- Z. n. operativer Entfernung eines Plattenepithelkarzinoms des Oropharynx und adäquater Lymphknotendissektion
- Indikationsstellung zur adjuvanten Strahlentherapie oder Radiochemotherapie im interdisziplinären Tumorboard
- Guter Allgemeinzustand (ECOG performance status 0 oder 1)
- Adäquate Compliance zur Sicherstellung der engmaschigen Tumornachsorge
- Alter =18 Jahre
- Einwilligungsfähigkeit des Patienten und schriftliches Einverständnis
- Neck dissection mindestens der Tumor tragenden Seite

Zusätzliche Einschlusskriterien Arm intermediate risk (IR, mindestens ein Kriterium muss erfüllt werden):
- pT3 und R0 und/oder
- Histologisch gesicherter LK Befall (n=1-3) und keine extrakapsuläre Extension der LK-Metastase

Zusätzliche Einschlusskriterien Arm high risk (HR, mindestens ein Kriterium muss erfüllt werden):
- Residueller Tumor (R1-Status) und/ oder
- pT4-Status und/ oder
- mehr als 3 befallene Lymphknoten und/ oder
- Extrakapsuläre Extension von mindestens einer LK-Metastase

- Kumulativer Nikotinabusus > 30 Packyears für Interventionsarme.
Diese Patienten werden immer (unabhängig vom HPV-Status) in die Beobachtungsarme eingeschlossen.
- Radiologisch vermutete oder histologisch gesicherte Fernmetastasierung
- R2-Resektion oder makroskopisch sichtbarer Resttumor nach erfolgter Operation
- Keine neck dissection erfolgt
- Intervall zwischen letzter Operation und geplantem Bestrahlungsbeginn > 7 Wochen
- Kontraindikation gegen die Durchführung einer Leitlinien gerechten adjuvanten Strahlen- oder Radiochemotherapie entsprechend der klinischen Risikokonstellation
- Durchgemachte Tumorerkrankung in den letzten fünf Jahren vor Studienbeginn (außer Basaliome der Haut, In-Situ Karzinome von Cervix uteri oder Brust oder Tumoren mit ähnlich guter Prognose die als sehr wahrscheinlich geheilt eingeschätzt werden)
- Durchgemachte bösartige Tumorerkrankung im Kopf-Hals-Bereich unabhängig von Therapie, Intervall und Prognose
- Vorbestrahlung mit Gefahr der Dosisüberschneidung
- Teilnahme des Patienten an einer anderen klinischen Studie, wenn aufgrund dessen noch eine weitere experimentelle Therapie notwendig ist oder die Therapien/ Studienprotokolle sich gegenseitig ausschließen
- Erkrankungen oder Zustände, die es der oder dem Betreffenden nicht erlauben, Wesen und Tragweite sowie mögliche Folgen der klinischen Studie abzuschätzen
- schwangere oder stillende Frauen
- Anzeichen darauf, dass die teilnehmende Person das Studienprotokoll voraussichtlich nicht einhalten wird (z. B. mangelnde Kooperationsbereitschaft),
- Fehlende schriftliche Einwilligungserklärung

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.

Screening Part I

In order to allow for pre-cCRT tumor sample collection, Part I Screening procedures begin before cCRT is initiated.

1) Participant must be = 18 years of age, at the time of signing the informed consent form (ICF).

2) Histologically or cytologically documented locally advanced squamous cell carcinoma of the OPC, HP, OC, or LX with no evidence of M0.

3) Confirmed unresected cancer, staging according to AstraZeneca Study eVOLVE- HNSCC protocol Table 9.

4) Confirmation of acceptable FFPE tumor tissue sample to assess PD-L1 expression. Samples must be acquired = 6 months prior to first dose of cCRT. If such a sample is not available, a fresh tumor biopsy is required.

Eligibility and Sample Requirements:
Sample age: FFPE tumor sample must be = 6 months old before first cCRT dose.
If not available, a new biopsy is required.
Sample type: FFPE block or recent unstained tissue from CNB, excisional, or incisional biopsy.

Evaluation Criteria:

Initial review:
- H&E stained section to confirm:
- Squamous cell carcinoma diagnosis.
- = 100 viable tumor cells.
- Proper fixation and preparation.
- Not Evaluable If:
- < 100 viable tumor cells.
- Excessive folding/fragmentation.
- Excessive necrosis.

5) For participants with OPC only: documented HPV status by IHC analysis with CINtec Histology p16 Assay. If not available at the time of screening, tumor sample should be collected for testing at the central laboratory.

Informed Consent

6) Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in Screening Part I ICF and Screening Part II ICF. Provision of signed and dated written Part I Screening ICF prior to any mandatory study-specific procedures and analyses is required. Before entering Screening Part II, a separate signed and dated written ICF is required. Participants may enter Screening Part II even if the results of the Screening Part I procedures are still pending. If investigators have confirmation of tumor tissue sample availability (per tissue sample requirements in Inclusion Criteria 4 and 5), Screening Part I and II ICFs may be signed at the same visit.´


Screening Part II

Participants may enter Screening Part II even if the results of the Screening Part I procedures are still pending. Participants are eligible to be randomized to the study only if all of the following Screening Part II inclusion criteria and none of the exclusion criteria apply.

