Randomized Phase III Trial of Pembrolizumab vs. Pembrolizumab/Cetuximab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma With Platinum Refractory Disease

Plain English Summary

Testing the Addition of Anti-Cancer Drug, Cetuximab, to Standard of Care Treatment (Pembrolizumab) for Returning or Spreading Head and Neck Cancer After Previous Treatment is a Phase 3 clinical trial sponsored by National Cancer Institute (NCI) studying Metastatic Head and Neck Squamous Cell Carcinoma, Metastatic Hypopharyngeal Squamous Cell Carcinoma, Metastatic Laryngeal Squamous Cell Carcinoma, Metastatic Oral Cavity Squamous Cell Carcinoma, Metastatic Oropharyngeal Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Neck Squamous Cell Carcinoma of Unknown Primary, Recurrent Oral Cavity Squamous Cell Carcinoma. This trial compares adding cetuximab to pembrolizumab versus pembrolizumab alone for treating head and neck cancer that has come back or spread. Eligible patients have head and neck squamous cell carcinoma that is platinum-refractory and has measurable disease. Participation involves IV treatments of pembrolizumab and/or cetuximab, blood draws, and imaging scans. Alternative treatments include standard chemotherapy and radiation, or other immunotherapy options. The trial aims to enroll 158 participants.

Official Summary

This phase III trial compares the effect of adding cetuximab to pembrolizumab versus pembrolizumab alone in treating patients with head and neck squamous cell carcinoma (HNSCC) that has come back after a period of improvement (recurrent) and/or that has spread from where it first started (primary site) to other places in the body (metastatic). Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving cetuximab and pembrolizumab together may be more effective at treating patients with recurrent and/or metastatic HNSCC than pembrolizumab alone.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible patients have head and neck squamous cell carcinoma that is platinum-refractory and has measurable disease. Patients must be 18 years or older and have a combined positive score PD-L1 (CPS >= 1). Patients cannot have received prior treatment in the recurrent or metastatic setting. Patients must not have a history of severe hypersensitivity to pembrolizumab or cetuximab. This trial is studying Metastatic Head and Neck Squamous Cell Carcinoma, Metastatic Hypopharyngeal Squamous Cell Carcinoma, Metastatic Laryngeal Squamous Cell Carcinoma, Metastatic Oral Cavity Squamous Cell Carcinoma, Metastatic Oropharyngeal Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Neck Squamous Cell Carcinoma of Unknown Primary, Recurrent Oral Cavity Squamous Cell Carcinoma, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures overall survival, which means it assesses how long patients live after starting the treatment. The specific primary outcome measures are: Overall survival (OS) (Time from randomization to death from any cause, assessed up to 5 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial addresses a significant treatment gap by evaluating a new combination therapy for advanced head and neck cancer. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Metastatic Head and Neck Squamous Cell Carcinoma, Metastatic Hypopharyngeal Squamous Cell Carcinoma, Metastatic Laryngeal Squamous Cell Carcinoma, Metastatic Oral Cavity Squamous Cell Carcinoma, Metastatic Oropharyngeal Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Neck Squamous Cell Carcinoma of Unknown Primary, Recurrent Oral Cavity Squamous Cell Carcinoma, where improved treatment options are needed.

Investor Insight

The market for head and neck cancer treatments is large, with this trial potentially offering a new effective option, improving patient outcomes. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor if you have head and neck cancer that has come back or spread and if you are platinum-refractory. Participation involves IV treatments, blood draws, and imaging scans. This trial is currently recruiting participants. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 158 participants

Interventions

• PROCEDURE: Biospecimen Collection — Undergo blood sample collection
• BIOLOGICAL: Cetuximab — Given IV
• PROCEDURE: Computed Tomography — Undergo CT or PET/CT
• PROCEDURE: Magnetic Resonance Imaging — Undergo MRI
• BIOLOGICAL: Pembrolizumab — Given IV

Primary Outcomes

• Overall survival (OS) (Time from randomization to death from any cause, assessed up to 5 years)

Secondary Outcomes

• Confirmed response rate (Up to 5 years)
• Duration of response (From the date at which the patient's earliest best objective status is first noted to be either a complete response or partial response to the earliest date progression is documented, assessed up to 5 years)
• Progression free survival (Time from randomization to the first of either disease progression or death from any cause, assessed up to 5 years)
• Incidence of adverse events (Up to 5 years)
• Patient-reported toxicity (Up to 5 years)

Full Eligibility Criteria

Inclusion Criteria:

* Histologically confirmed diagnosis head and neck squamous cell carcinomas (HNSCC).
* Previously untreated for recurrent and/or metastatic disease incurable by local therapies.
* Primary tumor location of oral cavity, oropharynx, larynx, or hypopharynx.

