Registration step 1

Main Inclusion criteria

- 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 (sub-sites are defined as lateral (lateral pharyngeal wall, tonsil, glosso-tonsillar sulcus, lateral wall of piriform sinus) vs. central lesions (base of tongue, vallecula, all supraglottic sites, medial wall of piriform sinus))

- TNM stage I-III (7th AJCC classification) for OPSCC and SGSCC: T1 or T2, N0 or T1 or T2, N1 with one single neck node = 3cm 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, medical oncologist, radiologist, radiotherapist, and pathologist of the treatment naive patient and suitable for either TOS or IMRT based on:
- Contrast enhanced CT and/or MRI done within 4 weeks prior to randomization
- Repeat contrast enhanced CT and/or MRI or US 1 week or less prior to enrollment in case of suspicious nodes <1cm on initial scan if per local practice
- Panendoscopy with assessment of trans-oral exposure for resection.
- Peri-nodal infiltration either via CT-scan or MRI.

- ECOG Performance status <= 2;

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

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

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


Randomization step 2

Main Inclusion criteria

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

- Women of childbearing 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 measuresuntil 6 months after completion of treatment, especially if they will undergo any chemotherapy or 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.

Registration step 1

Main Exclusion criteria

- Any previous anti-cancer therapy for HNSCC (surgery, chemo, radiotherapy or molecularly 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 common carotid artery

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

- Arytenoid involvement in case of SGSCC

- Infiltration of apex for piriform sinus in case of HPSCC

- Cancer originating from the soft palate or posterior pharyngeal wall

- Requirement of a reconstruction with a free or regional flap (i.e. involvement of >50% of the soft palate)

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


Randomization step 2

Main Exclusion criteria

- Any psychological, cognitive, familial, sociological or geographical condition potentially hamperingcompliance 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;

Important note: All eligibility criteria must be adhered to, in case of deviation discussion with EORTC Headquarters and study coordinator is mandatory. However, a maximum of +/- 2 days for timelines may be acceptable.

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

1. Male and female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of squamous cell carcinoma (SCC) of the larynx or hypopharynx according to the decision of the multidisciplinary tumor board suitable for total laryngectomy can be enrolled in this study.

2. Stage II, III, IVA, IVB hypopharyngeal SCC, whenever clear resection margins R0 > 5 mm can be achieved and no radiologic signs of extranodal extension of neck nodes are present.

3. Have provided newly obtained excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.

4. PD-L1-expression* within the tumor biopsy, CPS = 1 as measured by the PD-L1 IHC 22C3 pharmDx (Agilent).

5. Male participants:

A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.

6. Female participants:

A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days after the last dose of study treatment.

7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization.

8. Have adequate organ function as defined in the following table (Table 4). Specimens must be collected within 10 days prior to the start of study treatment.

* Note, that the assessment of PD-L1 status must be performed according to guidelines for first line treatment with Pembrolizumab and using the clinically established and CE-certified assay PD-L1 IHC 22C3 pharmDx (Agilent). The test procedure can be found in the data sheets of the product.

Adequate Organ Function Laboratory Values

System: Laboratory Value

HEMATOLOGICAL
Absolute neutrophil count (ANC): = 1500/µL
Platelets: =100 000/µL
Hemoglobin: = 9.0 g/dL or = 5.6 mmol/La

RENAL
Creatinine OR Measured or calculated^b creatinine clearance (GFR can also be used in place of creatinine or CrCl): = 1.5 x ULN OR = 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN

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): = 2.5 x ULN

COAGULATION
International normalized ratio (INR) OR prothrombin time (PT)
Activated partial thromboplastin time (aPTT): = 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants


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

^a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
^b Creatinine clearance (CrCl) should be calculated per institutional standard.

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:

1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to receiving the first dose of study medication (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory receptor on T or NK cells (e.g., CTLA-4, OX-40, CD137).

3. Has received prior systemic anti-cancer therapy including investigational agents.

4. Has received prior radiotherapy.

5. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first
dose of study drug. Administration of killed vaccines is allowed.

6. 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.

7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

8. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.

Note: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in-situ cancers

9. Has known distant metastases including active CNS metastases and/or carcinomatous meningitis.

10. Has severe hypersensitivity (= Grade 3) to pembrolizumab and/or any of its excipients.

11. Has 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 and is allowed.

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

13. Has an active infection requiring systemic therapy.

14. Has a known history of Human Immunodeficiency Virus (HIV) infection.

Note: No HIV testing is required unless mandated by local health authority.