Type of Participant and Disease Characteristics

7) Participants will have completed standard-of-care definitive cCRT with curative intent within 6 weeks (42 days) prior to randomization. Allowed regimens presented in section 1.3 of the CSP.

8) Participants must not have progressed following definitive cCRT therapy with curative intent. Absence of unequivocal recurrence and/or progression including absence of metastatic disease outside of the radiation field will be assessed by the following imaging procedure after completion of cCRT ideally as close as possible to the date of randomization.

(a) Local diseases of the head and neck will be assessed by MRI (preferred) or CT with contrast from mid-orbits to thoracic inlet.

(b) Assessment of disease outside of the head and neck will be assessed by CT with contrast (preferred) of the chest, abdomen including liver, and pelvis as clinically indicated or by MRI if CT with IV contrast is contraindicated.

9) Confirmation of PD-L1 expression from tumor tissue sample per Inclusion Criterion 4 (all participants) by the central laboratory. Participants with unknown PD-L1 expressions prior to randomization are not eligible for the study.

10) For participants with OPC only: confirmation of HPV status by CINtec Histology p16 Assay. If the local test result is not available, then submission of tumor tissue sample per Inclusion Criterion 5 (if applicable) for HPV status testing at the central laboratory. Participants with unknown HPV status (if OPC) prior to randomization are not eligible for the study.

11) World Health Organization/Eastern Cooperative Oncology Group (WHO/ECOG) performance status (PS) of 0 or 1 with no deterioration (that is, WHO/ECOG PS > 1) over the previous 2 weeks prior to baseline at Screening Part II and prior to randomization.

12) Adequate organ and bone marrow function (in the absence of transfusions or growth factor support within 14 days prior to Screening Part II) as defined in section 1.3 of the CSP.

Weight

13) Body weight > 35 kg at screening and at randomization.

Sex and Contraceptive/Barrier Requirements

14) Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Further details will be provided in the CSP.

15) Male participants: Use of a condom plus an additional contraceptive method from enrollment and throughout study until at least 90 days after last dose of study intervention.

16) Female participants:


(a) Females receiving hormone-replacement therapy (HRT) and whose menopausal status is in doubt must use one of the contraception methods outlined for females of childbearing potential (FOCBP) if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to study enrollment.

(b) FOCBP must use one highly effective form of contraception from enrollment, throughout the study, and until at least 90 days after the last dose of study intervention.

(c) All FOCBP must have a negative serum pregnancy test result during the study Screening Part II period.

17) Participants must refrain from breastfeeding and must not donate, or retrieve for their own use, from enrollment throughout the study and until 90 days after the last dose of study intervention.

18) Participants must avoid fathering a child or donating sperm from enrollment through 90 days after the last study dose. Those on infliximab or mycophenolate mofetil must follow local prescribing guidelines for contraception and related precautions

Optional Genetic Research

19) Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.

Other Inclusion Criteria

20) Participants of any race, ethnicity, or gender are eligible for this study.

Additional Tumor Tissue criteria

Confirmation of acceptable FFPE tumor tissue sample to assess PD-L1 expression. Samples must be acquired = 6 months prior to first dose of cCRT. If such a sample is not available, a fresh tumor biopsy is required

Additional criteria (all must apply):

- FFPE sample (block or recently cut unstained tissue)
- Samples should be collected via CNB or as an excisional or incisional tumor biopsy sample.

A specimen may be excluded from the study due to:
- Tumor biopsy must not be taken from previously irradiated lesion.
- Tumor lesions used for fresh biopsies should not be the same lesions.
- Used as RECIST 1.1 target lesions, unless there are no other lesions suitable for biopsy.
- Collection of tumor cells from liquid cytologies, such as ascites or pleural effusion and pericardial fluids, consisting of discohesive tumor cells or scattered tumor cell clusters, separate from or in the absence of intact stroma is not permitted.
- Samples obtained through a fine-needle aspirates (FNA) or via a cryobiopsy are not acceptable.
- Specimens from metastatic bone lesions are typically unacceptable unless there is a significant soft tissue component.

If a sample is deemed Non-Evaluable, another tissue section should be prepared for evaluation. This applies to situations including but not limited to:

- Samples with insufficient tumor content (i.e. less than 100 viable tumor cells)
- Specimens with incorrect histological diagnosis
- The specimen has been not properly fixed and prepared for IHC staining
- Sections are excessively folded and/or fragmented or decalcified.
- The specimen is excessively necrotic.

Re-sectioning or re-biopsy may be requested for specimens evaluated as non-evaluable (e.g., few viable tumor cells, or excessively necrotic) during PD-L1 assessment.

Screening Part I

- Previously irradiated lesions.
- RECIST 1.1 target lesions (unless no alternatives).
- Liquid cytologies (e.g., ascites, pleural fluid).
- Fine-needle aspirates (FNA) or cryobiopsies.
- Bone metastases unless soft tissue only, no bone, and no decalcification.

