Study of Pembrolizumab (MK-3475) in Previously-Treated Participants With Advanced Carcinoma of the Esophagus or Esophagogastric Junction (MK-3475-180/KEYNOTE-180)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02559687
• Collaborator: (none)
• Enrollment: 121
• Arm: 1
• Actual Duration (Months): 70.9

Study Details

Study Description

Brief Summary

In this study participants with advanced/metastatic adenocarcinoma of the esophagus (EAC), squamous cell carcinoma of the esophagus (ESCC), or advanced/metastatic Siewert type I adenocarcinoma of the esophagogastric junction (EGJ), who had been previously treated with two standard therapies, will be treated with pembrolizumab.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Carcinoma; Esophagogastric Junction Carcinoma	Biological: pembrolizumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 121 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Pembrolizumab Monotherapy in Third Line Previously Treated Subjects With Advanced/Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus or Advanced/Metastatic Siewert Type I Adenocarcinoma of the Esophagogastric Junction (KEYNOTE-180)
• Actual Study Start Date: Dec 2, 2015
• Actual Primary Completion Date: Jul 30, 2018
• Actual Study Completion Date: Oct 29, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab 200 mg Participants receive pembrolizumab 200 mg, intravenously (IV), every 3 weeks (Q3W) for up to 35 treatments (approximately 2 years)	Biological: pembrolizumab; IV Q3W; Other Names: MK-3475

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) According to Response Evaluation Criteria for Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) [Up to approximately 28 months]

   ORR was defined as the percentage of participants who have 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 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a CR or PR based on modified RECIST 1.1 was reported.

Secondary Outcome Measures

1. Number of Participants Who Experienced an Adverse Event (AE) [Up to approximately 28 months]

   An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who experienced ≥1 AE was reported.

2. Number of Participants That Discontinued Study Treatment Due to an AE [Up to approximately 24 months]

   An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants that discontinued study treatment due to an AE was reported.

3. Duration of Response (DOR) According to RECIST 1.1 Assessed by BICR [Up to approximately 28 months]

   For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. 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. DOR assessments were based on blinded central imaging review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR was reported.

4. Progression Free Survival (PFS) According to RECIST 1.1 Assessed by BICR [Up to approximately 28 months]

   PFS was defined as the time from first day of study treatment to the first documented PD 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 ≥1 new lesions was also considered PD. PFS as assessed by blinded independent central review per RECIST 1.1 was reported.

5. Overall Survival (OS) [Up to approximately 28 months]

   OS was defined as the time from first day of study treatment 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Life expectancy greater than 3 months

• Histologically-proven advanced/metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ

• Documented objective radiographic or clinical disease progression on two previous lines of standard therapy

• Measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1

• Can provide either a newly obtained or archival tumor tissue sample for intratumoral immune-related testing and for anti-programmed cell death (PD-1)

• Female participants of childbearing potential must be willing to use adequate contraception for the course of the study through 120 days after the last dose of study medication

• Male participants must agree to use adequate contraception starting with the first dose through 120 days after the last dose of study medication

• Adequate organ function

Exclusion Criteria:

• Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study medication

• Has active autoimmune disease that has required systemic treatment within the 2 years prior to the first dose of study medication

• 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 medication

• Known central nervous system (CNS) metastases and/or carcinomatous meningitis

• Prior anti-cancer mAb, chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to first dose of study medication or not recovered from adverse events due to a previously administered agent

• Prior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1), or anti-PD-L2 agent, or previously participated in a Merck pembrolizumab (MK-3475) study

• Has a known additional malignancy that has progressed or required active treatment within the last 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, in-situ cervical cancer, and in-situ or intra-mucosal pharyngeal cancer

• Received a live vaccine within 30 days of the first dose of study medication

• Known history of Human Immunodeficiency Virus (HIV) infection

• Known active Hepatitis B or C

• History of non-infectious pneumonitis that required steroids or current pneumonitis

• Active infection requiring systemic therapy

• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study

• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study medication

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 30, 2017

More Information

Additional Information:

• Merck Oncology Clinical Trials Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02559687
• Other Study ID Numbers: 3475-180; 2015-002427-26; 163188; MK-3475-180; KEYNOTE -180
• First Posted: Sep 24, 2015
• Last Update Posted: Nov 11, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Merck Sharp & Dohme LLC: Programmed Cell Death-1 (PD-1, PD1); Programmed Cell Death-Ligand 1 (PD-L1, PDL1); Programmed Cell Death-Ligand 2 (PD-L2, PDL2)
• Additional relevant MeSH terms: Carcinoma; Esophageal Neoplasms; Pembrolizumab

Study Results

Participant Flow

Pre-assignment Detail	Of 185 participants screened for inclusion, 121 were enrolled and received treatment.

