- 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 of the following criteria apply:

TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
1. Have histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma as assessed by the Investigator based on baseline imaging and clinical assessment that is either:
a. Stage III oropharyngeal p16 positive that is T4 (N0-N2), M0
OR
b. Stage III or IVA oropharyngeal p16 negative
OR
c. Stage III or IVA larynx/hypopharynx/oral cavity (independent of p16).
Note: Participants with multiple primary HNSCC tumors are eligible for the study if at least one of the tumors meets eligibility criteria based on staging after consultation with and approval by the Sponsor.
Note: If an excisional or incisional biopsy has been performed, participants remain eligible for the study provided the residual disease meets the staging criteria required for the study (eg, excisional biopsy of a lymph node with residual T4a primary).
Note: Prior surgical debulking, including tonsillectomy, for the head and neck cancer under study is not allowed.
2. Be eligible for primary surgery based on investigator decision and per local practice.
This decision must be validated by members of a multidisciplinary team, including the surgical oncologist, medical oncologist and radiation oncologist.

DEMOGRAPHICS
3. Male/female participants who are at least 18 years of age on the day of signing informed consent

Male participants:
4. A male participant must agree to use a contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

Female participants:
5. A female participant is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 180 days after the last dose of study treatment.

INFORMED CONSENT
6. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for Future Biomedical Research. However the participant may participate in the main study without participating in Future Biomedical Research.

STUDY ASSESSMENTS
7. Have evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST 1.1 as assessed by the local site investigator/radiology.
8. Have provided newly obtained core or excisional biopsy of a tumor lesion not previously irradiated for central PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate [FNA] is not adequate) for stratification prior to randomization. Repeat samples may be required if adequate tissue is not provided.
Formalin-fixed, paraffin embedded tissue blocks are preferred to slides.
Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the Vendor Manual).
9. Have results from (local) testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using standard protocol. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70 % or more of the tumor cells (please see Section 9.1.6 - Presurgery Tumor Tissue Collection for details). If HPV status was previously tested using this method, no additional testing is required.
Note: HPV testing will be performed using local testing of HPV status in participants with oropharyngeal cancer using the specified method.
Note: If local p16 testing results are not available, or cannot be assessed locally by the specified method, a tumor tissue sample must be submitted for p16 testing at the designated central laboratory.
Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing by p16 IHC as by convention these tumor locations are assumed to be HPV-negative.
10. Have an ECOG performance status of 0 to 1 performed within 10 days of randomization.
Note: Investigators to confirm no deterioration prior to initiation of treatment.
11. Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 10 days prior to randomization. If a screening lab does not meet eligibility criteria and is repeated and assessed on Day 1 and the Day 1 lab meets eligibility criteria, the participant is eligible, ie, the Day 1 lab result will be used for eligibility.

ADEQUATE ORGAN FUNCTION LABORATORY VALUES

HEMATOLOGICAL
- Absolute neutrophil count >= 1500/MikroL
- Platelets >= 100 000/MikroL
- Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L

RENAL
- Measured or calculated^a creatinine clearance (CrCl; glomerular filtration rate [GFR] can also be used in place of CrCl) >= 60 mL/min
- Calcium (corrected for albumin)^c <= 11.5 mg/dL or <= 2.9 mmol/L
- Albumin – Result used to provide corrected calcium value only

HEPATIC
- Total bilirubin <= 1.5 x ULN or direct bilirubin <= ULN for participants with total bilirubin levels > 1.5 x ULN
- AST (SGOT) and ALT (SGPT) <= x ULN

COAGULATION
- International normalized ratio (INR) or prothrombin time (PT). Activated partial thromboplastin time (aPTT) or Partial Thromboplastin Time (PTT)^b
<= 1.5 ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CrCl = creatinine clearance; GFR = glomerular filtration rate; ULN = upper limit of normal.

^a Cockcroft Gault calculation of CrCl preferred, but CrCl can be calculated per institutional standard. The formula used to calculate creatinine clearance should be the same and consistent for all participants at the site.

^b. PTT may be performed if the local lab is unable to perform aPTT.

^c Calcium corrected for albumin is required during screening only for participants with albumin outside the normal range.

Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

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

MEDICAL CONDITIONS
1. Has Stage T4B and/or N3 LA HNSCC and/or distant metastases.
Note: As per the AJCC Cancer Staging Manual, 8th edition, the diagnosis of ENE (eg, N3b disease) requires clear evidence of gross ENE on clinical examination supported by strong radiographic evidence. Chapter 5, Staging Head and Neck Cancers, in the AJCC Cancer Staging Manual, 8th edition, defines criteria for evidence of gross ENE on clinical evaluation.
2. Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary HNC.
3. A WOCBP who has a positive urine pregnancy test within 3 days prior to randomization or within 24 hours prior to the start of RT +/- cisplatin (see Appendix 5).
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

PRIOR/CONCOMITANT THERAP
Y 4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
5. Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to randomization/allocation.
Note: Radiation therapy to treat a prior HNC is also grounds for exclusion.
6. Has received a live vaccine within 30 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist [Influenza Vaccine Live, AstraZeneca]) are live attenuated vaccines and are not allowed.

PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
7. 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 randomization.
Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

DIAGNOSTIC ASSESSMENTS
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization.
9. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, in situ cervical cancer or breast carcinoma) that have undergone potentially curative therapy are not excluded.
10. Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis as assessed by local site investigator and radiology review.
11. Has Grade >=2 audiometric hearing loss.
Note: Audiometric abnormalities without corresponding clinical symptoms of Grade >= 2 hearing loss will not be grounds for exclusion.
Note: Participants with complete non-tumor-related hearing loss (ie, congenital deafness) are eligible for this study.
12. Has Grade >= 2 neuropathy.
13. Has Grade 3-4 bleeding due to the underlying malignancy.
14. If participant has received major surgery, and the participant has not recovered adequately from the toxicity and/or complications from the intervention prior to randomization.
15. Has had previous allogeneic tissue/solid organ transplant.
16. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients (refer to the Investigator’s Brochure for a list of excipients), RT or cisplatin or their analogs.
17. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
18. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
19. Has an active infection requiring systemic therapy.
20. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. Refer to Appendix 8 for Germany-specific requirements.
21. Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus [HCV] RNA [qualitative] is detected). Refer to Appendix 8 for Germany-specific requirements.
Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
23. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.

OTHERS EXCLUSIONS:
24. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment.
25. Refer to Appendix 8 for additional France-specific exclusion criterion.
26. Refer to Appendix 8 for additional France-specific exclusion criterion.
27. Refer to Appendix 8 for additional France-specific exclusion criterion.

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

Subjects may be enrolled if they meet all of the following criteria at screening:

1. Willing to give written informed consent and to comply with the protocol.
NOTE: signed and dated informed consent has to be obtained prior to any protocol related procedure.

2. Histologically- or cytologically-confirmed recurrent disease not amenable to curative treatment with local or systemic therapy, or metastatic (disseminated) HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx that is considered incurable by local therapies and to be treated in the first line palliative setting and who are PD-X naive.

3. Availability of tissue for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate is not sufficient). A newly obtained biopsy (within 90 days prior to start of trial treatment) is preferred but an archival sample is acceptable.

4. Availability of PD-L1 biomarker result by using the FDA approved Dako standardized diagnostic test (PD-L1 IHC 22C3 pharmDx).

5. Availability of tissue for testing of human papillomavirus (HPV) status for oropharyngeal carcinoma (p16 expression testing).
NOTE: If HPV status was previously tested using this method and result is available, no additional testing in central laboratory is required for this trial.

6. Female or male >= 18 years of age on the day of signing the informed consent.

7. All female subjects of childbearing potential must have a negative highly sensitive pregnancy test at screening (within 72 hours prior to cycle 1 day 1); all subjects of reproductive potential must agree to use highly effective method for contraception from trial entry until at least 4 months after the last administration of any trial treatment.

8. A woman must either be,
a) not of childbearing potential: postmenopausal (>= 60 years of age, or < 60 years of age and amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression with follicle-stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L, or if taking tamoxifen or toremifene, and age < 60 years, then FSH and estradiol in the postmenopausal range), permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy), or otherwise incapable of pregnancy.
b) of childbearing potential and practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; male partner sterilization (the vasectomized partner should be the sole partner for that subject).

9. ECOG performance status 0-1.

10. Evidence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

11. Subjects who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
NOTE: Subjects should remain on anti-viral therapy throughout trial intervention and follow local guidelines for HBV anti-viral therapy post completion of trial intervention. Hepatitis B screening test are not required unless: a) known history of HBV infection; b) mandated by local health authority.

12. Subjects with history of HCV infection are eligible if HCV viral load is undetectable at screening.
NOTE: Subjects must have completed curative anti-viral therapy at least 4 weeks prior to randomization. Hepatitis C screening tests are not required unless:
a) known history if HCV infection;
b) mandated by local health authority.

13. HIV infected subjects must be on anti-retroviral therapy and have a well-controlled HIV infection/disease defined as:
a) Subjects on ART must have a CD4+ T-cell count > 350 cells/mm^3 at time of screening.
b) Subjects on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening.
c) Subjects on ART must have been on stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to cycle 1 day 1.
NOTE: no HIV testing is required unless mandated by local health authority.