Tissue Handling and Processing:

- Fixation:
- Ischemia time < 30 minutes.
- Fix in 10% neutral buffered formalin for 24-48 hours.
- No alternative fixatives.
- Embedding:
- Block thickness: 3-4 mm.
- Paraffin temp = 60 Grad C.
- Sectioning:
- Cut into 4-5 µm sections.
- Mount on Superfrost Plus or FLEX IHC slides.
- Bake at 58 +/- 2 Grad C for 1 hour.

Storage and Staining:
- Storage Conditions:
- Dark, 2-8 Grad C or = 25 Grad C.
- Stain within 1 month, or:
- Up to 172 days at 2-8 Grad C.
- Up to 312 days at = 25 Grad C.
- Temperature must not exceed 25 Grad C post-mounting.


Screening Part II

Exclusion Criteria should be assessed at Screening Part II only. Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

1) Histologically/cytologically confirmed head and neck cancer of any other primary anatomic location in the head and neck not specified in the Inclusion Criteria including participants with squamous cell carcinoma of unknown primary or non-squamous histologies (,e.g., nasopharynx or salivary gland). Participants with > 1 primary tumors are not eligible for the study.

2) Participants with any of the following:

(a) Criterion removed as no longer applicable. e.g.,

(b) LA-HNSCC that was resected before definitive cCRT

(c) LA-HNSCC that was treated and is recurrent at the time of screening.

NOTE: For participants who are eligible for the study and who are later deemed to require neck dissection/salvage surgery for local SoC, this procedure can be performed on study. 3) Participants who have received surgery alone or RT alone as definitive local therapy for HNSCC.

4) History of another primary malignancy except for malignancies listed in section 5.2 of CSP.

5) Unresolved toxicities caused by previous anticancer therapy, defined as toxicities (other than alopecia and vitiligo) not yet resolved to NCI CTCAE Version =5.0 Grade 1 or baseline. Note: Participants with NCI CTCAE Version 5.0 = Grade 2 local toxicities due only to RT following completion of cCRT may be eligible if toxicities are manageable, improving, and do not pose any undue safety risk in the investigator’s opinion. Participants with an irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (e.g. hearing loss, neuropathy).

6) As judged by the investigator, any condition that would interfere with evaluation of the study intervention or interpretation of participant safety or study results.

7) Evidence of infections listed in section 5.2 of CSP.

8) As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including, but not limited to, ongoing or active infection, , interstitial lung disease (ILD), serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations, and active bleeding diseases) and/or history of organ transplant or allogeneic stem cell transplant, which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.

9) Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease (,e.g., colitis or Crohn’s disease), diverticulitis (with the exception of diverticulosis), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, pneumonitis (past medical history of ILD, drug-induced ILD, or radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD), etc. The following are exceptions to this criterion:

(a) Participants with vitiligo or alopecia.

(b) Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on HRT.

(c) Any chronic skin condition that does not require systemic therapy.

(d) Participants without active disease in the last 5 years prior to enrollment may be included but only after consultation with the Study Clinical Lead.

(e) Participants with celiac disease controlled by diet alone.

10 Participant meets one or more of the following:

(a) History of QT prolongation is associated with other medications that required discontinuation of that medication.

(b) Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.

(c) History of symptomatic or treatment-requiring arrhythmias (e.g., multifocal PVCs, bigeminy, trigeminy, VT, or uncontrolled AF), or asymptomatic sustained VT. Controlled AF or pacemaker-managed arrhythmias may be allowed at the investigator’s discretion, with cardiologist input recommended.

11) Untreated or progressive central nervous system (CNS) metastatic disease, any leptomeningeal disease, or cord compression.

12) Prior/Concomitant Therapy

- Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines
- Receipt of the last dose of anticancer therapy (CTx and/or or RT) > 6 weeks (42 days) prior to randomization. (or > 8 weeks [56 days] prior to randomization in case of unresolved toxicities due to cCRT.

13) Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are excluded.

14) Any concurrent chemotherapy, RT, investigational, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for noncancer-related conditions (,e.g., insulin for diabetes and HRT) is acceptable. Note: Local treatment of isolated lesions for palliative intent is not acceptable.

15) Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention is excluded. The following are exceptions to this criterion:

- Intranasal, inhaled, and topical steroids, or local steroid injections (,e.g., intraarticular injection)
- Steroids as premedication for hypersensitivity reactions (,e.g., CT scan premedication or premedication for chemotherapy per local standard clinical practice) or a single dose for palliative purpose (,e.g., pain control)

16) Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study. Note: Local surgery of isolated lesions for palliative intent is acceptable.

17) Receipt of live-attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live vaccines while receiving study intervention and up to 30 days after the last dose of study intervention.

Prior/Concurrent Clinical Study Experience

18) Concurrent enrollment in another clinical study, (unless it is an observational [non-interventional] clinical study), or the follow-up period of an interventional study.

19) Participants with a known hypersensitivity to volrustomig or any excipients of the product.

Other Exclusions

20) Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

21) Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

22) Previous enrollment or randomization in the present study.

23) Currently pregnant (confirmed with positive pregnancy test) or breast-feeding, or who are planning to become pregnant.

For more information please refer to the CSP, section 5.0.

