- OPSCC in one of the following sub-sites: base of tongue, lateral pharyngeal wall, tonsil, glosso-tonsillar sulcus, vallecula or SGSCC in one or more of the following sub-sites: epiglottis, aryepiglottic fold, false cord or HPSCC in one or more of the following subsites: Lateral and medial wall of piriform sinus (subsites are defined as lateral (lateral pharyngeal wall, tonsil, glosso-tonsillar sulcus, lateral piriform sinus) vs. central lesions (base of tongue, vallecula, all supraglottic sites, medial wall of piriform sinus))

- TNM stage I-III (7th AJCC classification): T1 or T2, N0 or T1 or T2, N1 with one single neck node <= 3 cm without radiographic signs of extracapsular extension (ECE), M0;

- TNM stage I for HPSCC: T1, N0, M0.; Within 2 weeks before randomization, assessment by a Multi-Disciplinary Team (MDT) composed of at least a head and neck/ENT surgeon, oncologist, radiologist, radiotherapist, and pathologist of the treatment naive patient and suitable for either TOS or IMRT based on:
- CT with contrast and/or MRI done within 4 weeks prior to randomization
- Pan-endoscopy with assessment of trans-oral exposure for resection.

- AGE 18 and older; AGE 18 to 70 for SGSCC

- ECOG Performance status <= 2;

- Availability of biological material for HPV/p16 testing for OPSCCs

- Study information and Informed consent discussed by the surgeon and radiooncologist and signed by the patient.

- Within 2 weeks prior randomization:
- Baseline MDADI score available;
- Adequate bone marrow function as demonstrated by neutrophils count > 1,5 x 10^9 /L , platelets count > 75 x 10^9 /L, WBC >= 3.0 x 10^9 /L;
- Prothrombin time (PT) with an international normalized ratio (INR) <= 1.2
- Partial thromboplastin time (PTT) <= 1.2 times ULN

- Normal 12-lead ECG;

- Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test no more than 72 hours prior to randomization.

- Patients of childbearing / reproductive potential should agree to use adequate birth control measures for 3 months, especially if they will undergo any radiotherapy treatment at any time during the study. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1 % per year) when used consistently and correctly.

- Patient with bilateral tumors

- Any previous anti-cancer therapy for HNSCC (chemo or radiotherapy or molecular targeted therapy);

- Any active malignancy (other than non-melanoma skin cancer or localized cervical cancer or localized and presumed cured prostatic cancer) within the last 5 years with ongoing systemic treatment

- Cancer in contact with the internal and/or external carotid artery

- Extension of OPSCC across the midline of the base-of-tongue

- Arytenoid involvement in case of SGSCC

- Involvement of > 50 % of the soft palate by cancer, requiring a reconstruction with a free flap or any other involvement of the soft palate requiring a reconstruction with a free flap judged by the surgeon

- Cancer originating from the soft palate or posterior pharyngeal wall

- Pre-existing dysphagia not related to the oropharyngeal cancer or diagnostic biopsies

- Any psychological, cognitive, familial, sociological or geographical condition potentially hampering compliance with the study protocol, completion of patient reported measures and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

Participants are eligible to be included in the study only if all the following criteria apply:

1. Provide signed informed consent. Participant must be capable of providing informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

2. Participants = 18 years of age at the time of signing the ICF, or the legal age of consent in the jurisdiction in which the study is taking place.

3. Have histologically or cytologically-confirmed R/M HNSCC that is considered incurable by local therapies.
a. Subjects must not have had prior systemic therapy administered in the R/M setting. Chemoradiation therapy which was completed more than 4 months prior to signing consent if given as part of multimodal treatment for locally advanced disease is allowed.
b. The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.
c. Subjects may not have a primary tumor site of nasopharynx (any histology).

4. Has measurable (target) disease based on RECIST 1.1 (Section 10.10), as determined by the investigator.

5. Has an ECOG PS (Section 10.6) of 0 or 1.

6. Provides a tumor tissue sample obtained at the time of or after the initial diagnosis of R/M HNSCC. Although a fresh tumor tissue sample obtained within 90 days of screening is highly preferred, an archival tumor specimen (= 2 years old) is acceptable. Biopsies obtained prior to the administration of any systemic therapy administered for the treatment of a participant’s tumor (such as neoadjuvant/adjuvant therapy) are not acceptable. Needle or excisional biopsies or resected tissue is required. Cytological specimens such as fine needle aspirates, bone marrow samples, or cell blocks are not acceptable. Bone specimen is not acceptable.

