Clinical trial NCT02252042: Pembrolizumab (MK-3475) Versus Standard Treatment for Recurrent or Metastatic Head and Neck Cancer (MK-3475-040/KEYNOTE-040)
Official title: A Phase III Randomized Trial of MK-3475 (Pembrolizumab) Versus Standard Treatment in Subjects With Recurrent or Metastatic Head and Neck Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Head and Neck Squamous Cell Cancer
Keywords: Squamous cell carcinoma
Head and neck carcinoma
Programmed Cell Death-1 (PD1, PD-1),
Programmed Death-Ligand 1 (PDL1, PD-L1)
Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2014-09-29
Enrollment: 495
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a study of pembrolizumab (MK-3475, KEYTRUDA®) versus standard treatment (methotrexate, docetaxel or cetuximab) for the treatment of recurrent or metastatic head and neck squamous cell cancer (HNSCC). Participants will be randomly assigned to receive either pembrolizumab or Investigator's choice of standard treatment. The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment.


Eligibility criteria: Inclusion Criteria:

* Has histologically- or cytologically-confirmed recurrent disease not amenable to curative treatment with local or systemic therapy, or metastatic (disseminated) head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies
* Failure of prior platinum therapy
* Radiographically-measurable disease based on RECIST 1.1
* Tumor tissue available for PD-L1 biomarker analysis
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate organ function
* Female participants of childbearing potential must be willing to use 2 methods of birth control or abstain from heterosexual activity for the course of the study through 120 days after last dose of pembrolizumab or through 120-180 days after the last dose of docetaxel, methotrexate or cetuximab, acccording to local standard of care
* Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after last dose of pembrolizumab or through 120-180 days after the last dose of docetaxel, methotrexate or cetuximab, acccording to local standard of care

Exclusion Criteria

* Disease is suitable for local therapy administered with curative intent
* Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to randomization
* Previously treated with 3 or more systemic regimens given for recurrent and/or metastatic disease
* Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study therapy
* Not recovered from adverse events due to therapy more than 4 weeks earlier
* Prior anti-cancer monoclonal antibody (mAb) therapy within 4 weeks prior to study Day 1, or not recovered from adverse events due to agents administered more than 4 weeks earlier
* Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1
* Diagnosed and/or treated additional malignancy within 5 years of randomization, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin, and/or curatively-resected in situ cervical and/or breast cancers
* Active autoimmune disease that has required systemic therapy in the past 2 years with modifying agents, corticosteroids, or immunosuppressive agents
* Active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Active, non-infectious pneumonitis
* Active infection requiring systemic therapy
* Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial therapy according to local standard of care
* Prior therapy with an anti-PD-1 or anti-PD1-L1 or -L2 therapy or previously participated in a Merck pembrolizumab (MK-3475) trial
* Human immunodeficiency virus (HIV)
* Hepatitis B or C
* Live vaccine within 30 days of planned start of study therapy

Primary outcomes:
measure: Initial Overall Survival (OS) for All Participants
timeFrame: Up to approximately 2 years
measure: Updated Final OS for All Participants
timeFrame: Up to approximately 2 years
Secondary outcomes:
measure: OS for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Expression Defined by ≥1% Combined Positive Score (CPS)(PD-L1 ≥1% CPS)
timeFrame: Up to approximately 2 years
measure: Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants
timeFrame: Up to approximately 2 years
measure: PFS Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
timeFrame: Up to approximately 2 years
measure: Objective Response Rate (ORR) Per RECIST 1.1 in All Participants
timeFrame: Up to approximately 2 years
measure: ORR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
timeFrame: Up to approximately 2 years
measure: Duration of Response (DOR) Per RECIST 1.1 in All Participants
timeFrame: Up to approximately 2 years
measure: DOR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
timeFrame: Up to approximately 2 years
measure: Time to Progression (TTP) Per RECIST 1.1 in All Participants
timeFrame: Up to approximately 2 years
measure: TTP Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
timeFrame: Up to approximately 2 years
measure: PFS Per Modified RECIST in All Participants
timeFrame: Up to approximately 2 years
measure: PFS Per Modified RECIST 1.1 in Participants With PD-L1 ≥1% CPS
timeFrame: Up to approximately 2 years
measure: Number of Participants Who Experienced At Least One Adverse Event (AE) in All Participants
timeFrame: Up to approximately 33 months
measure: Number of Participants Who Experienced At Least One AE in Participants With PD-L1 ≥1% CPS
timeFrame: Up to approximately 33 months
measure: Number of Participants Who Discontinued Study Treatment Due to an AE in All Participants
timeFrame: Up to approximately 30 months
measure: Number of Participants Who Discontinued Study Treatment Due to an AE in Participants With PD-L1 ≥1% CPS
timeFrame: Up to approximately 30 months
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Xin W, Ding H, Fang Q, Zheng X, Tong Y, Xu G, Yang G. Cost-effectiveness of pembrolizumab for treatment of platinum-resistant recurrent or metastatic head and neck squamous cell carcinoma in China: an economic analysis based on a randomised, open-label, phase III trial. BMJ Open. 2020 Dec 18;10(12):e038867. doi: 10.1136/bmjopen-2020-038867.
citation: Emancipator K, Huang L, Aurora-Garg D, Bal T, Cohen EEW, Harrington K, Soulieres D, Le Tourneau C, Licitra L, Burtness B, Swaby R. Comparing programmed death ligand 1 scores for predicting pembrolizumab efficacy in head and neck cancer. Mod Pathol. 2021 Mar;34(3):532-541. doi: 10.1038/s41379-020-00710-9. Epub 2020 Nov 25.
citation: Pai SI, Faivre S, Licitra L, Machiels JP, Vermorken JB, Bruzzi P, Gruenwald V, Giglio RE, Leemans CR, Seiwert TY, Soulieres D. Comparative analysis of the phase III clinical trials of anti-PD1 monotherapy in head and neck squamous cell carcinoma patients (CheckMate 141 and KEYNOTE 040). J Immunother Cancer. 2019 Apr 3;7(1):96. doi: 10.1186/s40425-019-0578-0.
citation: Cohen EEW, Soulieres D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, Soria A, Machiels JP, Mach N, Mehra R, Burtness B, Zhang P, Cheng J, Swaby RF, Harrington KJ; KEYNOTE-040 investigators. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019 Jan 12;393(10167):156-167. doi: 10.1016/S0140-6736(18)31999-8. Epub 2018 Nov 30.
citation: Guo T, Califano JA. Molecular biology and immunology of head and neck cancer. Surg Oncol Clin N Am. 2015 Jul;24(3):397-407. doi: 10.1016/j.soc.2015.03.002. Epub 2015 Apr 20.