15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.

16. Has a known history of active TB (Bacillus Tuberculosis).

17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

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

19. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

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

21. Has a known intolerance to one of the substances administered during treatment including e.g. antiemetics, etc. or any other component of concurrent auxiliary medication.

Patients must fulfill all of the following requirements to enter the study:

1. Signed informed consent form (ICF) before initiation of any study-specific procedures

2. Age = 18 years at signing of ICF

3. Histologically confirmed HNSCC with evidence of metastatic or locally recurrent disease not amenable to local therapy with curative intent. Patients with HNSCC primary tumor locations in oropharynx, oral cavity, hypopharynx, and larynx are eligible.

4. HNSCC patients eligible to receive pembrolizumab as 1L monotherapy with tumors expressing PD-L1, CPS =1, as determined by an IHC test in a central laboratory

5. HNSCC patients should not have had previous systemic therapy administered in the incurable recurrent or metastatic setting, although previous systemic therapy as part of multimodal treatment for locally advanced disease is allowed if progressive disease (PD) was =6 months after the last platinum-containing therapy dose. Previous treatments with anti PD-(L)1 or anti-EGFR therapies are not allowed. In the case of cetuximab, patients who have received cetuximab with radiotherapy as a local treatment and PD was >1 year after the last dose of cetuximab are eligible.

6. A new tumor biopsy to enable determination by central laboratory of PD-L1 status (and p16 status for oropharynx primaries). If the patient has an archival tumor sample and has not received further anticancer treatment since sample collection, then a new tumor biopsy is not necessary. If a new tumor biopsy cannot be performed, an archival sample may be acceptable with Sponsor approval.

7. Measurable disease per Investigator assessment as defined by RECIST v1.1 by radiologic methods.

8. ECOG PS of 0 or 1

9. Life expectancy = 12 weeks, as per Investigator assessment

10. Left ventricular ejection fraction (LVEF) = 50% or = institutional normal limit, whichever is higher, by echocardiogram (ECHO) or multigated acquisition (MUGA) scan

11. Adequate organ function:

a) Absolute neutrophil count (ANC) = 1.5 x 10^9/L

b) Hemoglobin = 9 g/dL; red blood cell (RBC) transfusion is permitted to meet criteria, if there is no suspicion of active bleeding or hemolysis.

c) Platelets = 100 x 10^9/L

d) Serum magnesium within the normal range or Grade 1 alteration (if corrected with supplements or treatment during screening, then it should be re-tested and in the eligible range before
randomization).

e) If corrected calcium, phosphate, sodium, and potassium are not within the normal range, patients should be under appropriate treatment for correction or replacement before randomization, as clinically indicated.

f) Alanine aminotransferase (ALT), aspartate aminotransferase (AST) = 2.5 x upper limit of normal (ULN); in cases of liver metastases, ALT/AST = 5 x ULN, but in both situations, the bilirubin levels are required to be = 1.5 x ULN, unless due to known Gilbert’s syndrome when total bilirubin = 3.0 x ULN or direct bilirubin = 1.5 x ULN will be allowed.

g) Serum creatinine = 1.5 x ULN or creatinine clearance = 60 mL/min calculated according to the Cockroft and Gault formula

h) Serum albumin = 3 g/dL

i) Prothrombin time (PT)/International Normalized Ratio (INR) =1.5xULN, unless patient is receiving anticoagulant therapy and PT/INR is in therapeutic range of intended used anticoagulant

j) Activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT) = 1.5 x ULN, unless patient is receiving anticoagulant therapy and APTT or PTT is in therapeutic range of intended used anticoagulant

12. Human immunodeficiency virus (HIV)-positive patients are eligible only if the cluster of differentiation 4 (CD4+) count is = 300/MikroL, viral load is undetectable, and the patient is currently receiving highly active antiretroviral therapy (HAART). Note: Screening test for HIV is not required unless there is clinical suspicion or testing is mandated by local health authorities for study participation. Patients with a history of HIV are required to complete CD4 and viral load testing.

The presence of any of the following criteria excludes a patient from participating in the study:

1. Central nervous system (CNS) metastases that are untreated or already treated but symptomatic, or require radiation, surgery, or continued steroid therapy to control symptoms within 21 days prior to randomization.

