Cetuximab + Pembrolizumab for Head and Neck Cancer

Recruiting at 170 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Pregnancy, Pneumonitis, Organ transplant, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 45

Duration: up to 18 cycles (approximately 18 months)

158 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding cetuximab to pembrolizumab is more effective than using pembrolizumab alone for treating head and neck cancer that has recurred or spread. Cetuximab targets specific proteins on cancer cells to inhibit their growth, while pembrolizumab aids the immune system in attacking cancer cells. The trial aims to determine if the combination of these treatments is more effective than pembrolizumab alone. Suitable participants have head and neck squamous cell carcinoma that cannot be cured by local treatments and have not yet received treatment for their recurrent or metastatic cancer. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering patients the opportunity to contribute to a treatment that could soon become widely available.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it does mention that you should not have received chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to registration.

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

Research shows that both cetuximab and pembrolizumab have been studied for treating head and neck cancer. Studies indicate that pembrolizumab, when used alone, is generally well-tolerated. This immunotherapy helps the body's immune system fight cancer. Some side effects, such as tiredness, rash, and itching, have been reported, but these are usually manageable.

Research also suggests that the combination of cetuximab and pembrolizumab is reasonably safe. One study found that adding cetuximab, which targets a protein on cancer cells, does not significantly increase severe side effects. Common issues might include skin reactions and mild reactions during treatment, like a headache or chills, but these are often treatable.

Overall, both treatments have been used in people before, and safety data show they are generally well-tolerated. However, as with any treatment, risks exist, so discussing them with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for head and neck cancer?

Researchers are excited about cetuximab and pembrolizumab for head and neck cancer because these treatments offer a novel approach compared to the standard therapies like cisplatin-based chemotherapy and radiation. Cetuximab targets the epidermal growth factor receptor (EGFR), which is often overexpressed in head and neck cancer cells, potentially blocking their growth. Pembrolizumab, on the other hand, is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells more effectively. This combination could enhance the body's ability to fight cancer while potentially offering fewer side effects than traditional treatments.

What evidence suggests that this trial's treatments could be effective for head and neck cancer?

Research has shown that pembrolizumab, one of the treatments in this trial, effectively treats head and neck squamous cell carcinoma (HNSCC) that has recurred or spread. One study found that pembrolizumab treatments helped patients live longer compared to cetuximab alone. In this trial, some participants will receive pembrolizumab alone, while others will receive a combination of pembrolizumab and cetuximab. Using pembrolizumab with cetuximab has shown promising results in treating these cancers. A review of several studies suggests that adding cetuximab to a PD-1 inhibitor like pembrolizumab can be more effective than using the PD-1 inhibitor alone, especially for certain patients. These findings suggest that combining cetuximab with pembrolizumab could improve treatment for HNSCC. ^{6 7 8 9 10}

Who Is on the Research Team?

Siddharth Sheth, MD

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

This trial is for adults with head and neck squamous cell carcinoma that has returned or spread after initial treatment. Eligible patients must have a specific protein on their tumor cells, haven't been treated in the recurrent/metastatic setting, and should not have progressed during prior anti-cancer therapies if received more than 6 months ago.

Inclusion Criteria

Measurable disease

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

My cancer is a type of head and neck cancer known as squamous cell carcinoma.

Exclusion Criteria

My cancer is not in the nasopharynx, but if its origin is unknown, I might still qualify.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive pembrolizumab or pembrolizumab with cetuximab intravenously. Cycles repeat every 42 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity.

up to 18 cycles (approximately 18 months)

Visits every 42 days for treatment administration and imaging

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs within 4 weeks after treatment and then every 3 to 6 months for up to 5 years.

up to 5 years

Follow-up visits every 3 to 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Pembrolizumab

Trial Overview

The study compares adding Cetuximab (a monoclonal antibody targeting EGFR) to Pembrolizumab (another type of immunotherapy) versus using Pembrolizumab alone. The goal is to see if the combination works better for treating recurrent or metastatic head and neck cancer.

How Is the Trial Designed?

Group I: Arm 2 (cetuximab, pembrolizumab) Experimental Treatment 6 Interventions

Patients receive cetuximab IV over 120 minutes on day -14 prior to cycle 1 and then on days 1, 15 and 29 of each cycle and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, PET/CT or MRI throughout the trial and optionally undergo blood sample collection on study and at disease progression or end of treatment.

Group II: Arm 1 (pembrolizumab) Active Control 5 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, PET/CT or MRI throughout the trial and optionally undergo blood sample collection on study and at disease progression or end of treatment.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 38 patients with p16+ oropharyngeal squamous cell carcinoma, there was a 76% agreement in PD-L1 combined positive scores (CPS) between primary tumors and lymph node metastases, indicating variability in scoring between these specimens.

The interobserver agreement for CPS scoring was fair to substantial, suggesting that additional evaluations may be necessary to ensure accurate scoring, especially for patients who might benefit from immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma. Kaur, A., Kuchta, K., Watkin, W., et al.[2023]

In a study involving 133 patients with locally advanced squamous cell carcinoma of the head and neck, pembrolizumab combined with radiotherapy did not show a significant improvement in locoregional control or survival compared to the standard treatment of cetuximab with radiotherapy.

