NCT02252042

Pembrolizumab (MK-3475) Versus Standard Treatment for Recurrent or Metastatic Head and Neck Cancer (MK-3475-040/KEYNOTE-040)

Completed Phase 3 Results posted Last updated 17 July 2023

What this trial tests

Phase 3 trial testing Pembrolizumab in Head and Neck Squamous Cell Cancer in 495 participants. Completed in 15 August 2022.

Timeline

17 November 2014

Primary endpoint
15 May 2017

15 August 2022

Quick facts

Lead sponsor	Merck Sharp & Dohme LLC
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	495
Start date	17 November 2014
Primary completion	15 May 2017
Estimated completion	15 August 2022

Drugs / interventions tested

• Pembrolizumab (pembrolizumab) — full drug profile →
• Methotrexate — full drug profile →
• Docetaxel (Docetaxel) — full drug profile →
• Cetuximab (cetuximab) — full drug profile →

Conditions studied

• Head and Neck Squamous Cell Cancer — all drugs for Head and Neck Squamous Cell Cancer →

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

18 and older, any sex, with Head and Neck Squamous Cell Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Initial Overall Survival (OS) for All Participants Primary · Up to approximately 2 years

OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. The OS for all participants is presented. These initial OS results are based on a data cutoff date of 15-May-2017 with a database lock date of 04-Jun-2017. At the time of the database lock of 04-Jun-2017, there was incomplete collection of survival data for 12 participants.

Group	Value	95% CI
Pembrolizumab	8.4	6.5 – 9.4
Standard Treatment	7.1	5.9 – 8.1

Updated Final OS for All Participants Primary · Up to approximately 2 years

OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. The updated OS for all participants is presented. These OS results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.

Group	Value	95% CI
Pembrolizumab	8.4	6.4 – 9.4
Standard Treatment	6.9	5.9 – 8.0

OS for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Expression Defined by ≥1% Combined Positive Score (CPS)(PD-L1 ≥1% CPS) Secondary · Up to approximately 2 years

OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The OS for all participants with PD-L1 expression ≥1% CPS was presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.

Group	Value	95% CI
Pembrolizumab	8.7	6.9 – 11.4
Standard Treatment	7.1	5.7 – 8.3

Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants Secondary · Up to approximately 2 years

PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The PFS per RECIST 1.1 for all participants is presented. These efficacy re

Group	Value	95% CI
Pembrolizumab	2.1	2.1 – 2.3
Standard Treatment	2.3	2.1 – 2.8

PFS Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS Secondary · Up to approximately 2 years

PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The PFS per RECIST 1.1 for all participants with PD-L1 expression ≥1% CPS i

Group	Value	95% CI
Pembrolizumab	2.2	2.1 – 3.0
Standard Treatment	2.3	2.1 – 3.0

Objective Response Rate (ORR) Per RECIST 1.1 in All Participants Secondary · Up to approximately 2 years

ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based on blinded central imaging vendor review with or without confirmation. The ORR per RECIST 1.1 for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.

Group	Value	95% CI
Pembrolizumab	14.6	10.4 – 19.6
Standard Treatment	10.1	6.6 – 14.5

ORR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS Secondary · Up to approximately 2 years

ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1 based on blinded central imaging vendor review with or without confirmation. The ORR per RECIST 1.1 for all participants with PD-L1 expression ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-201

Group	Value	95% CI
Pembrolizumab	17.3	12.3 – 23.4
Standard Treatment	9.9	6.1 – 15.1

Duration of Response (DOR) Per RECIST 1.1 in All Participants Secondary · Up to approximately 2 years

For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as the time from first documented evidence of a confirmed CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. DOR assessments we

Group	Value	95% CI
Pembrolizumab	18.4	2.7 – 18.4
Standard Treatment	5.0	1.4 – 18.8

DOR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS Secondary · Up to approximately 2 years

For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as the time from first documented evidence of a confirmed CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. DOR assessments we

Group	Value	95% CI
Pembrolizumab	18.4	2.7 – 18.4
Standard Treatment	9.6	1.4 – 18.8

Time to Progression (TTP) Per RECIST 1.1 in All Participants Secondary · Up to approximately 2 years

TTP was defined as the time from randomization to the first documented disease progression based on assessments by the blinded central imaging vendor review per RECIST 1.1. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The TTP per RECIST 1.1 for all participants is presented. These efficacy results were reported after complet

Group	Value	95% CI
Pembrolizumab	2.2	2.1 – 3.3
Standard Treatment	2.2	2.1 – 3.4

TTP Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS Secondary · Up to approximately 2 years

TTP was defined as the time from randomization to the first documented disease progression based on assessments by the blinded central imaging vendor review per RECIST 1.1. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The TTP per RECIST 1.1 for all participants with PD-L1 ≥1% CPS is presented. These efficacy results were rep