For Device clinical performance study inclusion/exclusion criteria, please refer to Appendix G.

Subjects eligible for inclusion in this study must meet all of the following criteria:

1. Subject or legally authorized representative, if applicable, has signed and dated informed consent form (ICF) indicating that the subject (or legally authorized representative, if applicable) has been informed of all the pertinent aspects of the study prior to enrollment and the subject must be willing to comply with all study procedures for the duration of the study.

2. Subject is >18 years of age on the day the ICF is signed.

3. Subject has histologically or cytologically confirmed R or M HNSCC. Eligible primary tumor locations are oral cavity, hypopharynx, larynx or oropharynx (with documented HPV-negative disease if presenting with OPSCC). Note: Primary tumor location of paranasal sinuses and nasopharynx, any histology are excluded.

4. No prior systemic therapy administered in the R or M setting; and completed systemic therapy >6 months prior if given as part of multimodal treatment for locoregionally advanced disease in the adjuvant or definitive setting.

5. Subject is willing to provide archival tumor tissue (a paraffin-embedded tumor tissue block sufficient to obtain 20 sections of 4 to 10 micrometer thickness) or willing to undergo pretreatment biopsy at Screening if archival tissue is insufficient or unavailable.

6. Subject has documentation of HPV-negative disease per central testing performed with Qiagen therascreen HPV Panel RGQ PCR Kit if presenting with OPSCC. Tumor tissue from excisional/incisional or core biopsy (fine needle aspirates and bone biopsies are not acceptable) must be provided for central testing. Archival tumor tissue is acceptable. A fresh tumor biopsy, using a procedure that is safe for the subject on a lesion not previously irradiated (unless lesion progressed) will be required if tumor tissue is not available. Note: To be eligible to participate in this study, subjects with OPSCC must have HPV-negative documentation based on testing performed by a central laboratory.

7. Subject is eligible to receive pembrolizumab as frontline monotherapy with documented tumor PD-L1 CPS =1 (by PD-L1 IHC 22C3 pharmDx assay), determined locally or centrally. If local documentation of PD-L1 is not available, tumor tissue from excisional or core biopsy (fine needle aspirates and bone biopsies are not acceptable) must be
provided for central testing to determine eligibility (see further details regarding archival tissue collection Section
7.10).

8. Subject has measurable disease based on RECIST 1.1 as determined by BICR. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated. Baseline Scan must be transferred to BICR for assessment.

9. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

10. Subject demonstrates adequate organ function, defined as follows:

Hematological
- Absolute neutrophil count (ANC) = 1500/MikroL (1.5 x 10^9/L)
- Platelets = 100,000/MikroL (100 x 10^9/L)
- Hemoglobin = 9 g/dL (90 g/L) or = 5.6 mmol/L. Must be met without packed red blood cell transfusion in the prior 7 days

Renal
- Creatinine clearance (CrCl) measured or calculated per institutional standards (CrCl or glomerular filtration rate [GFR] = 30 mL/min)

Hepatic
- Total serum bilirubin = 1.5 x upper limit of normal (ULN) (except for subjects with documented Gilbert’s syndrome)
- AST (SGOT) and ALT (SGPT) = 2.5 x ULN OR = 5 x ULN for subjects with liver metastases

Coagulation
- INR, PT, PTT, or activated partial thromboplastin time (aPTT) = 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

11. Women of childbearing potential (WOCBP) must have a negative blood pregnancy test within 7 days prior to receiving the first dose of study treatment. A urine pregnancy test can be considered if a blood test is not appropriate.

12. WOCBP should be willing to use highly effective contraception for birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study treatment and are not permitted to donate oocytes during this time. WOCBP are those who have not been surgically sterilized or have not been free from menses for > 1 year (see Section 7.7.1.5).

13. Male subjects should agree to use a condom and to not donate sperm starting with the first dose of study treatment through 90 days after the last dose of study medication (see Section 7.7.1.5).

Subjects meeting any of the following criteria are not eligible for inclusion in this study.

1. Prior systemic therapy in the recurrent or metastatic setting.

2. Disease suitable for local therapy administered with curative intent.

3. Prior treatment with anti-TGFß therapy.

4. Prior therapy with an anti-EGFR antibody (with the exception of radiosensitizing agents and multimodal treatment for locoregionally advanced disease).

5. Prior history of Grade = 2 intolerance or hypersensitivity reaction to anti-EGFR therapy or other murine proteins, or the active substances of either ficerafusp alfa, pembrolizumab, or any of their excipients.

6. Prior (neoadjuvant and/or adjuvant) therapy with an immune checkpoint inhibitors completed within 6 months prior to study treatment initiation.

7. PD (radiologically or pathologically confirmed) <6 months from completion of curative intent systemic therapy for locoregionally advanced HNSCC.

8. Life expectancy of less than 3 months and/or has rapidly progressing disease in the treating investigator's opinion.

9. Known active central nervous system metastases, history of spinal cord compression from tumor involvement, a history of carcinomatous meningitis, or leptomeningeal disease are excluded. Subjects with a history of treated central nervous system metastases (by surgery or radiation therapy) may be eligible if central nervous system metastases have been stable for at least 4 weeks, i.e., without evidence of progression by repeat imaging and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.

