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Re‑radiation with chemotherapy plus pembrolizumab versus pembrolizumab (± chemotherapy) for recurrent PD‑L1 positive head and neck cancer

Randomized Phase III Trial of Sequential Re-Radiochemotherapy and Pembrolizumab Versus Immuno(Chemo)Therapy for Locoregionally Recurrent PD-L1 Positive HNSCC (CPS≥1)

Phase 3 Interventional Universität des Saarlandes · NCT07026474

This trial tests whether adding re‑radiation with chemotherapy followed by pembrolizumab helps people with PD‑L1 positive (CPS≥1) locoregionally recurrent head and neck cancer live longer than pembrolizumab alone (with or without chemotherapy).

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment214 (estimated)
Ages18 Years and up
SexAll
SponsorUniversität des Saarlandes Academic / other
Drugs / interventionspembrolizumab, chemotherapy, prednisone, immunotherapy
Locations18 sites (Chemnitz and 17 other locations)
Trial IDNCT07026474 on ClinicalTrials.gov

What this trial studies

This is an open‑label, randomized phase III trial comparing re‑radiochemotherapy followed by sequential pembrolizumab versus pembrolizumab alone (with optional chemotherapy) in patients with locoregionally recurrent or second primary PD‑L1 positive (CPS≥1) head and neck squamous cell carcinoma that is unresectable or would cause major functional loss if removed. Eligible patients must have no distant metastases, prior radiotherapy at least 6 months earlier, and adequate organ function; performance status must be ECOG 0–2. The experimental arm includes re‑irradiation combined with cisplatin (or carboplatin/5‑FU alternative) and subsequent pembrolizumab, while the control arm receives pembrolizumab with or without standard chemotherapy. The primary outcome is overall survival, with secondary endpoints likely including local control, progression‑free survival, and safety/treatment tolerability.

Who should consider this trial

Good fit: Adults (≥18) with histologically confirmed locoregionally recurrent or second primary unresectable HNSCC, PD‑L1 CPS≥1, no distant metastases, prior radiotherapy ≥6 months earlier, ECOG 0–2, and adequate organ and marrow function are ideal candidates.

Not a fit: Patients with distant metastases, PD‑L1 CPS <1, poor performance status, or those who cannot tolerate re‑irradiation, platinum chemotherapy, or PD‑1 blockade are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could improve overall survival and local tumor control for people with locoregionally recurrent PD‑L1 positive head and neck cancer.

How similar studies have performed: Pembrolizumab has shown survival benefit in recurrent/metastatic HNSCC and re‑irradiation approaches have had variable success, but combining re‑radiation with immunotherapy in this setting remains under active study with limited phase III precedent.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* Written informed consent obtained from the subject prior to performing any protocol-related procedures.
* Age ≥ 18 years at time of study entry.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
* Locoregionally recurrent or second primary HNSCC.
* Histological confirmation of HNSCC.
* Tumor is surgically not resectable or surgical resection bears great potential for relevant functional morbidity or patient refuses surgery.
* No distant metastases (cM0).
* PD-L1 combined positive score (CPS) ≥1 according to local pathological PD-L1 assessment. A validated test must be used in an accredited laboratory.
* Prior radio(chemo)therapy of the neck (time interval ≥ 6 months).
* Adequate normal organ and marrow function as defined: Haemoglobin ≥ 9.0 g/dL; Leukocytes (WBC) ≥ 3,000 per mm3or Neutrophils ≥ 1,500 per mm3; Platelet count \> 100,000 per mm3.
* Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology).
* AST (SGOT) / ALT (SGPT) ≤ 2.5 x institutional ULN.
* Creatinine Clearance ≥ 40ml/min (calculated from serum creatinine using the Cockcroft-Gault formula).
* Female subject of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of RT and/or the first dose of pembrolizumab. A highly sensitive pregnancy test must be used.
* Female subjects of childbearing potential must be willing to use a highly effective contraceptive measure (see also Section 7.1.9 Contraception and pregnancy testing during the trial). Highly effective contraception is required for the course of the trial through 120 days after the last dose of trial therapy.
* Generative male subjects must agree to use a highly effective method of contraception (see also Section 7.1.9 Contraception and pregnancy testing during the trial), starting with the first dose of trial therapy through 120 days after the last dose of trial therapy.
* Subject is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits and examinations including.

Exclusion Criteria:

* Prior radio(chemo)therapy of the neck less than 6 months ago.
* Distant metastases (cM1).
* Is currently participating and receiving trial therapy or has participated in a trial of an investigational agent and received trial therapy or used an investigational device within 4 weeks of the first dose of treatment.
* Current or prior use of immunosuppressive medication within 14 days before the first dose of trial treatment. The following are exceptions to this criterion:

  1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
  3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
* Prior chemotherapy or targeted small molecule therapy within 2 weeks or anti-cancer monoclonal antibody (mAb) within 4 weeks prior to trial day 1 or who has not recovered from AEs due to a previously administered agent. (Subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the trial.)
* History or concurrent other malignancy. Exceptions include patients, who have been disease free for at least 3 years. Further exceptions are completely resected basal cell carcinoma or squamous cell carcinoma of the skin or successfully treated in situ carcinoma.
* Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
* Has an active or chronic infection requiring systemic antibacterial, antifungal or antiviral therapy within 14 days prior to randomization or first dose of study drugs.
* Known hypersensitivity to the active substances or to any of the excipients.
* History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
* Infection with human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
* Active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
* Live vaccine within 30 days of planned start of trial therapy.
* Performance status of \>2 on the ECOG Performance Scale.
* Prior treatment with a PD-1/PD-L1 antibody in primary treatment of locally advanced HNSCC less than 6 months ago.

Where this trial is running

Chemnitz and 17 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Recurrent Head and Neck Squamous Cell Carcinoma
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.