Group	Value	95% CI
Pembrolizumab	2.7	2.1 – 3.5
Standard Treatment	2.3	2.1 – 3.4

PFS Per Modified RECIST in All Participants Secondary · Up to approximately 2 years

PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. Modified RECIST is similar to RECIST 1.1 with the exception that a confirmation assessment of PD (\>4 weeks after

Group	Value	95% CI
Pembrolizumab	3.5	3.1 – 4.4
Standard Treatment	4.8	4.1 – 5.7

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to approximately 92 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Pembrolizumab First Course

Serious: 110/246 (45%)

Deaths: 228/247

Standard Treatment First Course

Serious: 92/234 (39%)

Deaths: 243/248

Pembrolizumab Second Course

Serious: 0/2 (0%)

Deaths: 2/2

Serious adverse events (150 terms)

Reaction	System	Pembrolizumab First Course	Standard Treatment First C…	Pembrolizumab Second Course
Pneumonia	Infections and infestations	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—
Tumour haemorrhage	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Hypercalcaemia	Metabolism and nutrition disorders	—	—	—
Pneumonia aspiration	Infections and infestations	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Death	General disorders	—	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—
Mouth haemorrhage	Gastrointestinal disorders	—	—	—
Sepsis	Infections and infestations	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Hypercalcaemia of malignancy	Endocrine disorders	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—
Pyrexia	General disorders	—	—	—
Cellulitis	Infections and infestations	—	—	—
Neutrophil count decreased	Investigations	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—
Malaise	General disorders	—	—	—
Clostridium difficile colitis	Infections and infestations	—	—	—
Lower respiratory tract infection bacterial	Infections and infestations	—	—	—
Oral candidiasis	Infections and infestations	—	—	—

Other adverse events (42 terms — click to expand)

Reaction	System	Pembrolizumab First Course	Standard Treatment First C…	Pembrolizumab Second Course
Fatigue	General disorders	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Asthenia	General disorders	—	—	—
Hypothyroidism	Endocrine disorders	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—
Mucosal inflammation	General disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—
Pyrexia	General disorders	—	—	—
Weight decreased	Investigations	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Neutrophil count decreased	Investigations	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—
Dermatitis acneiform	Skin and subcutaneous tissue disorders	—	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—
Hypophosphataemia	Metabolism and nutrition disorders	—	—	—
Productive cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Hypercalcaemia	Metabolism and nutrition disorders	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Lymphocyte count decreased	Investigations	—	—	—
Platelet count decreased	Investigations	—	—	—
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Anxiety	Psychiatric disorders	—	—	—
Haemoptysis	Respiratory, thoracic and mediastinal disorders	—	—	—

Most-reported serious reactions: Pneumonia, Febrile neutropenia, Tumour haemorrhage, Hypercalcaemia, Pneumonia aspiration, Anaemia, Diarrhoea, Death.

Data from ClinicalTrials.gov NCT02252042 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Immune checkpoint inhibitors: recent progress and potential biomarkers.
   Darvin P, Toor SM, Sasidharan Nair V, Elkord E. · · 2018 · cited 1495× · PMID 30546008 · DOI 10.1038/s12276-018-0191-1
2. 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.
   Cohen EEW, Soulières D, Le Tourneau C, Dinis J, et al · · 2019 · cited 1234× · PMID 30509740 · DOI 10.1016/s0140-6736(18)31999-8
3. Immunology and Immunotherapy of Head and Neck Cancer.
   Ferris RL. · · 2015 · cited 515× · PMID 26351330 · DOI 10.1200/jco.2015.61.1509
4. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends.
   Sun Q, Hong Z, Zhang C, Wang L, et al · · 2023 · cited 387× · PMID 37635168 · DOI 10.1038/s41392-023-01522-4
5. Implications of the tumor immune microenvironment for staging and therapeutics.
   Taube JM, Galon J, Sholl LM, Rodig SJ, et al · · 2018 · cited 277× · PMID 29192647 · DOI 10.1038/modpathol.2017.156
6. PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients.
   Kim HR, Ha SJ, Hong MH, Heo SJ, et al · · 2016 · cited 207× · PMID 27841362 · DOI 10.1038/srep36956
7. The Evolving Role of Immune Checkpoint Inhibitors in Cancer Treatment.
   Pennock GK, Chow LQ. · · 2015 · cited 172× · PMID 26069281 · DOI 10.1634/theoncologist.2014-0422
8. FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy.
   Larkins E, Blumenthal GM, Yuan W, He K, et al · · 2017 · cited 167× · PMID 28533473 · DOI 10.1634/theoncologist.2016-0496