10. Subjects who are at higher risk of bleeding including subject with known bleeding diathesis, or have current active major bleeding, or a recent major bleeding episode within 4 weeks prior to enrollment. Note: A major bleeding episode is defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria, which include fatal bleeding, symptomatic bleeding in a critical organ/area (e.g., intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal), hemoglobin drop =2 g/dL, or transfusion of =2 units of blood.

11. Any of the following <6 months before starting study treatment: ST-elevation myocardial infarction, severe/unstable angina, uncontrolled cardiac ventricular arrythmia, coronary/peripheral artery bypass graft or stent, cerebrovascular accident/stroke less than 6 months prior to enrollment or congestive heart failure. Subjects with deep vein thrombosis that are hemodynamically stable can enroll if they are on a stable dose of anticoagulants for at least 3 months.

12. Major surgery (including eye surgery) or palliative radiotherapy < 2 weeks prior to randomization. Subjects must have recovered adequately from any surgery (major or minor) or radiation and/or its complications before randomization.

13. Subject who participated in another clinical study or received treatment with another investigational drug must wait at least 5 half-lives of the treatment received or 4 weeks (whichever is shorter) following prior therapy or at least 4 weeks if half live of the agent received is not known before enrollment.

14. Active autoimmune disease requiring 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.

15. Serious systemic infection (bacterial, viral, or fungal) within 4 weeks before first dose of study treatment, or active systemic infection requiring either hospitalization or parenteral anti-infective therapy within 2 weeks before first dose of study treatment.

16. Known psychiatric, behavioral, or substance abuse disorders that would interfere with cooperation of the study requirements.

17. Subjects with chronic hepatitis B virus (HBV) infection with active disease who meet the criteria for anti-HBV therapy and are not on a suppressive antiviral therapy prior to initiation of study treatment. Subjects who are hepatitis B surface antigen 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 antiviral therapy throughout the study treatment period and follow local guidelines for HBV antiviral therapy post completion of study treatment.

18. Subjects with a known history of hepatitis C virus (HCV) who have not completed curative antiviral treatment or have an HCV viral load above the limit of quantification at Screening. Note: subjects must have completed curative antiviral therapy at least 4 weeks prior to randomization.

19. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). HIV testing is not required unless mandated by local health authority.

20. Receipt of any organ transplantation, including autologous and allogeneic stem cell transplantation, with the exception of transplants that do not require immunosuppression.

21. Known to be diagnosed and/or treated for any other additional malignancy within 2 years prior to randomization with the exception of the following: curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, and curatively resected in situ cervical cancer, and curatively resected in situ breast cancer, and 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. Other exceptions may be considered with the Sponsor’s consultation. The time requirement for no malignancy for 2 years does not apply to the cancer for which a subject is enrolled in the study.

22. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 7 days prior to the first dose of study treatment, except for topical, intranasal, intrabronchial, or ocular steroids. Corticosteroid use as premedication for allergic reactions (e.g., intravenous contrast), or as a prophylactic management of AEs related to the therapies specified in the protocol is allowed. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.

23. Use of a live or live attenuated vaccine within 4 weeks prior to Screening. Note: Administration of killed, recombinant or inactivated vaccines is allowed.

24. Active pregnancy or breastfeeding

Um in die KP aufgenommen zu werden, müssen folgende Einschlusskriterien erfüllt sein:

1. Eine vom Patienten und vom Hauptprüfer/Prüfer eigenhändig datierte und vollständig unterschriebene Einwilligungserklärung liegt vor

2. Patienten mit einem Mindestalter von 18 Jahren

3. Patienten mit einem Karnofsky Index = 70 %

4. Patienten mit einer angenommenen Lebenserwartung von mindestens 12 Monaten

5. Patienten mit soliden Tumoren

6. Patienten, bei denen eine unmodifizierte und in Deutschland zugelassene Chemotherapie mit Taxanen oder Platinderivaten oder deren Kombination mit einer geplanten Therapiedauer von mind. 3 Monaten (Lunarmonate/ 12 Wochen) geplant ist

7. Bei Patientinnen im gebärfähigen Alter liegt ein negativer Schwangerschaftstest vor

Um in die KP aufgenommen zu werden, dürfen folgende Ausschlusskriterien nicht zutreffen:

1. Teilnahme an einer interventionellen Studie (mit einem Prüfpräparat), die zeitgleich er folgt oder innerhalb von 4 Wochen vor Einschluss in diese Studie erfolgt ist

2. Schwangere und stillende Patientinnen oder Patientinnen ohne effektive Kontrazeption (Pearl-Index < 1)

3. Patienten, die innerhalb von 4 Wochen vor Einschluss in diese Studie mit topischen und/oder innerlich verabreichten Arzneimitteln oder Kosmetika, die Blauen Eisenhut (Aconitum napellus), Kampfer (Camphora), ätherisches Lavendelöl (Lavandulae aetheroleum) und/oder Quarz enthalten, behandelt wurden

