Pembrolizumab in Combination with Chemotherapy for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma, SINERGY Study

Inclusion Criteria

• Have histologically or cytologically-confirmed R/M HNSCC that is considered incurable by local therapies. (Patients with recurrent and/or metastatic disease that would be potentially amenable to curative-intent salvage surgery or re-irradiation but are recommended to first receive systemic therapy ARE eligible for this study. However, in this case, patients must receive at least one ctDNA-guided decision point and at least one on-treatment radiology evaluation prior to initiation of subsequent cancer-specific treatment.)
• Patients should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 3 months prior to signing consent if given as part of multimodal treatment for locally advanced disease is allowed
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Have measurable disease (either primary site and/or nodal disease) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the site. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Hemoglobin >= 9 g/dL
• Platelets >= 100,000/mcL
• Total bilirubin =< 1.5 or direct bilirubin =< upper limit of normal (ULN) with total bilirubin > 1.5
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal or =< 5 in patients with known liver metastases
• Creatinine =< 1.5 x ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above 1.5
• Results for HPV for patients with oropharyngeal primary is required * p16 immunohistochemistry (IHC) is sufficient (p16 IHC interpretation to follow guidelines by Jordan and Lingen et al) * Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo human papillomavirus (HPV) testing by p16 IHC as by convention these tumor locations are assumed to be HPV negative
• Patients must have provided tissue for PD-L1 biomarker analysis from a core or excisional biopsy (preferred). Fine needle aspirate [FNA] is permissible in cases where a core or excisional biopsy is not available for analysis. Repeat samples may be required if adequate tissue is not provided. A newly obtained biopsy (within 90 days prior to start of study treatment) is strongly preferred, but an archival sample is acceptable
• Tissue for Signatera initial test setup: * Formalin-fixed paraffin-embedded (FFPE) tissue required. Natera will provide collection kits, includes paid FedEx envelope for sample return * Tissue requirements: ** Tissue block and 1 hematoxylin and eosin (H&E) slide is preferred, OR ** 10 - 20 unstained slides + 1 H&E slide, OR *** 6 x 10um slides (5 unstained and 1 H&E), or 11 x 5um slides (10 unstained and 1 H&E) *** Unbaked *** > 20% tumor content ** 4-6 cores from core needle biopsies + 1 H&E slide * While signatera assay must be in process at time of enrollment, a result is not anticipated prior to initiation of therapy. A result is anticipated during the first two cycles (6 weeks) of therapy prior to the first decision point (cycle 3 day 1). In the unlikely scenario of an undetectable signatera ctDNA at baseline after patients start therapy within the first 6 weeks of therapy, patients will come off protocol specific therapy and proceed with standard of care
• Patients must sign a study-specific informed consent form prior to study entry. Patients should have the ability to understand and the willingness to sign a written informed consent document
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of study drug
• Women must not be breastfeeding
• Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment
• Men who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s)

Exclusion Criteria

• Has disease that is suitable for local therapy administered with curative intent
• Has progressive disease (PD) within three (3) months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC
• Patients who are receiving any other investigational agents
• Has had radiation therapy (or other non-systemic therapy) within 2 weeks prior to enrollment or patient has not fully recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered treatment * Note: Patients with =< grade 2 neuropathy, =< grade 2 alopecia, are an exception to this criterion and may qualify for the study * Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Active, known, or suspected, autoimmune or inflammatory disorders requiring immunosuppressive therapy, with the exception of low-dose prednisone (=< 10 mg or equivalent). The following are exceptions to these criteria: * Patients with vitiligo or alopecia * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic treatment
• Has a life expectancy of less than 3 months and/or has rapidly progressing disease (e.g. tumor bleeding, uncontrolled tumor pain) in the opinion of the treating investigator
• Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for >= 3 years
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• Has had an allogeneic tissue/solid organ transplant
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Pembrolizumab or other agents used in study
• Has received prior therapy with an anti-PD1 therapy
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Pregnant women are excluded from this study because pembrolizumab is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab, breastfeeding should be discontinued if the mother is treated with pembrolizumab. These potential risks may also apply to other agents used in this study
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pembrolizumab, carboplatin, and paclitaxel. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected). However, if eradicated (no measurable hepatitis [hep] B DNA (viral load) patient is eligible
• Has a history of active infection requiring systemic therapy
• Has received a live vaccine within 28 days of planned start of study therapy * Note: Vaccines for coronavirus disease 2019 (COVID-19) are allowed except for any live vaccine that may be developed