Arm/Group Title	Pembrolizumab 200 mg
Arm/Group Description	Participants receive pembrolizumab 200 mg, intravenously (IV), every 3 weeks (Q3W) for up to 35 treatments (approximately 2 years).
Period Title: Overall Study
STARTED	121
COMPLETED	0
NOT COMPLETED	121

Baseline Characteristics

Arm/Group Title	Pembrolizumab 200 mg
Arm/Group Description	Participants receive pembrolizumab 200 mg IV Q3W for up to 35 treatments (approximately 2 years).
Overall Participants	121
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.5 (10.6)
Sex: Female, Male (Count of Participants)
Female	21 17.4%
Male	100 82.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 1.7%
Not Hispanic or Latino	108 89.3%
Unknown or Not Reported	11 9.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	42 34.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 1.7%
White	71 58.7%
More than one race	0 0%
Unknown or Not Reported	6 5%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR) According to Response Evaluation Criteria for Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR)
Description	ORR was defined as the percentage of participants who have 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 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a CR or PR based on modified RECIST 1.1 was reported.
Time Frame	Up to approximately 28 months

Outcome Measure Data

Analysis Population Description

All allocated participants who received at least 1 dose of study treatment.

Arm/Group Title	Pembrolizumab 200 mg
Arm/Group Description	Participants receive pembrolizumab 200 mg IV Q3W for up to 35 treatments (approximately 2 years).
Measure Participants	121
Number (95% Confidence Interval) [percentage of participants]	9.9 8.2%

2. Secondary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who experienced ≥1 AE was reported.
Time Frame	Up to approximately 28 months

Outcome Measure Data

Analysis Population Description

All allocated participants who received at least 1 dose of study treatment.

Arm/Group Title	Pembrolizumab 200 mg
Arm/Group Description	Participants receive pembrolizumab 200 mg IV Q3W for up to 35 treatments (approximately 2 years).
Measure Participants	121
Count of Participants [Participants]	116 95.9%

3. Secondary Outcome

Title	Number of Participants That Discontinued Study Treatment Due to an AE
Description	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants that discontinued study treatment due to an AE was reported.
Time Frame	Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

All allocated participants who received at least 1 dose of study treatment.

Arm/Group Title	Pembrolizumab 200 mg
Arm/Group Description	Participants receive pembrolizumab 200 mg IV Q3W for up to 35 treatments (approximately 2 years).
Measure Participants	121
Count of Participants [Participants]	13 10.7%

4. Secondary Outcome

Title	Duration of Response (DOR) According to RECIST 1.1 Assessed by BICR
Description	For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. 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. DOR assessments were based on blinded central imaging review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR was reported.
Time Frame	Up to approximately 28 months

Outcome Measure Data

Analysis Population Description

All allocated participants who received at least 1 dose of study treatment and who experienced a confirmed CR or confirmed PR.

Arm/Group Title	Pembrolizumab 200 mg
Arm/Group Description	Participants receive pembrolizumab 200 mg IV Q3W for up to 35 treatments (approximately 2 years).
Measure Participants	12
Median (Full Range) [Months]	NA

5. Secondary Outcome

Title	Progression Free Survival (PFS) According to RECIST 1.1 Assessed by BICR
Description	PFS was defined as the time from first day of study treatment to the first documented PD 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 ≥1 new lesions was also considered PD. PFS as assessed by blinded independent central review per RECIST 1.1 was reported.
Time Frame	Up to approximately 28 months

Outcome Measure Data

Analysis Population Description

All allocated participants who received at least 1 dose of study treatment.

Arm/Group Title	Pembrolizumab 200 mg
Arm/Group Description	Participants receive pembrolizumab 200 mg IV Q3W for up to 35 treatments (approximately 2 years).
Measure Participants	121
Median (95% Confidence Interval) [Months]	2.0

6. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from first day of study treatment 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.
Time Frame	Up to approximately 28 months

Outcome Measure Data

Analysis Population Description

All allocated participants who received at least 1 dose of study treatment.

Arm/Group Title	Pembrolizumab 200 mg
Arm/Group Description	Participants receive pembrolizumab 200 mg IV Q3W for up to 35 treatments (approximately 2 years).
Measure Participants	121
Median (95% Confidence Interval) [Months]	5.8

