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.

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.