Encorafenib + Cetuximab for Colorectal Cancer

Recruiting at 434 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

827 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that: * has spread to other parts of the body (metastatic); * has a certain type of abnormal gene called "BRAF"; and * has not received prior treatment. Participants in this study will receive one of the following study treatments: * Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic. * Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home. * Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home. This study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone. The study team will monitor how each participant responds to the study treatment for up to about 3 years.

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.

What data supports the effectiveness of the drug combination of Encorafenib and Cetuximab for colorectal cancer?

Research shows that the combination of Encorafenib and Cetuximab significantly improves survival in patients with metastatic colorectal cancer that has a specific mutation (BRAF V600E) compared to standard treatments. Patients receiving this combination lived longer and had a longer period before the cancer worsened. ^{1 2 3 4 5}

What safety data exists for the combination of encorafenib and cetuximab in treating colorectal cancer?

The combination of encorafenib and cetuximab for colorectal cancer has been associated with side effects such as fatigue, nausea, diarrhea, skin issues, abdominal pain, joint pain, decreased appetite, vomiting, and rash. BRAF inhibitors like encorafenib can also cause skin, gastrointestinal, and kidney issues, as well as fever and secondary skin cancers. Cetuximab alone can cause infusion reactions and skin problems. ^{1 3 6 7 8}

How is the drug Encorafenib + Cetuximab unique for treating colorectal cancer?

Encorafenib + Cetuximab is unique because it specifically targets colorectal cancer with a BRAF V600E mutation, offering longer survival and better response rates compared to standard treatments for patients who have already received other therapies. ^{1 2 4 9 10}

Research Team

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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]

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]

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 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]

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 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]

References

1. England 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. [2021]

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

Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. [2021]

3. New Zealand 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. [2021]

4. England 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. [2022]

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

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England. [2021]

6. England pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. [2022]

7. Japan pubmed.ncbi.nlm.nih.gov

[The efficacy of cetuximab for metastatic colorectal cancer]. [2018]

8. England 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. [2022]

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

Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer. [2023]

10. Japan pubmed.ncbi.nlm.nih.gov

Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer: an early post-marketing phase vigilance study. [2023]