Adverse Events

Time Frame	Up to approximately 28 months
Adverse Event Reporting Description	All-Cause Mortality was reported for all allocated participants. Serious AEs and Other AEs were reported for all allocated participants who received at least 1 dose of study treatment. Per protocol, disease progression of cancer on study was not considered an AE unless considered related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.
Arm/Group Title	Pembrolizumab 200 mg
Arm/Group Description	Participants receive pembrolizumab 200 mg IV Q3W for up to 35 treatments (approximately 2 years).
All Cause Mortality
	Pembrolizumab 200 mg
	Affected / at Risk (%)	# Events
Total	107/121 (88.4%)
Serious Adverse Events
	Pembrolizumab 200 mg
	Affected / at Risk (%)	# Events
Total	47/121 (38.8%)
Cardiac disorders
Atrial fibrillation	2/121 (1.7%)	2
Atrial flutter	1/121 (0.8%)	1
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula	1/121 (0.8%)	1
Endocrine disorders
Hypopituitarism	2/121 (1.7%)	2
Inappropriate antidiuretic hormone secretion	1/121 (0.8%)	1
Gastrointestinal disorders
Abdominal pain upper	1/121 (0.8%)	1
Diarrhoea	1/121 (0.8%)	2
Gastrointestinal haemorrhage	1/121 (0.8%)	1
Haematochezia	1/121 (0.8%)	1
Intestinal pseudo-obstruction	1/121 (0.8%)	1
Melaena	1/121 (0.8%)	1
Nausea	1/121 (0.8%)	1
Odynophagia	1/121 (0.8%)	1
Oesophageal stenosis	2/121 (1.7%)	2
Pancreatitis	1/121 (0.8%)	1
Small intestinal obstruction	1/121 (0.8%)	1
Vomiting	1/121 (0.8%)	1
General disorders
Malaise	1/121 (0.8%)	1
Pyrexia	1/121 (0.8%)	1
Infections and infestations
Cellulitis	1/121 (0.8%)	1
Herpes zoster	1/121 (0.8%)	1
Lung infection	3/121 (2.5%)	3
Pneumonia	13/121 (10.7%)	14
Sepsis	1/121 (0.8%)	1
Injury, poisoning and procedural complications
Infusion related reaction	1/121 (0.8%)	1
Limb injury	1/121 (0.8%)	1
Pubis fracture	1/121 (0.8%)	1
Metabolism and nutrition disorders
Decreased appetite	1/121 (0.8%)	1
Diabetic ketoacidosis	2/121 (1.7%)	2
Failure to thrive	1/121 (0.8%)	1
Hypercalcaemia	1/121 (0.8%)	1
Malnutrition	1/121 (0.8%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/121 (0.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour necrosis	1/121 (0.8%)	1
Nervous system disorders
Cerebrovascular accident	1/121 (0.8%)	1
Psychiatric disorders
Anxiety	1/121 (0.8%)	1
Delirium	2/121 (1.7%)	2
Renal and urinary disorders
Acute kidney injury	4/121 (3.3%)	4
Nephritis	1/121 (0.8%)	1
Urinary retention	1/121 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
Choking	1/121 (0.8%)	1
Chronic obstructive pulmonary disease	1/121 (0.8%)	1
Dyspnoea	1/121 (0.8%)	1
Pneumonia aspiration	5/121 (4.1%)	5
Pneumonitis	3/121 (2.5%)	3
Pneumothorax	1/121 (0.8%)	1
Pulmonary embolism	1/121 (0.8%)	1
Vascular disorders
Deep vein thrombosis	1/121 (0.8%)	1
Hypotension	1/121 (0.8%)	1
Other (Not Including Serious) Adverse Events
	Pembrolizumab 200 mg
	Affected / at Risk (%)	# Events
Total	104/121 (86%)
Blood and lymphatic system disorders
Anaemia	18/121 (14.9%)	22
Endocrine disorders
Hypothyroidism	11/121 (9.1%)	13
Gastrointestinal disorders
Abdominal pain	9/121 (7.4%)	9
Constipation	23/121 (19%)	24
Diarrhoea	18/121 (14.9%)	22
Dry mouth	7/121 (5.8%)	7
Dysphagia	8/121 (6.6%)	8
Nausea	22/121 (18.2%)	26
Vomiting	19/121 (15.7%)	25
General disorders
Asthenia	9/121 (7.4%)	10
Fatigue	34/121 (28.1%)	37
Oedema peripheral	10/121 (8.3%)	11
Pyrexia	9/121 (7.4%)	14
Investigations
Alanine aminotransferase increased	12/121 (9.9%)	13
Aspartate aminotransferase increased	13/121 (10.7%)	14
Blood alkaline phosphatase increased	10/121 (8.3%)	11
Blood bilirubin increased	9/121 (7.4%)	9
Weight decreased	7/121 (5.8%)	8
Metabolism and nutrition disorders
Decreased appetite	23/121 (19%)	23
Hypokalaemia	7/121 (5.8%)	10
Hyponatraemia	7/121 (5.8%)	8
Musculoskeletal and connective tissue disorders
Back pain	12/121 (9.9%)	13
Myalgia	8/121 (6.6%)	8
Nervous system disorders
Neuropathy peripheral	7/121 (5.8%)	7
Psychiatric disorders
Insomnia	10/121 (8.3%)	10
Respiratory, thoracic and mediastinal disorders
Cough	24/121 (19.8%)	26
Dyspnoea	16/121 (13.2%)	19
Skin and subcutaneous tissue disorders
Pruritus	13/121 (10.7%)	13
Rash	10/121 (8.3%)	13

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.