2. Known leptomeningeal involvement

3. Any systemic anticancer therapy or investigational drug (including those with indications other than anticancer therapy) within 4 weeks or 5 half-lives (if known), whichever is shorter, before randomization.

4. Requirement for immunosuppressive medication (e.g., methotrexate, cyclophosphamide).

5. Major surgery or radiotherapy within 3 weeks of randomization

6. Clinically significant toxicities related to prior anticancer therapy that have not returned to = Grade 1 or baseline except for =Grade 2 myalgia, alopecia, and prior therapy-related endocrinopathies.

7. History of hypersensitivity reaction to any of the excipients of petosemtamab or pembrolizumab required for this study

8. Unstable angina; history of congestive heart failure of Class II-IV New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (except appropriately treated atrial fibrillation, paroxysmal supraventricular tachycardia); or history of myocardial infarction within 6 months prior to randomization

9. History of prior malignancies within the last 5 years, with the exception of excised local cancer (e.g., cervical intraepithelial neoplasia, non-melanoma skin cancers)

10. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy. Patients with a history of non-infectious pneumonitis/interstitial lung disease (ILD) or evidence of current pneumonitis/ILD on baseline chest imaging will be excluded

11. Current serious illness or medical conditions including, but not limited to, uncontrolled active infection, clinically significant pulmonary, metabolic, or psychiatric disorders that preclude safety and efficacy evaluation, or unwillingness or inability to comply with procedures required in either arm of this protocol.

12. Patients with known infectious diseases:

a) Active hepatitis B infection (hepatitis B surface antigen [HBsAg] positive) without receiving antiviral treatment. Note:
- Patients who are hepatitis B surface antigen (HbsAg) positive must receive antiviral treatment (e.g., lamivudine, tenofovir, entecavir, or other antiviral agents), starting = 7 days before
randomization.
- Patients with antecedents of hepatitis B (i.e., anti-hepatitis B core [HBc] positive, HBsAg and hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] negative) are eligible.

b) Known positive test for hepatitis C virus (HCV) RNA. Note: Patients in whom HCV infection resolved spontaneously (i.e., positive HCV antibodies without detectable HCV RNA) or who achieved a sustained response after antiviral treatment and show absence of detectable HCV RNA =6 months (with the use of interferon [IFN]-free regimens) or =12 months (with the use of IFN-based regimens) after cessation of antiviral treatment are eligible.
Note: testing for Hepatitis B and Hepatitis C is not required unless there is a known history or clinical suspicion of infection or testing is mandated by local health authorities for study participation.

13. Pregnant or breastfeeding patients; patients of childbearing potential must use highly effective contraception methods per local standards prior to study entry, for the duration of study participation, and for 6 months after the last dose of petosemtamab or 4 months after the last dose of pembrolizumab, whichever is longer. Fertile male patients must use highly effective contraception methods per local standards with their partners for the duration of study participation, and for 6 months after the last dose of petosemtamab or 4 months after the last dose of pembrolizumab, whichever is longer (see Section 14.9).

14. The patient has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy of prednisone > 10 mg/day or equivalent, or any other form of immunosuppressive therapy. Corticosteroids used as premedication for IRRs before Cycle 1 Day 1 as specified in the protocol are allowed (see Section 6.1.4.2).

15. The patient has an active autoimmune disease that has required systemic immune suppressive treatment in the past 2 years; replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered immune suppressive treatment.

16. The patient has had an allogeneic tissue/solid organ transplant

17. Patient has a primary tumor site of nasopharynx, or sinonasal carcinoma (any histology)

- Patienten mit erfolgreich abgeschlossener Therapie eines Plattenepithel-Karzinoms des Kopf-Hals-Bereichs (ICD-10 Diagnosecodes: C00-C14, C30-C33, C44.0-C44.4, C44.6,C44.9, C76, C77.0, C80.0)
- Einschluss innerhalb eines Jahres nach Abschluss der Therapie
- Patientenalter >= 18 Jahre (Volljährigkeit)
- Einwilligungsfähigkeit
- Vorliegen einer unterschriebenen Einwilligungserklärung

- Physische oder psychische Erkrankungen (z.B. Demenz, Abhängigkeitserkrankungen), welche eine telefonische Kontrolle durch das Studienzentrum verhindern
- Vorliegen anderer Tumorentitäten als Plattenepithelkarzinome
- Teilnahme an anderen klinischen Studien, welche die Nachsorgeintervalle beeinflussen
- Patienten, welche nicht einwilligungsfähig sind und/oder unter gesetzlicher Betreuung stehen
- Patienten, welche nach Meinung der Studienärzte und/oder Ambulanz-Oberärzte aufgrund der vorliegenden Erkrankung, den Nebenerkrankungen oder der sozialen Situation nicht fähig sind, an der Studie teilzunehmen
- Patienten, welche Ihre Einwilligung zur Studienteilnahme zurückziehen