  * Note: Other primary tumor sites of HNSCC, including nasopharynx primary tumor are not eligible. Unknown primary tumors may be eligible and can be enrolled at the discretion of the treatment team with approval by the study chair.
* Measurable disease.
* Must have platinum-refractory disease defined as disease progression during or ≤ 29 weeks after completion of definitive therapy (chemoradiation therapy) or adjuvant (post-operative) therapy.
* Patient must have a combined positive score PD-L1 positive (CPS \>/= 1) tumor.
* Any radiation therapy must be completed \>= 10 days prior to registration.
* Patients should not have received any prior treatment in the recurrent or metastatic setting.
* Prior therapy with neoadjuvant or induction anti PD-1/PD-L1 monoclonal antibody or cetuximab in the curative setting is allowed if last treatment dose was \>= 26 weeks prior to registration without evidence of disease progression during that treatment period.
* Patient has not received a live vaccine within 30 days prior to registration.
* Patient does not have a history of any contraindication or has a severe hypersensitivity to any component of pembrolizumab or cetuximab (≥ grade 3).
* Patient has not received chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to registration.
* Patient with oropharyngeal cancer only must have negative results from testing of human papillomavirus (HPV) status defined as p16 immunohistochemistry (IHC) and/or HPV in situ hybridization (ISH).

  * Note: A Clinical Laboratory Improvement Act (CLIA) certified circulating tumor HPV deoxyribonucleic acid (ctHPVDNA) assay can be used if tissue sample is not available.
* Age ≥ 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* Absolute neutrophil count (ANC) ≥ 1,500/mm\^3.
* Platelet count ≥ 100,000/mm\^3.
* Hemoglobin (Hgb) ≥ 9 g/dL (if \< 9 g/dL, then transfusions are acceptable to increase hemoglobin above 9 g/dL).
* Creatinine ≤ 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault formula for participant with creatinine levels \> 1.5 x institutional ULN.
* Total bilirubin ≤ 1.5 x ULN OR direct bilirubin \< ULN for participant with total bilirubin \> 1.5 x institutional ULN.
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\]) ≤ 3.0 x ULN unless liver metastases are present in which case \< 5.0 x ULN.
* Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects.

  * Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 days prior to registration is required.
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen should be included.
* For treated/stable brain metastases: Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.

  * Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial.
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
* Patients does not have a history of active myocarditis.
* Patients does not have a history of any form of pneumonitis or diffuse idiopathic or immune mediated interstitial pulmonary disease.
* Patient does not have a history of solid organ transplantation.

Trial Locations

• University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
• Fremont - Rideout Cancer Center, Marysville, California, United States
• VA Palo Alto Health Care System, Palo Alto, California, United States
• UCHealth Memorial Hospital Central, Colorado Springs, Colorado, United States
• Memorial Hospital North, Colorado Springs, Colorado, United States
• Poudre Valley Hospital, Fort Collins, Colorado, United States
• Cancer Care and Hematology-Fort Collins, Fort Collins, Colorado, United States
• Lutheran Hospital - Cancer Centers of Colorado, Golden, Colorado, United States
• UCHealth Greeley Hospital, Greeley, Colorado, United States
• Medical Center of the Rockies, Loveland, Colorado, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Metastatic Head and Neck Squamous Cell Carcinoma
• Metastatic Hypopharyngeal Squamous Cell Carcinoma
• Metastatic Laryngeal Squamous Cell Carcinoma
• Metastatic Oral Cavity Squamous Cell Carcinoma
• Metastatic Oropharyngeal Squamous Cell Carcinoma
• Recurrent Head and Neck Squamous Cell Carcinoma
• Recurrent Hypopharyngeal Squamous Cell Carcinoma
• Recurrent Laryngeal Squamous Cell Carcinoma
• Recurrent Neck Squamous Cell Carcinoma of Unknown Primary
• Recurrent Oral Cavity Squamous Cell Carcinoma

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