However, patients receiving pembrolizumab experienced significantly lower toxicity, with only 74% reporting severe adverse events compared to 92% in the cetuximab group, suggesting it may be a safer option for patients unfit for high-dose cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial. Tao, Y., Biau, J., Sun, XS., et al.[2023]

Pembrolizumab (KEYTRUDA) received accelerated FDA approval for treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) based on a study of 174 patients, showing an objective response rate of 16% and a duration of response ranging from 2.4 to 27.7 months.

The safety profile included serious adverse reactions such as pneumonia and respiratory failure, but the overall benefit-risk assessment was deemed acceptable, marking pembrolizumab as the first new treatment option for HNSCC since 2006.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. Larkins, E., Blumenthal, GM., Yuan, W., et al.[2019]

The study evaluated the effectiveness of pembrolizumab and cetuximab, both alone and in combination, on head and neck squamous cell carcinoma (HNSCC) using the FLAVINO assay, revealing significant variability in patient responses, particularly in those with cisplatin-resistant cases.

An 'IP-10 score' was developed to predict patient outcomes based on their response to treatment, indicating that higher levels of IP-10 release in response to interferon gamma (IFN-γ) stimulation may correlate with better outcomes for certain HNSCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine Profiles of Head and Neck Squamous Cell Carcinoma Undergoing Dual Immunotherapy With Cetuximab and Pembrolizumab Identify Interferon Gamma-Induced Protein 10 as Novel Biomarker. Berszin, M., Michaelides, I., Siemert, J., et al.[2022]

In a phase IB study involving 59 patients with locally advanced head and neck squamous cell carcinoma, the combination of pembrolizumab with cisplatin-based chemoradiotherapy was found to be safe, with a high completion rate of treatment and only 8.8% of patients experiencing immune-related adverse events.

The treatment showed promising efficacy, with complete response rates of 85.3% for HPV-positive and 78.3% for HPV-negative patients, suggesting that this combination warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. Powell, SF., Gold, KA., Gitau, MM., et al.[2022]

In a phase 1b trial involving 60 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, pembrolizumab was found to be well tolerated, with only 17% experiencing severe drug-related adverse events and no drug-related deaths.

The treatment showed clinically meaningful antitumor activity, with an overall response rate of 18%, and particularly higher in HPV-positive patients at 25%, indicating its potential as a viable therapy for advanced head and neck cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Seiwert, TY., Burtness, B., Mehra, R., et al.[2022]

In a study involving 882 participants with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), pembrolizumab alone significantly improved overall survival compared to cetuximab with chemotherapy, especially in patients with high PD-L1 expression (CPS of 20 or more).

Pembrolizumab combined with chemotherapy also showed improved overall survival compared to cetuximab with chemotherapy across all populations, indicating that pembrolizumab is an effective first-line treatment option for HNSCC, particularly for those with PD-L1 positivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Burtness, B., Harrington, KJ., Greil, R., et al.[2021]

In a phase 3 study involving 495 patients with recurrent or metastatic head-and-neck squamous cell carcinoma, pembrolizumab demonstrated a median overall survival of 8.4 months, compared to 6.9 months for standard-of-care treatments, indicating a significant improvement in survival rates.

Pembrolizumab was associated with fewer severe treatment-related adverse events (13%) compared to standard-of-care therapies (36%), suggesting a better safety profile for patients receiving pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Cohen, EEW., Soulières, D., Le Tourneau, C., et al.[2019]

The Phase III trial KEYNOTE-412 is designed to evaluate the efficacy and safety of pembrolizumab, an immune checkpoint inhibitor, when used alongside chemoradiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Previous Phase Ib studies have indicated that combining pembrolizumab with CRT is safe and feasible, supporting its potential use in this larger trial to improve treatment outcomes for patients with locally advanced HNSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Machiels, JP., Tao, Y., Burtness, B., et al.[2021]

Pembrolizumab, an immune checkpoint inhibitor, has been approved by the FDA for treating platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), offering a new option with potentially improved efficacy compared to traditional chemotherapy and EGFR inhibitors.

This review discusses the pharmacology and tolerability of pembrolizumab, emphasizing its mechanism of action by blocking the PD-1 receptor, which may enhance the immune response against HNSCC tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab and its use in the treatment of recurrent or metastatic head and neck cancer. Sheth, S., Weiss, J.[2019]

In a study with 882 patients over a median follow-up of 45 months, pembrolizumab and pembrolizumab-chemotherapy showed significant improvements in overall survival compared to cetuximab-chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma, particularly in patients with high PD-L1 expression (CPS ≥ 20).

The analysis also indicated that patients who received pembrolizumab-based therapies had favorable outcomes in subsequent treatments, with improved progression-free survival on next-line therapies, highlighting the long-term efficacy of pembrolizumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. Harrington, KJ., Burtness, B., Greil, R., et al.[2023]

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