Encorafenib + Binimetinib +/- Nivolumab for Thyroid Cancer

Overseen By George Morris, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Providence Health & Services

Must not be taking: BRAF/MEK inhibitors, Immunotherapy

Disqualifiers: Autoimmune disease, 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: 1

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for a specific type of thyroid cancer that has spread and does not respond to standard radioiodine therapy. It examines the combination of two drugs, encorafenib (Braftovi) and binimetinib (Mektovi), with or without nivolumab (Opdivo), an immunotherapy drug that may boost the immune system to fight cancer. The goal is to determine if these drug combinations are safe and effective for this type of cancer. Individuals with metastatic thyroid cancer with a BRAF V600 mutation who have not responded to radioiodine treatment might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use certain prohibited medications, including some herbal supplements, within one week before starting the study treatment.

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

Research has shown that the combination of encorafenib and binimetinib is generally safe for people with certain cancers, such as melanoma. In studies, patients with BRAF V600E-mutated thyroid cancer tolerated these drugs well, and they effectively reduced tumors. Most side effects were manageable and did not cause major issues for patients.

When researchers added nivolumab, the safety profile remained acceptable. This drug aids the immune system in fighting cancer and has been used safely in other conditions. While some side effects can occur, they are usually mild or moderate. Overall, based on available data, these combination treatments appear to be safe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of encorafenib and binimetinib, with or without nivolumab, for thyroid cancer because these treatments target the disease in innovative ways. Unlike traditional treatments like surgery or radioactive iodine therapy, which are often the standard of care, this regimen uses targeted therapy and immunotherapy. Encorafenib and binimetinib target specific proteins in cancer cells to halt their growth, while nivolumab enhances the immune system's ability to attack cancer cells. This multi-faceted approach holds the promise of improved effectiveness, especially in cases where conventional treatments are less effective.

What evidence suggests that this trial's treatments could be effective for metastatic radioiodine refractory thyroid cancer?

Research has shown that using encorafenib and binimetinib together can benefit patients with the BRAFV600E mutation. Studies have found that this combination can extend patients' lives, with one study reporting a survival time of 33.6 months compared to 16.9 months with another treatment. In this trial, some participants will receive this combination of encorafenib and binimetinib.

Another group in this trial will receive encorafenib and binimetinib along with nivolumab. Adding nivolumab has been shown to delay cancer progression. This combination has produced promising results in patients with advanced cancers. Overall, these treatments target specific enzymes and boost the immune system to fight cancer cells, offering hope for better management of metastatic thyroid cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Matthew H Taylor

Principal Investigator

Providence Health & Services

Are You a Good Fit for This Trial?

This trial is for adults with metastatic, radioiodine-refractory thyroid cancer that has a BRAF V600 mutation. Participants must have measurable disease, be in good physical condition (ECOG status <=1), and not be pregnant or nursing. They should not have had certain prior treatments or conditions that could affect the study's safety.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document

Your heart's QT interval is not longer than 480 milliseconds after being adjusted for your baseline heart rate.

Your heart's pumping ability is good, with a left ventricular ejection fraction (LVEF) of 50% or higher.

Exclusion Criteria

I haven't taken any prohibited medications in the last week.

I had major surgery less than 3 weeks ago or am still dealing with its side effects.

I have heart problems or significant heart disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive encorafenib and binimetinib orally. In Arm II, participants also receive nivolumab intravenously. Cycles repeat every 28 days.

Up to 2 years

Monthly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

12 months

1 visit at 30 days, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• Encorafenib
• Nivolumab

Trial Overview

The effectiveness of encorafenib and binimetinib, with or without nivolumab, is being tested on patients with specific thyroid cancer. The goal is to see if these drugs can stop tumor growth by blocking enzymes needed for cell growth and boosting the immune system's ability to fight cancer.

How Is the Trial Designed?

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

Patients receive encorafenib PO QD and binimetinib PO BID as in arm I. Patients also receive nivolumab IV over 30 minutes on day 1. Cycles with nivolumab repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (encorafenib, binimetinib) Experimental Treatment 2 Interventions

Patients receive encorafenib PO QD and binimetinib PO BID on days 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?

Providence Health & Services

Lead Sponsor

Trials

131

Recruited

827,000+

Providence Cancer Center, Earle A. Chiles Research Institute

Collaborator

Trials

21

Recruited

500+

Published Research Related to This Trial

In a Phase 3 study involving 392 patients with radioiodine-refractory differentiated thyroid cancer, lenvatinib treatment resulted in a median tumor size reduction of 42.9%, with responders experiencing an even greater reduction of 51.9%.

The initial assessment at 8 weeks showed a rapid tumor size decline of 24.7%, followed by a slower continuous shrinkage, indicating that early tumor response may be a predictor of longer progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer. Robinson, B., Schlumberger, M., Wirth, LJ., 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]

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 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 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 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]

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]

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]

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38343359/

A Phase 2 Study of Encorafenib in Combination with ...

Conclusions: Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAFV600E-mutated ...

2.

ono-pharma.com

ono-pharma.com/en/news/20240517.html

Ono Receives Approvals of BRAFTOVI® and MEKTOVI® ...

The study met its primary endpoint of objective response rate (ORR) as assessed by the Independent Central Review in the overall patient ...

3.

cda-amc.ca

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

Encorafenib in Combination With Binimetinib (Braftovi and ...

significant differences between the combination regimens for the efficacy outcomes of OS and PFS in this NMA. Similar results were found for the additional ...

4.

eocco.com

eocco.com/-/media/EOCCO/PDFs/Formulary/encorafenib_braftovi_binimetinib_mektovi.pdf

Encorafenib (Braftovi®), binimetinib (Mektovi®)

OS data was published in 2018, with OS duration of 33.6 months for combination therapy compared to 16.9 months with vemurafenib monotherapy (p< ...

5.

va.gov

va.gov/formularyadvisor/DOC_PDF/MON_Binimetinib_MEKTOVI_Jun_2022.pdf

Binimetinib (MEKTOVI) National Drug Monograph Jun 2022

Dabrafenib + trametinib has the longest follow-up data for survival (5 years vs 4 years) shown in 3 clinical trials plus FDA indications in non-small cell lung ...

6.

liebertpub.com

liebertpub.com/doi/10.1089/thy.2023.0547

A Phase 2 Study of Encorafenib in Combination with ...

The combination therapy of encorafenib plus binimetinib demonstrated clinically meaningful antitumor activity in patients with BRAFV600E-mutated thyroid cancer, ...

7.

annalsofoncology.org

annalsofoncology.org/article/S0923-7534(24)02207-5/fulltext

621P Phase II trial of encorafenib and binimetinib (E+B) in ...

The confirmed ORR was 32.7% (95% CI, 20.0-47.5), which showed expected efficacy. Median PFS and PFS rate at 6 months were 4.8 months (95% CI, 2.2-6.9) and 37.5% ...

8.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.TPS6085

Encorafenib and binimetinib with or without nivolumab in ...

... results in increased expression of PD-L1 in thyroid cancer. This clinical trial seeks to evaluate the safety and efficacy of encorafenib ...