4. Patienten mit einer bekannten Überempfindlichkeit gegen Kampfer und/oder einen der anderen Inhaltsstoffe von Aconit Schmerzöl sowie Erdnuss oder Soja

5. Patienten, bei denen davon auszugehen ist, dass sie aus sprachlichen, kognitiven bzw. anderen Gründen nicht in der Lage sind, die Bedeutung der klinischen Studie zu erfassen, die dafür notwendige Compliance aufzubringen und/oder die deutschsprachigen Patientenfragebogen und das Patiententagebuch auszufüllen

6. Patienten mit einer geplanten Applikation der Chemotherapie in =4-wöchigen Abständen

7. Patienten mit einer Alkohol-/Drogen-/Medikamentenabhängigkeit

8. Patienten mit bekannten genetischen Dispositionen für Polyneuropathien

9. Patienten mit vorangegangener oder bestehender Polyneuropathie unabhängig von der Ursache

10. Patienten mit vorangegangener oder aktueller neurotoxischer Medikation außerhalb des geplanten Chemotherapie-Protokolls, die einen Einfluss auf den primären Endpunkt hat (nach Ermessen des Prüfers) und vorangegangener Taxan- und/oder Platinderivat-Gabe

11. Patienten mit folgenden bekannten Begleiterkrankungen, die eine Prädisposition für eine CIPN haben: unzureichend substituierte Hypothyreose, Niereninsuffizienz ab Grad 4, Vaskulitis/Kollagenose, unzureichend behandelter Diabetes mellitus

12. Patienten mit aktuell bestehenden und/oder klinisch relevanten Infektionskrankheiten:
HIV, Borreliose, Hepatitis B/C, Herpes-Infektionen

13. Bekanntes Vorliegen eines multiplen Myeloms oder Non-Hodgkin-Lymphoms

14. Bestehende neurologische Erkrankungen Morbus Alzheimer, Multiple Sklerose, Morbus Parkinson und sonstige neurologische Erkrankungen, die nach Ermessen des Prüfarztes eine Beurteilung des primären Endpunkts erschweren oder unmöglich machen

15. Patienten mit Metastasen im zentralen Nervensystem

16. Vorangegangene Amputation von Extremitäten

17. Patienten mit distaler Muskelschwäche und/oder Atrophie

18. Hautläsionen oder andere Befunde im Bereich der Extremitäten, die eine Anwendung des Prüfpräparats unmöglich machen (z. B. Hand-Fuß-Syndrom)

19. Vorliegen einer anderen schwerwiegenden akuten oder chronischen organischen oder psychischen Erkrankung mit starker Beeinträchtigung des Allgemeinbefindens, die eine regelmäßige Studienteilnahme beeinträchtigt oder ausschließt

20. Einnahme von Co-Analgetika wie Gabapentin, Pregabalin, Amitriptylin, Nortriptylin, Clomipramin, Imipramin, Duloxetin 1 Woche vor Studienbeginn (Baseline) und Einnahme während der Studie vor Erreichen von CIPN Grad III

21. Geplante Akupunktur zur Behandlung einer CIPN während der Studie

22. Topische Anwendung von Substanzen wie Lidocain, Capsaicin, Botulinumtoxin, Amitriptylin, Menthol an Händen und/oder Füßen bis 1 Woche vor Studienbeginn (Baseline) und Anwendung während der Studie

23. Elektrotherapie an den Extremitäten bis 1 Woche vor Studienbeginn (Baseline) und während der Studie

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

Each potential participant must satisfy all of the following inclusion criteria to be enrolled in the study.

Age
1. Be =18 years of age (or the legal age of majorityin the jurisdiction in which the study is taking place, whichever is greater).

Type of Participant and Disease Characteristic(s)

2. Have an ECOG performance status of 0 or 1.

3. Criterion modified per Amendment EEA-1.

3.1 Have histologically or cytologically confirmed R/M HNSCC that is considered incurable by local therapies.

- The eligible primary tumor locations are the oral cavity, oropharynx, hypopharynx, or larynx.

- Must not have a primary tumor site of nasopharynx (any histology) or primary tumor of unknown location.

- Must have documented local testing results per local regulations using a 22C3 antibody assayfor PD-L1 status to determine the CPS score within 6 months prior to C1D1; participants must have PD-L1 CPS = 1to be considered eligible. The local test must be performed in accordance with local guidelines using an FDA-approved test or laboratory-developed test that is validated in a CLIA certified laboratory (sites in the US) or an accredited local laboratory (sites outside of the US). In the EU, the local test must be CE-marked or an in-house laboratory-developed testfrom health institutions in the EUin accordance with Article 5(5) of the IVDR2071/746, as amended. Tissue used for CPS testing should be obtained at orafter diagnosis of R/M diseaseand prior to any provision of systemic therapy for R/M disease. Reportdocumenting PD-L1 status must be included in participant records and a de-identified copy submitted to sponsor during the screening period.

- HPV status must be known for participants with primary tumor location in oropharynx via p16 test, HPV DNAtest,or high-risk HPV ISH.Any known p16, HPV DNA,or high-risk HPVISH status of tumor must be negative.