7. Has tumor PD-L1 expression (CPS = 1) as determined by the DAKO 22C3 assay performed by a local laboratory or at a central laboratory, and the subgroup (CPS = 1 to CPS < 20 or CPS = 20) is open for enrollment at time of consent. NOTE: Other assays for PD-L1 expression levels will not be accepted to determine eligibility.
Local laboratory testing for PD-L1 status must be performed on tumor tissue samples meeting the requirements specified in Inclusion Criterion 6.

8. If the primary tumor site is oropharyngeal carcinoma, the participant must have HPV results defined as p16 IHC testing using a p16 histology assay and a = 70% cutoff point (p16 IHC positive is = 70% of carcinoma TC(s) with nuclear and cytoplasmic moderate to strong staining; see Section 8.1.2 for details). Local test results are acceptable; if not available, a central lab testing will be needed. If HPV status was previously tested using this method, no additional testing is required.

9. Has adequate organ function, as defined in Table 7.

Definitions for Adequate Organ Function

System: Laboratory Values

Hematologic
ANC: = 1.5 x 10^9/L
Hemoglobin: = 9 g/dL
Platelets: = 100 x10^9/L

Hepatic
Total bilirubin - For participants with Gilbert’s Syndrome (only if direct bilirubin = 35%): = 1.5 x ULN, = 3.0 x ULN
ALT and AST - For participants with liver metastases: = 2.5 x ULN, = 5 x ULN

Renal
eGFR^a: = 30 mL/min/1.73m^2

Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate; ULN = upper limit of normal.
^a eGFR to be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula or, for participants enrolled in Japan only, the revised Japanese Society of Nephrology formula (see Section 10.2).

10. If of childbearing potential, female participants must be willing to use adequate contraception. Contraceptive use by female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies:

a. Is a woman of non-childbearing potential as defined in Section 10.4.

or

b. Is a woman of childbearing potential and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, as described in Section 10.4 during the study intervention period and for at least 4 months after the last dose of study intervention. Female participant agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.

c. A woman of childbearing potential must have a negative highly sensitive serum pregnancy test within 7 days before the first dose of study intervention.

Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.6.

The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk of inclusion of a woman with an early undetected pregnancy.

Participants are excluded from the study if any of the following criteria apply:

1. Has received prior therapy with any immune checkpoint inhibitors, including antibodies or drugs targeting PD-1, PD-L1, CTLA-4, TIGIT, CD96, or other immune checkpoint pathways.

2. Participants with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, esophageal, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period.

Note: Participants are allowed if they have low-risk early-stage prostate cancer defined as follows: Stage T1c or T2a with a Gleason score = 6 and prostatic-specific antigen < 10 ng/mL either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to randomization.
Additionally, participants are allowed if they have low risk intrathyroidal differentiated thyroid cancer either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to randomization.

3. Has had major surgery within 4 weeks of the first dose of study intervention. Participants must also have fully recovered from any surgery (major or minor) and/or its complications before initiating study intervention.

4. Have active tumor bleeding or a high risk of bleeding (examples include but are not limited to radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates > 90 degree abutment or encasement of a major vessel [carotid, jugular, bronchial artery] and/or exhibits other high-risk features such as arteriovenous fistula).

5. Has PD within 4 months of completion of curatively intended treatment for locoregionally advanced HNSCC.

6. Participants with any carcinomatous meningitis or leptomeningeal spread and those with uncontrolled or symptomatic CNS metastases.

Note: Participants with previously treated brain metastases may participate provided they are asymptomatic (any neurologic symptoms have returned to baseline [participants may be receiving stable doses of anticonvulsants]), radiographically stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment), have no evidence of new or enlarging brain metastases, and are clinically stable off steroids for at least 2 weeks prior to initiation of study treatment.

7. Active autoimmune disease that has required systemic disease-modifying or immunosuppressive treatment within the last 2 years. (Note: Stable, medically managed autoimmune endocrinopathies are acceptable if participant otherwise meets entry criteria.)

8. Has received systemic steroid therapy <= 3 days prior to the first dose of study intervention or is receiving any other form of immunosuppressive medication.

Replacement therapy is not considered a form of systemic therapy. Note the following:

a. Corticosteroid use is allowed as premedication for hypersensitivity reactions (e.g., IV contrast allergies/reactions).
b. Use of topical, inhaled, or intranasal corticosteroids, local steroid injection, or steroid eye drops is allowed.
c. Participants who receive daily steroid replacement therapy are an exception to this criterion. Daily prednisone at doses of = 10 mg is an example of replacement therapy. Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy.

