A Study of Pembrolizumab (MK-3475) Plus Platinum and Gemcitabine as First Line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (PIPER)

Inclusion Criteria:

1. Male/female participants who are at least 18 years of age on the day of signinginformed consent with histologically confirmed diagnosis of R/M HNSCC that isconsidered incurable by local therapies will be enrolled in this study:

• Subject may not have had prior systemic therapy administered in the recurrentor metastatic setting. Systemic therapy which was completed more than 6 monthsprior to signing consent if given as part of multimodal treatment for locallyadvanced disease is allowed.

• The eligible primary tumour locations are oropharynx, oral cavity, hypopharynx,and larynx.

• Subject may not have a primary tumour location site of nasopharynx (anyhistology).

2. A male participant must agree to use a contraception as detailed in Appendix 3:Contraceptive Guidance and Pregnancy Testing of this protocol starting with thefirst dose of study treatment through the treatment period and for at least 180 daysafter the last dose of study treatment and refrain from donating sperm during thisperiod.

3. A female participant is eligible to participate if she is not pregnant (see Appendix 3: Contraceptive Guidance and Pregnancy Testing), not breastfeeding, and at leastone of the following conditions applies:

4. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3:Contraceptive Guidance and Pregnancy Testing OR

5. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3:Contraceptive Guidance and Pregnancy Testingduring the treatment period and forat least 180 days after the last dose of study treatment.

6. The participant (or legally acceptable representative if applicable) willing andable to provides written informed consent for the trial. The participant may alsoprovide consent for Future Biomedical Research. However, the subject may participatein the main trial without participating in Future Biomedical Research.

7. Have measurable disease based on RECIST 1.1. Lesions situated in a previouslyirradiated area are considered measurable if progression has been demonstrated insuch lesions.

8. Archival or fresh tumor tissues must be available for evaluating relevantbiomarkers. Newly obtained core needle or excisional biopsy of a tumor lesion notpreviously irradiated is preferred to archived tissue. If newly obtained samplescannot be obtained due to inaccessibility or patient safety concern, submission ofparaffin block or formalin-fixed, paraffin embedded (FFPE) slides of up to 3 yearsprior to trial enrolment are acceptable (15 unstained slides of 5 microns inthickness). Refer to Section 6.1.5 for complete information on the tissue samplecollection.

9. 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 studyintervention.

10. Have adequate organ function as defined in the following table (Table 3). Specimensmust be collected within 10 days prior to the start of study intervention.

• Absolute neutrophil count (ANC) ≥1500/µL

• Platelets ≥100 000/µL

• Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

• Creatinine ≤1.5 × ULN

• Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with totalbilirubin levels >1.5 × ULN

• AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with livermetastases)

• International normalized ratio (INR) OR prothrombin time (PT), Activatedpartial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receivinganticoagulant therapy as long as PT or aPTT is within therapeutic range ofintended use of anticoagulants

Exclusion Criteria:

1. Has disease that is suitable for local therapy administered with curative intent.

2. Has progressive disease within six months of completion of curatively intendedtreatment for locoregionally advanced HNSCC.

3. Patient with an expected life expectancy of less than 3 months.

4. A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatmentallocation (see Appendix 4). If the urine test is positive or cannot be confirmed asnegative, a serum pregnancy test will be required.

5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or antiPDL2 agent or withan agent directed to another stimulatory or co-inhibitory T-cell receptor (eg,CTLA-4, OX40, CD137).

6. Has received prior systemic anti-cancer therapy including investigational agentswithin 4 weeks [could consider shorter interval for kinase inhibitors or other shorthalf-life drugs] prior to start of study treatment. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormonereplacement may be eligible Note: If the participant had major surgery, theparticipant must have recovered adequately from the procedure and/or anycomplications from the surgery prior to starting study intervention.

7. Has received prior radiotherapy within 2 weeks of start of study intervention.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

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

9. Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study intervention. Note: Participants who have entered the follow-up phase of an investigational studymay participate as long as it has been 4 weeks after the last dose of the previousinvestigational agent.

10. 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 ofimmunosuppressive therapy within 7 days prior to the first dose of study drug.

11. Has a known additional malignancy that is progressing or has required activetreatment within the past 5 years. Participants with basal cell carcinoma of theskin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breastcarcinoma, cervical cancer in situ) that have undergone potentially curative therapyare not excluded.

12. Has known active CNS metastases and/or carcinomatous meningitis. Participants withpreviously treated brain metastases may participate provided they are radiologicallystable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening),clinically stable and without requirement of steroid treatment for at least 14 daysprior to first dose of study intervention. This exception does not includecarcinomatous meningitis which is excluded regardless of clinical stability.

13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of itsexcipients.

14. Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment and is allowed.

15. Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

16. Has an active infection requiring systemic therapy.

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

18. 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] isdetected) infection. Note: no testing for Hepatitis B and Hepatitis C is requiredunless mandated by local health authority.

19. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with theparticipant's participation for the full duration of the study, or is not in thebest interest of the participant to participate, in the opinion of the treatinginvestigator.

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

21. Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment.

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