4. Be treatment-naive for systemic therapy in the R/M setting. Systemic therapy which was completed more than 6 months prior to signing consent, if given as part of treatment for locally advanced disease with curative intent, is allowed. The participant must not have had disease progressionwithin 6 months of completion of curativesystemic therapy for locally advanced disease.

- The participant must be treatment-naive to any prior anti-EGFR therapy and anti-MET therapyin any setting.
- The participant may have received anti-PD-1/PD-L1/PD-L2 agents for locally advanced disease with curative intent if given > 12 months prior to enrollment.

5. Have measurable disease according to RECIST v1.1. If only one measurable lesion exists, it may be used for the screening biopsy as long as baseline tumor assessment scans are performed =7 days after the biopsyand if lesion remains acceptable as a target lesion after that time. Tumor lesions situated in a previously irradiated area are considered measurable if progression following radiation has been demonstrated in such lesions.

6. Consent to a screening biopsy or provide archival tissue sample per protocol-defined specifications. Participants must have a screening biopsy within 28 days prior to C1D1 or archival tissue that was obtained within 6 months of diagnosis of R/M disease. Tissue must be submitted prior to C1D1.

Sex and Contraceptive/Barrier Requirements
7. Criterion modified per Amendment EEA-1.

7.1 While on study treatment and for up to 14 months after the last dose of study treatment, a participant must:

a. Not breastfeed or be pregnant.

b. Not donate gametes (ie, eggs or sperm) or freeze for future use for the purposes of assisted reproduction.

c. Wear an external condom.

d. If of childbearing potential, participant must:

- have a negative highly sensitive (eg, beta-human chorionic gonadotropin [Beta-hCG]) serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further pregnancy tests.

- practice at least 1 highly effective method of contraception; if oral contraceptives are used, a barrier method of contraception must also be used.

e. If a participant’s partner is of childbearing potential, the partner must practice a highly effective method of contraception unless the participant is vasectomized.

Participants should consider preservation of gametes prior to study treatment as anticancer treatments may impair fertility.

Informed Consent
8. Must sign an ICF indicating that the participant understands the purpose and procedures required for the study. If the participant is unable to read or write, an impartial witness must be present (which includes reading and explaining all written information) and must date and sign the ICF after oral consent of the participant.Where local regulations require, a separate ICF may be used for the required DNA component of the study.

9. Must be willing and able to adhere to the lifestyle restrictions specified in this protocol.

Any potential participant who meets any of the following criteria will be excluded from participating in the study.

Medical Conditions

1. Has an uncontrolled illness, including but not limited to the following:

a. Diabetes.

b. Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics 1 week prior to starting study treatment]) or diagnosed or suspected viral infection.

c. Active bleeding diathesis (including active bleeding from primary tumor, or recent bleeding within 2 weeks prior to first administration of study treatment requiring medical or surgical intervention).

d. Impaired oxygenation requiring continuous oxygen supplementation.

e. Psychiatric illness/social situation that would limit compliance with study requirements.

f. 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.

g. Participant has had an allogeneic tissue/solid organ transplant.

2. Hasuntreated brain metastasesor history ofknown presence of leptomeningeal disease.

Notes: Participants with definitively, locally treated metastases that are clinically stable and asymptomatic for at least 4 weeks and who are off or receiving low-dose corticosteroid treatment (= 10 mg prednisone or equivalent) for at least 4 weeks prior to study treatment are eligible, provided they havenotused steroids for at least 7days prior to studytreatment.

3. Has a history of (non-infectious) ILD/pneumonitis/pulmonary fibrosis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis/pulmonary fibrosis cannot be ruled out by imaging at screening.

4. Has a history of clinically significant cardiovascular disease including, but not limited to:

a. Diagnosis of deep vein thrombosis or pulmonary embolism within 8weeks prior to the first dose of study treatment or any of the following within 6 months prior to the first dose of study treatment: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non obstructive catheter-associated clots, are not exclusionary.

b. Prolonged QTcF interval > 480 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (eg, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate). Note: Participants with cardiac pacemakers who are clinically stable are eligible.

c. Uncontrolled (persistent) hypertension: systolic blood pressure > 180 mm Hg; diastolic blood pressure > 100 mm Hg.

d. Congestive heart failure defined as New York Heart Association (NYHA) class III, IV or Hospitalization for congestive heart failure (any NYHA class) within 6 months of study enrollment.

e. Pericarditis/clinically significant pericardial effusion.

f. Myocarditis.

5. Renal function:
Have an estimated glomerular filtration rate <50mL/min, based on the MDRD 4-variable formula (Section10.8) during the screening period and on the day of the start of study treatment.

6. Hepatic function:
Participants are excluded if they havethe following lab values:
a. AST = 3 x ULN (= 5 x ULN if liver metastases are present).
b. ALT = 3 x ULN (= 5 x ULN if liver metastases are present).
c. Total bilirubin = 1.5 x ULN: participants with congenital nonhemolytic hyperbilirubinemia such as Gilbert’s syndrome can enroll if conjugated bilirubin is within normal limits.