9. Has received any live vaccine within 30 days prior to first dose of study intervention.

Note: mRNA and adenoviral-based COVID-19 vaccines are considered non-live.
Study participants can be vaccinated against COVID-19 using vaccines authorized via the appropriate regulatory mechanisms (e.g., Emergency Use Authorization, Conditional Marketing Authorization, or Marketing Authorization Application). Refer to Section 6.9 and Section 10.10.1.4 for further information regarding COVID-19 vaccination recommendations and data to be collected in the eCRF.

10. Has any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis.

11. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment of these conditions (including therapeutic thoracentesis or paracentesis) is eligible if the participant otherwise meets entry criteria.

12. Has active inflammatory bowel disease, acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or peritoneal carcinomatosis.

13. History or evidence of cardiovascular risk including any of the following:

a. Recent history (within 6 months) of serious uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities including second degree (Type II), third-degree AV block or left bundle branch block.

b. Recent history (within 6 months) of myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within 6 months.

c. Congestive heart failure (Class III or IV) as defined by the New York Heart Association Functional Classification System [The Criteria Committee of the New York Heart Association, 1994] (Section 10.3.3).

d. History of myocarditis of any grade or recent history (within 6 months) of symptomatic pericarditis.

NOTE: Participants with troponin and/or NT-proBNP/BNP = 2 x ULN will require a cardiologist or locally appropriate specialist review to identify underlying conditions that may meet exclusion criteria or that may require increased monitoring on study. In addition, consider cardiologist or locally appropriate specialist review for potentially significant ECG abnormalities such as AV block (except for first degree), new cardiac arrhythmias, or frequent premature ventricular contractions. Please inform the sponsor regarding these participants.

14. QTcF>470 msc, or > 480 msec for participants with bundle branch block. QTcF can be machine-calculated or manually over-read.

15. Has current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.

Note: Stable chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.

16. Infectious diseases as below:

a. Active infection requiring systemic treatment,

b. Known HIV infection (including results from screening if permitted by local regulations), unless the participant can meet all the following criteria:

i. Documented evidence of plasma HIV-1 RNA persistently < 50 copies)/mL confirmed =3 months prior to AND at Screening; unless undetectable viral load is defined differently by local
guidelines and agreed with the sponsor’s medical monitor. In the > 3 to 12 months prior to Screening, plasma HIV-1 RNA consistently < 50 copies/mL is required; if single/isolated increases
= 50 copies/mL occurred and are thought not to be persistent and not associated with antiretroviral resistance as per investigator assessment, the participant would be eligible.

AND

ii. CD4 cell count = 350 cells/mm^3 over past 12 months and at Screening (and no measurement < 350 cells/mm3 during that period)
AND
iii. Must be on an uninterrupted combination antiretroviral therapy regimen for at least 3 months prior to Screening, with combination antiretroviral therapy regimen consistent with locally
recommended guidelines (see Section 10.12)

Note: follow-up and monitoring according to standard medical practice.

c. Participants who test positive for HCV antibodies and have positive HCV RNA.

d. Untreated chronic hepatitis B or chronic HBV inactive carriers with HBV DNA > 500 IU/mL (or > 2500 copies/mL) at screening.
See Section 10.11 for additional information on management of hepatitis B participants, additional procedures, and dose modification guidelines in case of hepatitis B reactivation.

17. Prior allogenic or autologous bone marrow transplantation or other solid organ transplantation.

18. Has a history of severe hypersensitivity to mAbs or to any of the excipients in the formulations of the components of the study interventions.

19. Has any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric, or other condition that could, in the opinion of the investigator, interfere with participant’s safety, obtaining informed consent, or compliance with the study procedures.

Patients are eligible for the trial if all of the following criteria are met:

- Histologically confirmed or suspected squamous cell carcinoma of the oropharynx.

- UICC/AJCC TNM 7^th edition stage T1-T3, N0-N2b (or UICC TNM 8^th edition stage T1-T3, N0-N1) disease. [Staging should be based on cross sectional imaging investigations carried out within 10 weeks of study entry].

- Multidisciplinary team (MDT) decision to treat with primary transoral resection and neck dissection.

- Patients considered fit for surgery and adjuvant radiotherapy

- Aged 18 or over.

- Written informed consent provided.

N.B. HPV positive by both P16 and either High Risk HPV In-Situ Hybridization (ISH) or validated Polymerase Chain Reaction (PCR) technique is essential prior to videofluoroscopy and randomisation.

Patients are not eligible for the trial if any of the following criteria apply:

- Known HPV negative squamous cell carcinomas of the head and neck: A negative result for p16 Immunohistochemistry automatically excludes a patient from the trial. If initial p16 testing is positive but High Risk HPV (HR HPV) In-Situ Hybridization (ISH) / Polymerase Chain Reaction (PCR) does not demonstrate the presence of HR HPV DNA, the patient will also be excluded.
Patients who are p16 positive may complete swallowing assessments, excluding videofluoroscopy, and surgery whilst HR HPV DNA status is being determined (with recourse to central concordance testing, if appropriate, for UK centres). HPV positivity, as determined by p16 and the demonstration of HR HPV DNA is essential before patients undergo videofluoroscopy or randomisation.

- T4 and/or T1-T3 tumours where transoral surgery is considered not feasible.

- UICC/AJCC TNM 7^th edition N2c-N3 nodal disease (or UICC/AJCC TNM 8^th edition N2-N3 nodal disease).

- Patients for whom transoral surgery and neck dissection is not considered the primary treatment modality.

- Current smokers with N2b disease (including smokers up to 6 months before diagnosis), even if HPV-positive. Vaping is permitted and should be considered as non-smoking status.

- Any pre-existing medical condition likely to impair swallowing function and/ or a history of pre existing swallowing dysfunction prior to index oropharyngeal cancer.

- Patients with distant metastatic disease as determined by routine pre-operative staging radiological investigations e.g., CT thorax and upper abdomen or PET-CT.

- Patients with a history of malignancy in the last 5 years, except basal cell carcinoma of the skin or carcinoma in-situ of the cervix.

- Women who are pregnant or breastfeeding and fertile women who will not be using contraception during the trial.
Patients with cT1-T2 N0 M0 tumours should be preferentially considered for the EORTC Best-of study in centres where both PATHOS and Best-of studies are open.

- Histologically proven malignancy of the nasal vestibulum and the sinonasal tract; T1-3, N0, M0; squamous cell carcinoma
- Primary tumor must be resectable endoscopically or via limited open approach without changing the facial appearance
- Written and signed informed consent
- ECOG PS <= 2, Karnofsky PS >= 60 %
- Age >= 18
- Curative treatment intent

MAIN EXCLUSION CRITERIA:
- Prior head and neck malignancy
- Entity other than squamous cell carcinoma
- Clinically suspected lymph node or distant metastases
- Serious co-morbidity, e.g. high-grade carotid artery stenosis, congestive heart failure NYHA grade 3 and 4, liver cirrhosis CHILD C
- Hemoglobin level < 9.5 g/dl
- Pregnancy or lactation
- Prior treatment of the neck of any cause
- Concurrent treatment with experimental drugs or participation in another clinical trial of any kind within 30 days prior to study screening
- Social situations that limit compliance with study requirements or patients with an unstable condition (e.g., psychiatric disorder, a recent history of drug or alcohol abuse, interfering with study compliance, within 6 months prior to screening) or otherwise thought to be unreliable or incapable of complying with the requirements of the protocol
- Patients institutionalized by official means or court order

- Alter <= 12 Jahre
- Einfluss von Alkohol
- Verdauungsprobleme
- Anamnese von Kopfschmerzen
- Migräne
- Schwindel oder Ohrenschmerzen.

Eine Absprache mit dem betreuenden Arzt sollte durchgeführt werden, wenn einer der folgenden Zustände vorliegt: Schwangerschaft, binokulare Beschwerden, psychiatrische
Störungen, Herzkrankheit oder andere schwere Erkrankungen.

Zudem sollte die Nutzung bei Patienten abgewogen werden, die bereits in der Vergangenheit Schwindel, epileptische Anfälle, Krämpfe, Zuckungen der Augenmuskeln
oder Bewusstlosigkeit im Zusammenhang mit Lichtblitzen, TV, Videospielen oder Virtual Reality erlitten haben.

Die VR-Brille kann Komponenten wie Magnete enthalten, die Radiowellen emittieren. Dies kann umliegende elektronische Geräte beeinflussen wie etwa Herzschrittmacher,
Hörgeräte und Defibrillatoren. Vor der Nutzung sollte eine Rücksprache mit dem Arzt erfolgen.

Die Nutzung der VR-Brille sollte sofort unterbrochen werden, wenn eines der folgenden Symptome auftritt: Krämpfe, Bewusstseinsverlust, Überanstrengung der Augen/
Augenschmerzen, Augen- oder Muskelzucken, ungewollte Bewegungen, veränderte, getrübte Sicht, Doppelbilder oder andere visuelle Abnormalitäten, Schwindel,
Desorientierung, Beeinträchtigung des Gleichgewichtssinnes, Beeinträchtigung der Hand-Augen-Koordination, starkes Schwitzen, gesteigerte Speichelbildung, Übelkeit,
Benommenheit, Kopfschmerzen, Erschöpfung/Müdigkeit, andere Symptome, die einer Reise-/ Seekrankheit gleichen.