Encorafenib + Cetuximab and Pembrolizumab for Colorectal Cancer

(SEAMARK Trial)

Not currently recruiting at 123 trial locations

Overseen By Pfizer CT.gov Call Center

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Pfizer

Must be taking: Pembrolizumab

Must not be taking: BRAF inhibitors, EGFR inhibitors

Disqualifiers: Immunodeficiency, Autoimmune disease, Cardiovascular, 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: Approximately 45 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three medicines—encorafenib, cetuximab, and pembrolizumab—to evaluate their effectiveness in treating colorectal cancer that has spread. The cancer must have a specific genetic profile, including a BRAF gene mutation and a tendency for DNA changes. Participants will receive either all three medicines or just pembrolizumab, administered through an IV. Individuals with colorectal cancer exhibiting these genetic traits who have not received other treatments for their metastatic cancer may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does mention that you should not have received certain treatments before, like BRAF inhibitors or immune checkpoint inhibitors.

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

Research shows that the combination of encorafenib, cetuximab, and pembrolizumab is under study for safety in treating certain types of colorectal cancer. Encorafenib and cetuximab have approval for use in patients with a specific type of colorectal cancer, indicating their safety for similar conditions.

Early studies with pembrolizumab indicate it is generally safe, though some people may experience side effects like tiredness and skin reactions. In rare cases, more serious reactions can occur, so doctors closely monitor patients during treatment.

Researchers continue to study the combination of these drugs to understand their interaction. The current trial is in an early phase, focusing on treatment tolerance and identifying any unexpected side effects.

In summary, while some information about the safety of these drugs individually is known, the combination remains under study. Researchers will closely monitor participants to ensure their safety throughout the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of encorafenib, cetuximab, and pembrolizumab for colorectal cancer because it targets the disease in a unique way. Unlike standard treatments, which often focus on chemotherapy, this combination leverages targeted therapy and immunotherapy. Encorafenib targets a specific mutation in the cancer cells, while cetuximab blocks a growth factor receptor on cancer cells, and pembrolizumab boosts the body's immune response to attack cancer cells more effectively. This multi-pronged approach not only aims to halt cancer growth but also engages the immune system, offering a potentially more comprehensive treatment strategy.

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

This trial compares two treatment approaches for colorectal cancer. In one arm, participants receive a combination of three drugs: encorafenib, cetuximab, and pembrolizumab. Research has shown that encorafenib and cetuximab can extend the lives of patients with a specific type of colorectal cancer. Pembrolizumab, which boosts the immune system, is added to enhance the body's ability to fight cancer. Early results suggest that using all three drugs together might be more effective than using pembrolizumab alone. In the other arm, participants receive pembrolizumab alone. While more research is needed, initial findings are promising for treating this aggressive cancer. ^{2 3 4 5 6}

Who Is on the Research Team?

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Are You a Good Fit for This Trial?

This trial is for adults with metastatic colorectal cancer that has specific genetic features (MSI-H/dMMR and BRAF V600E mutation), no prior treatments for metastatic disease, good performance status (ECOG 0 or 1), measurable disease, and adequate organ function. It excludes those with certain mutations, brain metastases, pancreatitis, recent live vaccines, previous treatment with similar drugs or immunotherapies.

Inclusion Criteria

I haven't had any systemic treatments for my cancer since it spread.

Measurable disease per RECIST 1.1

I am fully active or can carry out light work.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

I have pancreatitis.

My cancer has spread to my brain or its coverings.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab IV, with half also receiving encorafenib orally and cetuximab IV

Approximately 45 months

Regular visits at the study clinic

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Encorafenib
• Pembrolizumab

Trial Overview The study tests the combination of Encorafenib plus Cetuximab taken orally at home along with Pembrolizumab given via IV at a clinic compared to just Pembrolizumab alone. The goal is to see if this combo is more effective in treating patients who haven't had any previous systemic treatments for their advanced colorectal cancer.

