Encorafenib + Cetuximab for Colorectal Cancer

Not currently recruiting at 491 trial locations

Overseen By Pfizer CT.gov Call Center

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Pfizer

Disqualifiers: Infections, Brain metastases, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for colorectal cancer that has spread and contains a specific gene mutation called BRAF. Researchers aim to assess the effectiveness of two drugs, encorafenib (a targeted therapy) and cetuximab (a monoclonal antibody), both alone and combined with standard chemotherapy. Participants will receive either the two drugs with chemotherapy or standard chemotherapy alone. This trial suits individuals who have not yet received treatment for their metastatic colorectal cancer and know they have the BRAF mutation. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to a treatment that could soon become widely available.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

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

Research has shown that using encorafenib and cetuximab together is generally safe for people. Studies have found that common side effects include nausea, diarrhea, tiredness, skin rash, and stomach pain, affecting about 25% or more of patients.

Encorafenib and cetuximab have already received approval for treating a specific type of advanced colorectal cancer, indicating their relative safety when used as directed.

When combined with chemotherapy, the safety profile remains similar, though the likelihood of side effects may increase.

Overall, the treatment is usually well-tolerated, but side effects can occur. Discussing these risks with a doctor is important when considering participation in a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about treatments combining Encorafenib and Cetuximab for colorectal cancer because they target a specific mutation called BRAF V600E, which is present in some colorectal cancers. While standard chemotherapy treatments attack cancer cells broadly, this combination specifically blocks pathways that help cancer cells grow and survive. This targeted approach has the potential to be more effective for patients with this mutation compared to traditional chemotherapy alone. By honing in on the BRAF V600E mutation, these treatments could offer a more personalized and potentially more effective therapy for those affected by this specific type of colorectal cancer.

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

Research shows that using encorafenib and cetuximab together holds promise for treating BRAF-mutant metastatic colorectal cancer. In this trial, participants in various arms will receive different combinations of these drugs. Studies have found that this combination can help patients live longer without their cancer worsening and can also increase overall survival compared to standard treatments. When combined with chemotherapy, this approach has proven especially effective, reducing the risk of death by 51% compared to chemotherapy alone. This treatment is already approved for previously treated patients, demonstrating real-world benefits. These findings suggest that this treatment could be effective for patients with this specific type of colorectal cancer. ^{3 6 7 8 9}

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 Stage IV colorectal cancer that has spread and has a specific gene mutation (BRAF V600E). They should not have had previous treatments for metastatic cancer, although prior adjuvant therapy is allowed if relapse occurred within 6 months. Participants need to be in good physical condition with proper organ function and no symptomatic brain metastases or recent infections.

Inclusion Criteria

I am eligible for a Phase 3 trial with no specific requirements.

My colorectal cancer is stage IV with a BRAF V600E mutation.

I have received treatment for cancer after it spread.

Exclusion Criteria

My tumor is MSI-H/dMMR, and I can't take immune checkpoint inhibitors due to a health condition.

I have not had any bacterial or viral infections in the last 2 weeks.

I have brain metastases that are causing symptoms.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-in

Participants receive encorafenib and cetuximab with chemotherapy to evaluate tolerability and pharmacokinetics

12 months

Every two weeks

Phase 3 Treatment

Participants receive encorafenib plus cetuximab with or without chemotherapy, or standard chemotherapy alone

36 months

Every two weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 5-FU
• Bevacizumab
• Capecitabine
• Cetuximab
• Encorafenib
• Irinotecan
• Leucovorin
• Oxaliplatin

Trial Overview The study tests encorafenib plus cetuximab alone or combined with standard chemotherapy (Oxaliplatin, Irinotecan, Bevacizumab, Leucovorin, Capecitabine, 5-FU) against chemotherapy alone. Encorafenib is taken orally daily; cetuximab is given by IV every two weeks. The goal is to compare the effectiveness of these treatments over approximately three years.

How Is the Trial Designed?