14.1 Laboratory criteria:
a) Absolute neutrophil count > 1.5 x 10^9 /L.
b) Platelet count >= 100 x 10^9 /L.
c) Hemoglobin >= 9 g/dL or 5.58 mmol/L.
NOTE: Must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 2 weeks prior to screening.
d) Serum creatinine <= 1.5 x ULN, or if > 1.5 ULN with a clearance of >= 50 mL/min acc. to.
Gault-Cockcroft formula.
e) Total bilirubin <= 1.5 x ULN or direct bilirubin <= ULN for subjects with total bilirubin > 1.5 x ULN.
NOTE: subjects with known Gilbert’s syndrome can be enrolled.
f) AST (=SGOT) and ALT (=SGPT) <= 2.5 x ULN or <= 5 x ULN if liver metastases are present.
g) International normalized ratio (INR) or prothrombin time (PT) <= 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants.

Subjects are to be excluded from the trial at the time of screening for any of the following reasons:

1. Disease is suitable for local therapy administered with curative intent.

2.1 Previously treated with >= 1 systemic regimen for recurrent and/or metastatic disease (with the exception of systemic therapy completed > 6 months prior if given as part of multimodal treatment for locally or locoregionally advanced disease).

3. Histologically or cytologically confirmed head and neck carcinoma of any other primary anatomic location in the head and neck not specified in the inclusion criteria including subjects with HNSCC of unknown primary, squamous cell carcinoma originating from skin, or non-squamous histologies (e.g., nasopharynx, salivary gland, or mucosal melanoma).

4.1 Has progressive disease (PD) within 6 months of completion of curatively intended systemic treatment for locally or locoregionally advanced HNSCC, or requires chemotherapy based therapeutic regimen due to e.g., rapidly progressing disease or need of aggressive symptom control.

5. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

6. No PD-L1 expression result available by cycle 1 day 1.

7. Prior anti-LAG-3 therapy (e.g., anti-LAG-3 antibodies).

8. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.

9. Prior targeted small molecule therapy (i.e., kinase inhibitors), or radiation therapy within 2 weeks prior to cycle 1 day 1.
NOTE: Subjects must have recovered from all AEs due to previous therapies to <= Grade 1 or baseline. Subjects with <= Grade 2 neuropathy, alopecia and elevated transaminases in case of liver metastases may be eligible. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation to non-CNs disease

10. Has received prior chemotherapy, anti-cancer monoclonal antibody, major surgery, another systemic cancer therapy or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to cycle 1 day 1.
NOTE: Subjects must have recovered from all AEs due to previous therapies to <= Grade 1 or baseline. Subjects with <= Grade 2 neuropathy, alopecia, and elevated transaminases in case of liver metastases may be eligible. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting trial treatment. Subjects who have entered the follow-up phase of an investigational trial may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

11. Known active central nervous system metastasis and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable: i.e., without evidence of progression documented by repeat imaging performed after therapy completed for CNS metastasis and with at least 4 weeks difference, clinically stable and without requirement for steroid treatment for at least 14 days prior to cycle 1 day 1.

12. Pregnant, breastfeeding or expecting to conceive or father children within the projected duration of the trial starting with screening visit. A woman of child-bearing potential who has a positive serum pregnancy test (within 72 hours) prior to cycle 1 day 1.

13. Serious intercurrent infection within 4 weeks prior to cycle 1 day 1 or active acute or chronic infection.
NOTE: Subjects treated for moderately severe infections with oral antibiotics only, may be included, based on consultation with trial Medical Monitor.

14. Evidence of severe or uncontrolled cardiac disease within 6 months prior to first dose of trial treatment including: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 5.0 Grade >= 2, atrial fibrillation > grade 2 not controlled by a pacemaker, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (NYHA III-IV), cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.

15. Has interstitial lung disease or history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

16. Has active autoimmune disease that has required systemic treatment in 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) is not considered a form of systemic treatment and is allowed.

17. HIV-infected subjects with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
NOTE: No HIV testing is required unless mandated by local health authority.

18. Has a life-threatening illness unrelated to cancer.

19. Has had an allogenic tissue/solid organ transplant.

20. Has previous malignancies within the last three years other than described in inclusion criterion 2, except curatively treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, ductal carcinoma in situ of the breast, or in situ carcinoma of the cervix.

21. Receives continuous systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days prior to cycle 1 day 1.
Inhaled or topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalents are permitted in the absence of active auto-immune disease.

22. Has a hypersensitivity to efti and/or pembrolizumab and/or any of its excipients.

23. Live vaccine within 30 days of planned cycle 1 day 1. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed.
NOTE: non-live vaccines (e.g., non-live influenza vaccine, non-live COVID-19 vaccine) can be given until 3 days prior to planned cycle 1 day 1.

24. Has a 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.

25. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial.

- 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.