7. For hematological values, must not have:
a. Hemoglobin < 9g/dL
b. Absolute neutrophil count < 1.5 x 10^9/L
c. Platelets < 100 x 10^9/L

Participant must have adequate organ and bone marrow function as above, without history of red blood cell transfusion, platelet transfusion, use of granulocyte colony stimulating factor (G-CSF)within 7 days priorto the date of the laboratory test.

8. Thyroidfunction laboratory valuesnotwithin the normal range.

Note: If TSH is not within normal limits, the participant may still be eligible if triiodothyronine(either total or free) and free thyroxineare within normal limits.If TSH is above the upper normal limit, a participant may still be eligible if asymptomatic with no hypothyroidism symptoms or on thyroid supplementation.

9. Active hepatitis of infectious origin.

a. Seropositive for hepatitis B: defined by a positive test for hepatitis B surface antigen [HBsAg]. Participants with resolved infection (ie, participants who are HBsAg negative with positive antibodies to total hepatitis B core antigen [HBcAb]) must be screened using RT-PCR measurement of HBV DNA levels. Those who are RT-PCR positive will be excluded. Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by RT-PCR.

b. Known hepatitis C infection or positive serologic testing for hepatitis C virus (anti-HCV)antibody. Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative hepatitis C RNA test is obtained at screening or within 3 months prior to first dose of study treatment.

c. Other clinically active liver disease of infectious origin.

10. Current or chronic history of non-infectious liver disease. This includes (but is not limited to) drug- or alcohol-related liver disease, metabolic dysfunction-associated steatohepatitis, auto-immune hepatitis, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease considered clinically significant by the investigator.

11. Have a prior malignancy (other than the disease under study) in which itsnatural history or treatment is likely to interfere with any study endpoints of safety or the efficacy of the study treatment(s). The occurrence must be reviewed and agreed to with the sponsor’s medical monitor. Refer to Section 10.7for more details.

12. Has known allergies, hypersensitivity, contraindications, or intolerance to excipients of:
a. Amivantamab (refer to the IB, experimental arm)
b. Pembrolizumab (refer to product label)
c. Carboplatin (refer to product label)
d. Cisplatin (refer to product label)
e. 5-FU (refer to product label, control arm); participants with known complete absence of DPD activityare ineligible.Testing for DPD deficiency mustbe performed in accordance with local guidelines.
f. Hyaluronidase

13. Has, or will have, any of the following:
a. An invasive operative procedure with entry into a body cavity, including feeding tube placement and tracheostomy, within 4 weeks or without complete recovery before the first administration of study treatment.
b. Significant traumatic injury within 3 weeks before the start of the first administration of study treatment (all wounds must be fully healed prior to C1D1).
c. Expected major surgery while the investigational agent is being administered or within 6 months after the last dose of study treatment.

Prior/Concomitant Therapy

14. Taken any disallowed therapies including immunosuppressivemedications within 7 days prior to the first administration of study treatment. Refer to Section 6.9.3 for alist of prohibited medications ortherapies.

15. Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade 1 or less prior to the first dose of study treatment (except for alopecia or post radiation skin changes [any grade], Grade = 2 peripheral neuropathy, and Grade = 2 hypothyroidism stable on hormone replacement).

16. Use of live or live attenuated vaccines during study treatment, within 30 days prior to the first dose of study treatment.

(Except for live or live attenuated vaccines, vaccination is allowed per localguidelines, including annual influenza and inactivated SARS-CoV-2 vaccines).

17. Requires prohibited medication that cannot be discontinued, substituted, or temporarily interrupted during the study.

18. Has had radiation therapy within 2 weeks before the first administration of study treatment.

Prior/Concurrent Clinical Study Experience

19. Has used an invasive investigational medical device or received an investigational drug (including investigational vaccines) within 6 weeks before the planned first dose of study treatment, or is currently enrolled in an investigational study.

Has used investigational anti-cancer therapy within 6 months before the planned first dose of study treatment.

HIV Status

20. HIV-positive participants are only eligible if they meet all the following:
a. No detectable viral load (ie, < 50 copies/mL) at screening.
b. CD4+ count > 300 cells/mm3 at screening.
c. No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of screening.
d. Receiving highly active antiretroviral therapy (HAART). Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.

Note: HAART that could interfere with study treatment is excluded (consult the Sponsor for a review of medications prior to enrollment).

Other Exclusions

21. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

NOTE:Investigators must ensure that all study enrollment procedures have been completed during the screening period and eligibility confirmed prior to randomization. If a participant’s clinical
status changes/declines during the screening period, eligibility must be reconfirmed prior to randomization.

- Männliche und weibliche Patienten, die gemäß Leitlinie / Tumorboardempfehlung eine bilaterale Neck Dissection erhalten sollen.
- Alter = 18 Jahre
- Schriftliche Einwilligung nach Informationsgespräch über die Studienteilnahme

- Mentale Retardierung oder Beeinträchtigung der Einwilligungsfähigkeit (vulnerable Personen)
- Patienten*innen, die nach Ansicht des/der Prüfers*in nicht in der Lage sind die Studienuntersuchungen zuverlässig wahrzunehmen
- Geplante Hautresektionen oder Lappenplastiken im Bereich des Wundverschlusses der Neck Dissection