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

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

2. Pathologically proven new diagnosis of squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx or supraglottic larynx stage III-IVB according to TMM 8^th edition

3. PD-L1 combined positive score (CPS) = 1 (in sample prior to RCT) by central pathology review

4. Completed definitive RCT up to at least 68 Gy with at least 200mg/m^2 body surface area concomitant Cisplatin.

5. No progression during RCT. Study screening CT has to be compared to RCT baseline CT. (Study screening CT may be performed before the end of RCT, whereas a minimum radiation dose of 50 Gy has to be administered at the time point of the study screening CT.)

6. Male participants:
A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment(pembrolizumab or lenvatinib, whichever is administered last) and refrain from donating sperm during this period. In addition, contraception has to be used for 180 days after the last dose of cisplatin.

7. Female participants:
A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days after the last dose of study treatment (pembrolizumab or lenvatinib, whichever is administered last). In addition, contraception has to be used for 180 days after the last dose of cisplatin.

8. The participant provides written informed consent for the trial.

9. Have measurable disease based on RECIST 1.1.

10. Have provided archival tumor tissue sample with sufficient tumor content. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.

11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.

12. Have adequate organ function as defined in the following table (Table 2). Specimens must be collected within 10 days prior to the start of study intervention


Table 2 Adequate Organ Function Laboratory Values

SYSTEM: LABORATORY VALUE

HEMATOLOGICAL
Absolute neutrophil count (ANC): >= 1500/µL
Platelets: >= 1000 000/µL
Hemaglobin: >= 9.0 g/L or >= 5.6 mmol/L^a

RENAL
Calculated^b creatinine clearance: >= 30 mL/min

HEPATIC
Total bilirubin: <= 1.5 x ULN, except for unconjugated hyperbilirubinemia of Gilbert's syndrome
AST (SGOT) and ALT (SGPT): <= 2.5 x ULN

COAGULATION
International normalized ratio (INR): <= 1,5 x ULN

ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); ULN=upper limit of normal.
^a Criteria must be met without erythropoietin dependency.
^b Creatinine clearance (CrCl) should be calculated per institutional standard.

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

1. Have tumor infiltration/perforation of the skin or cervical fistula (either at timepoint of study inclusion or prior to RCT)

2. Have radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates > 90-degree abutment or encasement of a major blood vessel.

3. Had prior radical surgery for the head and neck cancer under study or induction chemotherapy with more than one cycle prior to definitive RCT. Patients with single cycle induction chemotherapy prior RCT can be included.

4. WOCBP who have a positive urine or serum pregnancy test within 72 hours prior to (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

5. Have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agentdirected to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).

6. Have received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to study drug administration (except from cisplatin concomitant to RCT).

7. Have received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed

8. Are currently participating in or have participated in a study of an investigational agent or have used an investigational device within 4 weeks prior to the first dose of study intervention.

9. Have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.

10. Have a known additional malignancy that is progressing or have required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

11. Have distant metastases.

12. Have severe hypersensitivity (>= Grade 3) to pembrolizumab, lenvatinib and/or any of their excipients.

13. Have 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 and is allowed.

14. Have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.

15. Have an active infection requiring systemic therapy.

16. Have a known history of Human Immunodeficiency Virus (HIV) infection.

17. Have a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection.

18. Have 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.

19. Have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

20. Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]).

21. Have had an allogenic tissue/solid organ transplant.

22. Have uncontrolled blood pressure (Systolic BP > 140 mmHg or diastolic BP > 90 mmHg) in spite of an optimized regimen of antihypertensive medication.

23. Have clinically relevant electrolyte abnormalities that have not been corrected.

24. Have significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening.

25. Have/had bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.

26. Have > 1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is < 1 g/24 hours.

27. Have not recovered adequately from any toxicity from other anti- cancer treatment regimens and/or complications from major surgery prior to starting therapy. Withhold lenvatinib for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing.

28. Have prolongation of QTc interval to > 480 ms in the ECG.

29. Have a LVEF below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO).

30. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.

- 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.