Pembrolizumab and Radiotherapy for Oligometastatic Head and Neck Cancer (PROLoNg)

Pembrolizumab and Radiotherapy for OLigometastatic Squamous Cell Carcinoma of the Head and Neck: a Randomized Phase III Study

This is a randomized open-label multicentre phase III superiority study of the effect of adding SABR to the standard of care treatment pembrolizumab on progression free survival in patients with oligometastases of a squamous cell carcinoma of the head and neck (SCCHN), histological confirmation of the primary disease at first diagnosis, and PD-L1 CPS ≥1. After eligibility check and signing informed consent, all patients will be prospectively enrolled in a 1:1 ratio between current standard of care treatment (pembrolizumab, Arm 1) vs. SABR + standard of care treatment (Arm 2) to oligometastases.

Any radical treatment to the synchronous primary/ recurrent primary tumor and/or involved cervical nodes (surgery or radiotherapy), as decided by the local tumor board/ treating physicians, should be completed prior to enrolment.Surgical removal of metastases is allowed for diagnostic purposes or for brain metastases, as long as these metastases count toward the total number of 5 and at least one metastasis is left for treatment with SABR. Such surgical procedures should be performed prior to enrolment.

Study Overview

• Status: Recruiting
• Conditions: Oligometastatic Squamous Cell Carcinoma of the Head and Neck
• Intervention / Treatment: Drug: Pembrolizumab; Radiation: stereotattic ablation radiotherapy (SABR)

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: EORTC HQ; Phone Number: +32 2 774 16 11; Email: eortc@eortc.org

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Recruiting
    • Cliniques Universitaires Saint-luc
  • Haine-Saint-Paul, Belgium, 7100
    • Not yet recruiting
    • CHU Helora Pole Hospitalier Jolimont - Hopital Jolimont
  • Kortrijk, Belgium, 8500
    • Recruiting
    • AZ Groeninge Kortrijk - Campus Kennedylaan
  • Namur, Belgium, 5000
    • Recruiting
    • CHU-UCL Namur - CHU Site Sainte-Elisabeth-UCL Namur
  • Sint-Niklaas, Belgium, 9100
    • Recruiting
    • VITAZ St Niklaas - VITAZ- Oncology
  • Wilrijk, Belgium, 2610
    • Recruiting
    • Ziekenhuis aan de Stroom (ZAS) - ZAS Augustinus (previous GZA)
• Italy
  • Bologna, Italy, 40139
    • Not yet recruiting
    • IRCCS--Ospedale Bellaria-Bologna
  • Cuneo, Italy, 12100
    • Not yet recruiting
    • Azienda Ospedaliera Santa Croce E Carle
  • Florence, Italy, 50134
    • Recruiting
    • Univ. of Florence -Azienda Ospedaliero-Universitaria Careggi
  • Milan, Italy, 20089
    • Recruiting
    • Istituto Clinico Humanitas
  • Milan, Italy, 20133
    • Recruiting
    • IRCCS - Fondazione Istituto Nazionale dei Tumori
  • Naples, Italy, 80147
    • Not yet recruiting
    • Azienda Sanitaria Locale Napoli 1 Centro
  • Ravenna, Italy, 48121
    • Not yet recruiting
    • AUSL Romagna - AUSL Della Romagna -Ospedale Santa Maria delle Croci
  • Rome, Italy, 00161
    • Recruiting
    • Azienda ospedaliero Univ Policlinico Umberto I
• Spain
  • Badalona, Spain, 08916
    • Not yet recruiting
    • Institut Català d'Oncologia - Hospital Duran i Reynals
  • Barakaldo, Spain, 48903
    • Not yet recruiting
    • Hospital Universitario de Cruces
  • Barcelona, Spain, 08908
    • Recruiting
    • ICO L'Hospitalet - Hospital Duran i Reynals (Institut Catala D'Oncologia)
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitari Vall d'Hebron -Vall d'Hebron Institut Oncologia
  • Las Palmas de Gran Canaria, Spain, 35010
    • Recruiting
    • Hospital Universitario de Gran Canaria Doctor Negrín
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28040
    • Recruiting
    • Hospital Universitario San Carlos
  • Madrid, Spain, 28041
    • Not yet recruiting
    • Hospital Universitario 12 de Octubre
  • Málaga, Spain, 29010
    • Not yet recruiting
    • Hospital Universitario Virgen de la Victoria
• Switzerland
  • Aarau, Switzerland, 5001
    • Not yet recruiting
    • Kantonsspital Aarau
  • Bellinzona, Switzerland, 6500
    • Not yet recruiting
    • Oncology Institute of Southern Switzerland (IOSI) - Oncology Institute of Southern Switzerland - Ospedale San Giovanni
  • Bern, Switzerland, 3010
    • Recruiting
    • Inselspital - Inselspital
  • Chur, Switzerland, 7000
    • Not yet recruiting
    • Kantonsspital Graubuenden
  • Lucerne, Switzerland, 6004
    • Recruiting
    • Luzerner Kantonsspital
  • Winterthur, Switzerland, 8401
    • Not yet recruiting
    • Kantonsspital Winterthur
  • Zurich, Switzerland, 8901
    • Recruiting
    • UniversitaetsSpital Zurich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Main inclusion Criteria:

• Male/female participants who are at least 18 years of age on the day of signing informed consent
• Histologically confirmed HNSCC of the oral cavity, oropharynx, hypopharynx, larynx or cervical primary occult and histologically or radiologically confirmed oligometastatic disease. Histological characterization of one metastatic lesion is strongly recommended.
• Patients with synchronous or metachronous oligometastatic disease according to the ESTRO/EORTC consensus (1-5 metastatic lesions, with or without primary/recurrent primary tumour and/or regional disease).
• Amenable to first-line systemic treatment for R/M SCCHN.
• For patients with oropharyngeal cancer: HPV status using p16 IHC evaluated locally.
• PD-L1 CPS of at least 1 as evaluated locally.
• Staging not older than 12 weeks before enrolment.
• All the 1-5 metastases must be amenable to SABR.
• Eligible for treatment with pembrolizumab.
• Have measurable disease based on RECIST 1.1.
• ECOG performance status of 0 to 1.
• Participants must have recovered from all treatment-related toxicities to baseline or grade ≤1, such as from previous radiotherapy, systemic treatment or surgery, and not requiring corticosteroids for managing treatment-related side effects.
• Adequate Organ Function Laboratory Values.
• Before patient registration/enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations.