How Is the Trial Designed?

Group I: Arm A: encorafenib, cetuximab and pembrolizumab Experimental Treatment 3 Interventions

Participants receive encorafenib orally + cetuximab IV + pembrolizumab IV.

Group II: Arm B: pembrolizumab Active Control 1 Intervention

Participants receive pembrolizumab IV.

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

Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

Who Is Running the Clinical Trial?

Pfizer

Lead 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

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Merck KGaA, Darmstadt, Germany

Industry Sponsor

Trials

449

Recruited

122,000+

Danny Bar-Zohar

Merck KGaA, Darmstadt, Germany

Chief Medical Officer since 2022

MD

Belén Garijo

Merck KGaA, Darmstadt, Germany

Chief Executive Officer since 2021

MD

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

Encorafenib in combination with cetuximab significantly improves overall survival (9.3 months) and progression-free survival (4.27 months) in adult patients with metastatic colorectal carcinoma (mCRC) with the BRAFV600E mutation compared to standard treatments, showing a hazard ratio of 0.61 for overall survival and 0.44 for progression-free survival.

The most common side effects reported with this treatment combination include fatigue, nausea, and skin-related issues, indicating that while the treatment is effective, it does come with a range of manageable adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The EMA assessment of encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal carcinoma harbouring the BRAFV600E mutation who have received prior therapy. Trullas, A., Delgado, J., Koenig, J., et al.[2021]

In the BEACON CRC clinical trial, the combination of encorafenib and cetuximab significantly improved median overall survival and progression-free survival in adults with metastatic colorectal cancer harboring a BRAF V600E mutation, compared to standard therapies.

The treatment was found to have a manageable safety profile, making it a promising targeted option for patients who have already undergone previous systemic therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. Al-Salama, ZT.[2021]

In a retrospective study of 25 patients with BRAFV600E mutated metastatic colorectal cancer who had previously been treated with anti-EGFR agents, the combination of encorafenib and cetuximab showed a promising overall response rate of 40% and a disease control rate of 80%.

The median progression-free survival was 4.8 months and overall survival was 10.1 months, indicating that this combination therapy can be effective even in patients who had previously shown resistance to anti-EGFR treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib plus cetuximab treatment in BRAF V600E-mutated metastatic colorectal cancer patients pre-treated with an anti-EGFR: An AGEO-GONO case series. Hafliger, E., Boccaccino, A., Lapeyre-Prost, A., et al.[2022]

In a study involving approximately 550 Japanese patients with BRAF V600E-mutated metastatic colorectal cancer, the triplet and doublet regimens of encorafenib plus cetuximab showed a safety profile consistent with previous studies, with no deaths reported due to adverse drug reactions (ADRs).

The most common ADRs included nausea, retinal detachment, and decreased appetite, while serious ADRs were reported in 42 patients, with 20 out of 22 patients with serious eye disorders recovering during the study period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer: an early post-marketing phase vigilance study. Sakata, H., Murase, M., Kato, T., et al.[2023]

Cetuximab and panitumumab are effective treatments for colorectal cancer, showing clinical activity as anti-EGFR monoclonal antibodies, and are generally well tolerated by patients.

While these medications have fewer severe adverse events compared to traditional cytotoxic agents, they can still cause issues like infusion reactions, skin toxicity, lung toxicity, and low magnesium levels, which need to be managed promptly to avoid treatment interruptions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anti-epidermal growth factor receptor monoclonal antibodies induced adverse events]. Tsuji, Y., Kogawa, T., Abe, M.[2018]

The combination of cytotoxic chemotherapy (FOLFOX or FOLFIRI) with the targeted therapy encorafenib + cetuximab (E+C) shows improved antitumor activity as a first-line treatment for BRAFV600E metastatic colorectal cancer (mCRC) compared to using either treatment alone.

Using FOLFOX with E+C as initial therapy, followed by E+C with or without 5-FU for maintenance, is the most effective strategy for long-term disease control, highlighting the importance of combining these treatment modalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer. Napolitano, S., Woods, M., Lee, HM., et al.[2023]

In a study of 8 patients with recurrent/advanced colorectal cancer, 6 patients showed a positive response to cetuximab, a targeted therapy that binds to epidermal growth factor receptors (EGFR), indicating its efficacy even in later lines of treatment.

Patients receiving cetuximab in combination with CPT-11 had significantly better progression-free survival (7.3 months) and time to treatment failure (9.3 months) compared to those on cetuximab monotherapy (3.0 months and 4.5 months, respectively), highlighting the potential benefits of combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy of cetuximab for metastatic colorectal cancer]. Katsumoto, Y., Aritake, N., Endoh, A.[2018]

Cetuximab and panitumumab are effective treatments for patients with previously untreated RAS wild-type metastatic colorectal cancer, showing cost-effectiveness when combined with standard chemotherapy regimens (FOLFOX or FOLFIRI) compared to chemotherapy alone.

Both drugs meet the National Institute for Health and Care Excellence's end-of-life criteria and are recommended for use within the UK National Health Service, indicating their potential benefit for patients not eligible for liver resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England. Tikhonova, IA., Huxley, N., Snowsill, T., et al.[2021]

In a post-marketing surveillance study involving 2126 patients with metastatic colorectal cancer, cetuximab was found to be well tolerated, with a median treatment duration of 15.3 weeks and a high incidence of adverse reactions at 89.6%.

The most common adverse reactions included skin disorders (83.7%) and infusion reactions (5.7%), primarily occurring during the first administration, indicating that while side effects are common, they align with previous reports and suggest that cetuximab is clinically useful in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Ishiguro, M., Watanabe, T., Yamaguchi, K., et al.[2022]

Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and show promise as therapies for colorectal cancer, particularly in cases where chemotherapy has failed.

The review discusses their effectiveness in both advanced and initial treatment settings, as well as factors that may predict patient response or resistance to these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of monoclonal antibodies to the epidermal growth factor receptor in colorectal cancer. Burtness, B.[2018]

Cetuximab, a monoclonal antibody targeting the EGFR, has been approved for first-line treatment of KRAS mutation-negative metastatic colorectal cancer (mCRC) in combination with FOLFIRI, showing significant improvements in progression-free survival and overall survival.

The combination of cetuximab with FOLFIRI also resulted in higher objective response rates compared to FOLFIRI alone, making it a valuable treatment option for patients with EGFR-expressing, KRAS wild-type mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. Lyseng-Williamson, KA.[2021]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2501912

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated ... Data have been limited with respect to first-line treatment targeting the activation pathway that can show improved efficacy in BRAF V600E– ...

2. cell.com cell.com/cancer-cell/fulltext/S1535-6108(25)00340-X

Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in ... The BRAF inhibitor encorafenib and anti-epidermal growth factor receptor (EGFR) antibody cetuximab modestly improve survival for patients ...

3. esmo.org esmo.org/oncology-news/improved-survival-benefit-with-encorafenib-plus-cetuximab-plus-mfolfox6-in-first-line-treatment-for-patients-with-braf-v600e-mutated-mcrc

Improved Survival Benefit with Encorafenib plus Cetuximab ... An ongoing open-label, randomised, phase III BREAKWATER study showed significant results for the two primary endpoints and the key secondary ...

4. nature.com nature.com/articles/s41591-024-03443-3

Encorafenib, cetuximab and chemotherapy in BRAF- ... Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12510239/

SEAMARK: phase II study of first-line encorafenib and ... SEAMARK is a randomized phase II study comparing the efficacy of the combination of pembrolizumab with encorafenib and cetuximab versus pembrolizumab alone in ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS3642

A phase II study of encorafenib and cetuximab (EC) ... While the combination of encorafenib and cetuximab (EC) has demonstrated improved outcomes in previously treated BRAF V600E-mutated mCRC ...