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Carcinoma, Squamous Cell

Head and Neck Neoplasms

Squamous Cell Carcinoma of Head and Neck

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Neoplasms, Squamous Cell

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Pembrolizumab

Cisplatin

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Immune Checkpoint Inhibitors

Participants receive a priming dose of pembrolizumab before initiation of CRT (either accelerated or standard fractionation radiotherapy regimen). During CRT, participants receive 2 doses of pembrolizumab and up to 3 cycles of Cisplatin (2 cycles during accelerated and 3 cycles during standard fractionation radiotherapy). Participants also receive up to an additional 14 cycles of pembrolizumab alone as maintenance therapy for a total of 17 cycles of pembrolizumab. If cisplatin and/or radiation therapy is discontinued, the participant may continue on treatment with pembrolizumab.

Participants receive placebo before initiation of CRT (either accelerated or standard fractionation radiotherapy regimen). During CRT, participants receive 2 doses of placebo and up to 3 cycles of Cisplatin (2 cycles during accelerated and 3 cycles during standard fractionation radiotherapy). Participants also receive up to an additional 14 cycles of placebo alone for a total of 17 cycles of placebo. If cisplatin and/or radiation therapy is discontinued, the participant may continue on treatment with placebo.

Administered as an intravenous (IV) infusion every 3 weeks (Q3W)

Normal saline or dextrose solution administered as an IV infusion Q3W

Placebo

100 mg/m\^2 administered as an IV infusion Q3W

70 Gray (Gy) given in 35 fractions over 6 weeks

Accelerated Fractionation (AFX) Radiotherapy

Standard Fractionation (SFX) Radiotherapy

Medical Director

The purpose of this study is to determine the efficacy and safety of pembrolizumab given concomitantly with chemoradiation (CRT) and as maintenance therapy versus placebo plus CRT in participants with locally advanced head and neck squamous cell carcinoma (LA HNSCC). The primary hypothesis is that pembrolizumab in combination with CRT is superior to placebo in combination with CRT with respect to event-free survival (EFS).

Study of Pembrolizumab (MK-3475) or Placebo With Chemoradiation in Participants With Locally Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-412/KEYNOTE-412)

A Randomized Phase III Study of Pembrolizumab Given Concomitantly With Chemoradiation and as Maintenance Therapy Versus Chemoradiation Alone in Subjects With Locally Advanced Head and Neck Squamous Cell Carcinoma (KEYNOTE-412)

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

EFS is the time from date of randomization to the date of first record of any of the following events: death due to any cause; progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR) or biopsy as indicated for locoregional progression or recurrence or distant metastasis. As well as the first record of the following types of surgery: salvage surgery for persistent or residual disease at the primary tumor site requiring surgical removal when invasive cancer is present on final pathology; neck dissection or surgery (performed for clinical or radiological disease progression per RECIST 1.1) ≤ 20 weeks from end of CRT when invasive cancer is present; or neck dissection or surgery \>20 weeks from end of CRT when invasive cancer is present. From product-limit (Kaplan-Meier) method for censored data.

OS is the time from randomization to death due to any cause, from product-limit (Kaplan-Meier) method for censored data. The hypothesis was that pembrolizumab in combination with CRT is superior to placebo in combination with CRT; but based on the protocol, because the statistical criterion for success in the primary EFS hypothesis was not met, the OS hypothesis was not tested

An AE is any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. An AE is any sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy.

The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) contains 30 items and measures five functional dimensions (physical, role, emotional, cognitive and social), three symptom items (fatigue, nausea/vomiting, and pain), six single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health and QoL scale. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100, so that a higher score indicates a better overall GHS. A change from baseline of 10 points on the 100-point EORTC QLQ-C30 scale is considered as clinically relevant. Based on a constrained longitudinal data analysis (cLDA) model with the patient reported outcomes (PRO) scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of human papilloma virus (HPV) status and overall cancer stage.

EORTC QLQ Head and Neck Questionnaire (H\&N35) consists of 7 multi-item scales (pain in the mouth, problems with swallowing, senses, speech, social eating, social contact, and sexuality), Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Change from baseline in swallowing, speech, and pain symptoms was measured. A change from baseline of 10 points on the 100-point EORTC QLQ-H\&N35 is considered as clinically relevant. Based on a cLDA model with the PRO scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of HPV status and overall cancer stage.

Participant responded to 5 questions from the EORTC QLQ-C30 about their physical functioning scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores were standardized, so that scores range from 0 to 100, where a higher score indicates a better quality of life. A change from baseline of 10 points on the 100-point scale is considered as clinically relevant. Based on a cLDA model with the PRO scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of HPV status and overall cancer stage.

Merck Sharp & Dohme LLC

The population analyzed for all-cause mortality consisted of all randomized participants. The population for AEs consisted of all allocated participants who received ≥1 dose of study drug. Per protocol disease progression of cancer was not considered an AE unless related to study drug. Therefore the following AE preferred terms not related to the drug were excluded: Neoplasm progression, Malignant neoplasm progression and Disease progression.

Participants received a priming dose of pembrolizumab before initiating CRT (either accelerated or standard fractionation radiotherapy regimen). During CRT, participants received 2 doses of pembrolizumab and up to 3 cycles of Cisplatin (2 cycles during accelerated and 3 cycles during standard fractionation radiotherapy). Participants also received up to an additional 14 cycles of pembrolizumab alone as maintenance therapy for a total of 17 cycles of pembrolizumab. If cisplatin and/or radiation therapy was discontinued, the participant may continue on treatment with pembrolizumab.

Pembrolizumab + CRT Followed by Pembrolizumab

Participants received placebo before initiation of CRT (either accelerated or standard fractionation radiotherapy regimen). During CRT, participants received 2 doses of placebo and up to 3 cycles of Cisplatin (2 cycles during accelerated and 3 cycles during standard fractionation radiotherapy). Participants also received up to an additional 14 cycles of placebo alone for a total of 17 cycles of placebo. If cisplatin and/or radiation therapy was discontinued, the participant may continue on treatment with placebo.

Placebo + CRT Followed by Placebo

Pembrolizumab + Cisplatin + CRT

Placebo + Cisplatin + CRT

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Senior Vice President, Global Clinical Development

Based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by HPV status and overall cancer stage. Hypothesis: Pembrolizumab in combination with CRT is superior to placebo in combination with CRT.

All randomized participants based on the treatment group to which they were randomized.

Event-free Survival (EFS)

Overall Survival (OS)

All randomized participants who received at least one dose of study treatment.

Number of Participants With Adverse Events (AEs)

Number of Participants Discontinuing Study Drug Due to an AE

Based on a cLDA model with the PRO scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of HPV status and overall cancer stage.

Participants with at least one PRO assessment available for this specific endpoint and who had received at least 1 dose of study intervention based on in the treatment group to which they were randomized.

Spots Global Cancer Trial Database for accelerated fractionation (afx) radiotherapy