Main exclusion Criteria:

• Nasopharynx, sino-nasal, and salivary gland cancers are excluded.
• In-field progression in < 6 months after curative intended locoregional irradiation of the head and neck.
• Lesions larger than 6 cm in the largest dimension as measured in the diagnostic CT or MRI scan for lesions outside the brain. Note: bone metastases over 6 cm may be included if in the opinion of the local radiation oncologist they can be treated safely and no inner organ is affected.
• Brain metastases only.
• Has received any previous radiotherapy to any of the 1-5 metastases that would be subject to SABR in the experimental arm unless the investigator agrees to treat only after discussion with the RTQA team.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
• Previously treated brain metastases that are radiologically non-stable. Patients with previously treated brain metastases, i.e., without evidence of progression for at least 4 weeks by repeat imaging, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention, can participate.
• Known contraindication to imaging tracer or any product of contrast media and MRI contraindications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 : Standard of Care; Pembrolizumab at a dose of 400mg every 6-weeks (Q6W) for a duration of 2 years (i.e 17 cycles) as per Standard of Care treatment of oligometastatic HNSCC disease. Palliative radiotherapy to oligometastatic disease is allowed if necessary as per standard of care to relieve symptomatic disease and prevent complications. Recommended dose regimens are 1x 8 Gy, 5x 4 Gy and 10x 3 Gy. Planning technique and target volume definition should be according to institutional standards.No ablative-stereotactic dose and no boost techniques are allowed with the exception of CNS-metastases treatment.	Drug: Pembrolizumab; Pembrolizumab: 400mg Q6W up to 2 years (i.e 17 cycles).
Experimental: Arm 2 : Standard of Care + stereotattic ablative radiation (SABR); The Experiemnt Arm consists of pembrolizumab at a dose of 400mg every 6-weeks (Q6W) for a duration of 2 years (i.e 17 cycles) as per Standard of Care treatment of oligometastatic HNSCC disease in combination with SABR. For each oligometastatic lesion treatment, specific SABR fractions and targeted dose(Gy) should be used depending on the location of the lesion. Three-fraction regimens will deliver a fraction every second day, and five-fraction regimens are delivered daily. All treatments have to be completed within 10 working days.	Drug: Pembrolizumab; Pembrolizumab: 400mg Q6W up to 2 years (i.e 17 cycles).; Radiation: stereotattic ablation radiotherapy (SABR); Total dose and number of fractions will depend on the site of the disease. Three-fraction regimens will deliver a fraction every second day, and five-fraction regimens are delivered daily. All treatments have to be completed within 10 working days.; Other Names: SBRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival by RECIST 1.1	To assess whether SABR added to pembrolizumab improves progression-free survival in patients with HNSCC disease, PD-L1 CPS ≥1 and 1-5 metastatic lesions, as compared to pembrolizumab alone.	2.6 years after first patient in

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	To assess whether SABR added to pembrolizumab improves OS	5.2 years after first patient in
Disease-specific survival	To assess whether SABR added to pembrolizumab improves disease-specific survival	5.2 years after first patient in
Time to disease progression	To assess whether SABR added to pembrolizumab improves time to disease progression	5.2 years after first patient in
Time to development of new metastatic lesions	To assess whether SABR added to pembrolizumab improves time to development of new metastatic lesions	5.2 years after first patient in
Time to progression in oligometastatic lesions initially present at enrolment	To assess whether SABR added to pembrolizumab improves time to progression in oligometastatic lesions initially present at enrolment	5.2 years after first patient in
Adverse events according to CTCAE version 5.0	To evaluate the safety and tolerability according to CTCAE v5.0 of SABR combined with pembrolizumab	5.2 years after first patient in
Health-related quality of life evaluated using self-administered EORTC QLQ-C30 questionnaire		5.2 years after first patient in
Health-related quality of life evaluated using self-administered EORTC QLQ-HN43 questionnaire		5.2 years after first patient in
Health-related quality of life evaluated using self-administered EORTC IL-198 questionnaire		5.2 years after first patient in

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: Merck Sharp & Dohme LLC; Swiss Cancer Institute
• Investigators: Study Chair: Panagiotis Belermpas, MD, University of Zurich; Study Chair: Jean-Pascal Machiels, MD, Clinicque Universitarie Saint Luc

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2025
• Primary Completion (Estimated): July 15, 2027
• Study Completion (Estimated): March 30, 2030

Study Registration Dates

• First Submitted: March 13, 2023
• First Submitted That Met QC Criteria: April 14, 2023
• First Posted (Actual): April 18, 2023

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Pembrolizumab; Stereotactic ablative radiotherapy; oligometastatic HNSCC
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Carcinoma; Carcinoma, Squamous Cell; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab
• Other Study ID Numbers: EORTC-2014-HNCG; 2023-504478-39-00 (Other Identifier: EU trial number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No