Group I: Safety Lead-in Cohort 2 Experimental Treatment 5 Interventions

Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120 minute IV infusion) every two weeks Oxaliplatin 85 mg/m2 (120-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks

Group II: Safety Lead-in Cohort 1 Experimental Treatment 5 Interventions

Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks Irinotecan 180 mg/m2 (90-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks

Group III: Phase 3 Arm B Experimental Treatment 6 Interventions

Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120 minute IV infusion) every two weeks Oxaliplatin 85 mg/m2 (120-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks

Group IV: Phase 3 Arm A Experimental Treatment 2 Interventions

Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks

Group V: Cohort 3 Arm D Experimental Treatment 5 Interventions

Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks Irinotecan 180 mg/m2 (90-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks

Group VI: Phase 3 Arm C Active Control 6 Interventions

Every two weeks: Oxaliplatin 85 mg/m2 (120-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Every two weeks: Irinotecan 165 mg/m2 (90-minute IV infusion) Oxaliplatin 85 mg/m2 (120-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 2400 or 3200 mg/m2 continuous IV infusion over 46 48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Oxaliplatin 130 mg/m2 (120-minute IV infusion) every 3 weeks Capecitabine 1000 mg/m2 oral tablet twice daily on Days 1-14 Bevacizumab (optional; given per prescribing instructions)

Group VII: Cohort 3 Arm E Active Control 4 Interventions

Irinotecan 180 mg/m2 (90-minute IV infusion) every 2 weeks, Leucovorin 400 mg/m2 (120-minute IV infusion) every 2 weeks, 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks, Bevacizumab (optional; given per prescribing instructions)

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

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

Ono Pharmaceutical Co. Ltd

Industry Sponsor

Trials

182

Recruited

97,100+

Shinji Takai

Ono Pharmaceutical Co. Ltd

Chief Medical Officer since 2023

MD from an unspecified institution

Gyo Sagara

Ono Pharmaceutical Co. Ltd

Chief Executive Officer since 2024

PhD in Pharmaceutical Sciences from Kyoto 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

Published Research Related to This Trial

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 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]

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 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 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, 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]

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]

The combination of the BRAF inhibitor encorafenib and the EGFR inhibitor cetuximab is the only approved targeted therapy for previously treated patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC), which is crucial given the poor prognosis associated with this mutation.

The BEACON CRC study highlights that this combination therapy has a distinct safety profile, with specific adverse events that differ from those seen with other treatments, emphasizing the need for tailored management strategies for these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events from the treatment of encorafenib plus cetuximab for patients with BRAF V600E-mutant metastatic colorectal cancer: insights from the BEACON CRC study. Tabernero, J., Velez, L., Trevino, TL., 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]

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]

Citations

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

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated ... This trial showed significantly longer progression-free survival and overall survival with first-line treatment with EC+mFOLFOX6 than with standard care.

2. 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.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38769450/

Efficacy-effectiveness analysis on survival in a population ... This real-world cohort of mCRC patients treated with encorafenib-cetuximab showed a clinically relevant efficacy-effectiveness gap for OS.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3551

Encorafenib plus cetuximab in patients with metastatic ... Encorafenib plus cetuximab in patients with metastatic, BRAF V600E-mutated, colorectal carcinoma: First effectiveness data of the European multi ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S104084282500335X

A Systematic Review and Meta-Analysis Results from a phase II study with a double regimen of encorafenib and cetuximab resulted in an overall response rate (ORR) of 24%, a median ...

6. braftovi-crc.com braftovi-crc.com/safety

Adverse Events The most common (≥25%) any-grade adverse events (AEs) with BRAFTOVI + cetuximab were nausea, diarrhoea, fatigue, acneiform dermatitis, abdominal pain, ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39255538/

Efficacy and safety of the combination of encorafenib ... This study aims to describe the efficacy and safety of encorafenib/cetuximab +/- binimetinib in patients with BRAF V600E-mutated mCRC in a real-world setting.

8. pfizer.com pfizer.com/news/press-release/press-release-detail/pfizers-braftovir-combination-regimen-cuts-risk-death-half

Pfizer's BRAFTOVI® Combination Regimen Cuts the Risk ... The BRAFTOVI combination regimen reduced the risk of death by 51% compared to standard-of-care chemotherapy with or without bevacizumab.

9. esmoopen.com esmoopen.com/article/S2059-7029(24)01465-0/fulltext

Efficacy and safety of the combination of encorafenib ... Efficacy and safety of the combination of encorafenib/cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer