. However, this combination carries a risk of developing new skin cancers, so monitoring skin health is crucial.

Many patients tolerated these drugs well, although some experienced side effects that doctors managed effectively. These treatments target specific cancer mutations, and their safety can vary based on individual health conditions.

Since the FDA has already approved these drugs for other uses, they have a strong safety record. However, joining a trial is a personal choice, and discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Binimetinib and Encorafenib because these treatments target specific pathways in solid cancers that are often not addressed by standard treatments. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, these drugs specifically inhibit the MEK and BRAF proteins, which are often mutated in cancer cells. This targeted approach has the potential to be more effective with fewer side effects. Additionally, the oral administration of these drugs offers a more convenient option compared to intravenous chemotherapy, improving patient comfort and adherence.

What evidence suggests that binimetinib and encorafenib might be effective for solid cancers?

Research has shown that the combination of binimetinib and encorafenib, which participants in this trial will receive, holds promise for treating certain cancers with specific BRAF mutations. Studies have demonstrated its effectiveness for patients with BRAF V600E-mutant cancers, leading to improved outcomes. Specifically, one study found a survival rate of up to 48% for patients treated with these drugs. This combination has also been compared to other similar treatments and has shown comparable effectiveness. These findings suggest that binimetinib and encorafenib could help manage cancer growth in patients with certain BRAF mutations. ^{3 5 6 7 8}

Who Is on the Research Team?

Anna Spreafico, MD

Principal Investigator

Princess Margaret Cancer Centre

Are You a Good Fit for This Trial?

Adults with advanced solid tumors that have specific non-V600E BRAF mutations, who can swallow pills and provide tumor biopsies. They must not have standard treatment options or must have failed previous therapies. Excluded are those with certain BRAF mutations, recent treatments, brain metastasis, heart issues, active infections like HIV or hepatitis B/C, pancreatitis history, gastrointestinal diseases affecting drug absorption, neuromuscular disorders potentially elevating CK levels.

Inclusion Criteria

I am older than 18 years.

Signed written and voluntary informed consent

Patient must be willing to provide serial blood samples for molecular profiling of ctDNA evolution

Exclusion Criteria

Has a known history of or is positive for active hepatitis B or hepatitis C

You plan to start a new intense exercise routine after your first dose of the study medication.

I have or am at risk for blocked blood vessels in my eye.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive binimetinib and encorafenib orally in 28-day cycles, with clinic visits up to 2 times every 4 weeks for tests and procedures

Until disease progression or unacceptable toxicity

Up to 2 visits every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• Encorafenib

Trial Overview The trial is testing the effectiveness of binimetinib and encorafenib taken orally on patients with advanced solid tumors harboring class 2 and 3 BRAF mutations. It aims to see how well these drugs stop cancer growth in patients without other treatment options.

How Is the Trial Designed?

Group I: Binimetinib + Encorafenib Experimental Treatment 2 Interventions

Binimetinib and encorafenib are administered orally on a twice daily or once daily schedule, respectively in 28-day cycles. Treatment will continue until it is discontinued due to unacceptable toxicity, clinical or radiological disease progression as per RECIST 1.1, investigator decision, and/or withdrawal of consent.

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?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

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]

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]

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]

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 was found to be safe and showed promising activity in patients with BRAF V600E-mutant solid tumors, with a recommended phase 2 dose established for further studies.

In phase II, the treatment resulted in confirmed responses in 67% of BRAFi-naïve melanoma patients, indicating significant efficacy, while the most common serious side effect was increased alanine aminotransferase levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K -mutant Solid Tumors. Sullivan, RJ., Weber, J., Patel, S., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11213720/

A Practical Review of Encorafenib and Binimetinib Therapy ... In the PHAROS study, encorafenib plus binimetinib was an effective therapy option for patients with BRAF V600E-mutant mNSCLC and was generally ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3104

Binimetinib and encorafenib for the treatment of advanced ... The BEAVER trial was designed to test the safety and efficacy of binimetinib and encorafenib (B+E) in patients (pts) with non-V600E BRAF mts.

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

A Randomized, Open-Label, Phase III Trial of Encorafenib ... The 5-year OS rates were 45% for patients treated with encorafenib plus binimetinib with normal LDH and 48% for those with low tumor burden at baseline.

4. cda-amc.ca cda-amc.ca/sites/default/files/DRR/2021/PC0232-combined.pdf

Encorafenib in Combination With Binimetinib (Braftovi and ... and data cuts used, provide additional support for comparable efficacy between encorafenib in combination with binimetinib and both dabrafenib in ...

5. braftovi.pfizerpro.com braftovi.pfizerpro.com/mektovi-m/overall-response-rate

Overall Response Rate Find details about the overall response rate (ORR) of BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib) and vemurafenib. See safety information.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/210496s014lbl.pdf

BRAFTOVI (encorafenib) - accessdata.fda.gov No overall differences in the safety or effectiveness of BRAFTOVI plus binimetinib or BRAFTOVI plus cetuximab were observed in older patients as compared to ...

7. braftovi.com braftovi.com/m

BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib) IMPORTANT SAFETY INFORMATION. BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) may cause serious side effects, including: Risk of new skin cancers. BRAFTOVI, ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2025/210498s011lbl.pdf

MEKTOVI® (binimetinib) tablets, for oral use The safety of MEKTOVI in combination with encorafenib ... The pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors.