Study of Pembrolizumab (MK-3475) in Participants With Advanced Non-small Cell Lung Cancer (MK-3475-025/KEYNOTE-025)

An Open-label, Non-randomized, Multi-center Phase Ib Study of MK-3475 in Subjects With PD-L1 Positive Advanced Non-small Cell Lung Cancer

This study is being done to evaluate the safety and efficacy of pembrolizumab (MK-3475) in participants with advanced non-small cell lung cancer (NSCLC) tumors that are positive for programmed cell death ligand 1 (PD-L1): the hypothesis is that treatment with pembrolizumab will result in a clinically meaningful Overall Response Rate (ORR).

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Biological: Pembrolizumab

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) that is PD-L1 positive per central laboratory review
• At least one measurable lesion
• Radiographic progression of NSCLC after treatment with a platinum-containing doublet for Stage IIIB/IV or recurrent disease
• Eastern Cooperative Oncology Group (ECOG) Performance Scale 0 or 1
• Adequate organ function

Exclusion Criteria:

• Systemic cytotoxic chemotherapy, biological therapy, or major surgery within 3 weeks of the first dose of trial treatment
• Systemic steroid therapy within 3 days prior to the first dose of trial treatment or any other form of immunosuppressive medication
• Expected to require any other form of systemic or localized antineoplastic therapy while on trial
• History of prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cancer
• Active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Active autoimmune disease or documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
• Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody
• Concurrent or past history of interstitial lung disease
• Pregnant or breast-feeding, or expecting to conceive or father children within the projected duration of the study, starting with screening visit through 120 days after the last dose of pembrolizumab

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab 10 mg/kg; Participants receive pembrolizumab 10 mg/kg intravenously over 30 minutes on Day 1 of each 21-day cycle for up to 2 years.	Biological: Pembrolizumab; Intravenous infusion; Other Names: MK-3475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Strongly PD-L1 Positive Participants	On-study imaging was to be performed every 9 weeks after the first dose of study drug, or more frequently if clinically indicated. ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR; disappearance of all target lesions) or Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters). The percentage of strongly PD-L1 positive participants who experienced a CR or PR is presented.	Up to 2 years
Number of Participants Experiencing Adverse Events (AEs)	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 was any unfavorable and unintended sign (including an abnormal laboratory finding), 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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. After discontinuation of study drug, each participant was monitored for a minimum of 30 days for AE monitoring (serious AEs were monitored for up to 90 days after last dose of study drug). The number of participants who experienced an AE is presented.	Up to 27 months (Up to 90 days after last dose of study drug)
Number of Participants Discontinuing Study Drug Due to AEs	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 was any unfavorable and unintended sign (including an abnormal laboratory finding), 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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The number of participants who discontinued study drug due to an AE is presented.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) by RECIST 1.1 in Strongly PD-L1 Positive Participants	PFS was defined as the time from the first day of study treatment to the first documented disease progression per RECIST 1.1 based on blinded independent central radiologists' review or death due to any cause, whichever occurred first. Using RECIST 1.1, progressive disease was defined as either a 20% relative increase in the sum of diameters of target lesions, taking as reference the smallest sum on study OR an absolute increase of >5 mm in the sum of lesions, OR the appearance of new lesions. PFS was analyzed using the Kaplan-Meier method and is reported in months. The median PFS for all strongly PD-L1 positive participants is presented.	Up to 2 years
Duration of Response (DOR) by RECIST 1.1 in Strongly PD-L1 Positive Participants	DOR was measured from the time measurement criteria were first met for CR/PR (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented (taking as reference for progressive disease the smallest measurements recorded on study). DOR was censored at the last tumor assessment date if a responder did not have PD or death. Non-responders were not included in the analysis. The lower and upper limits were estimated at the time of data cutoff. DOR was analyzed using the Kaplan-Meier method and is reported in days. The median DOR for all strongly PD-L1 positive participants with a confirmed response is presented.	Up to 2 years
Overall Survival (OS) in Strongly PD-L1 Positive Participants	OS was defined as the time from the first day of study treatment to death due to any cause. OS is reported for all strongly PD-L1 positive participants in months	Up to 2 years
ORR Per Immune-Related Response Criteria (irRC) in Strongly PD-L1 Positive Participants	ORR per irRC was defined as the percentage of participants in the analysis population who had a Complete Response (irCR: Complete disappearance of all tumor lesions [whether measureable or not, and no new lesions; irCR must be confirmed by repeated, consecutive assessments made no less than 4 weeks from the date first documented]) or Partial Response (irPR: Decrease in sum of the products of the two largest perpendicular diameters [SPD] of 50% or greater by a consecutive assessment at least 4 weeks after first documentation). The percentage of strongly PD-L1 positive participants who experienced an irCR or irPR is presented.	Up to 2 years
PFS Per irRC in Strongly PD-L1 Positive Participants	PFS was defined as the time from the first day of study treatment to the first documented disease progression per irRC or death due to any cause, whichever occurred first. Using irRC, progressive disease was defined as at least a 25% increase in SPD relative to minimum recorded tumor burden. Confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented was required. Median PFS was analyzed using the Kaplan-Meier method and is presented in months for all strongly PD-L1 positive participants.	Up to 2 years
DOR Per irRC in Strongly PD-L1 Positive Participants	DOR was measured from the time measurement criteria were first met for irCR/irPR (whichever was first recorded) until the first date that recurrent or progressive disease (PD) was objectively documented (taking as reference for progressive disease the smallest measurements recorded on study). PD was defined as at least a 25% increase in SPD relative to minimum recorded tumor burden. Confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented was required. DOR was censored at the last tumor assessment date if a responder did not have PD or death. Non-responders were not included in the analysis. DOR was analyzed using the Kaplan-Meier method, is reported in days and is presented for all strongly PD-L1 positive participants who experienced an irCR or irPR.	Up to 2 years
ORR Per RECIST 1.1 in PD-L1 Positive Participants	On-study imaging was to be performed every 9 weeks after the first dose of study drug, or more frequently if clinically indicated. ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters). The percentage of PD-L1 positive participants who experienced a CR or PR is presented.	Up to 2 years
PFS by RECIST 1.1 in PD-L1 Positive Participants	PFS was defined as the time from the first day of study treatment to the first documented disease progression per RECIST 1.1 based on blinded independent central radiologists' review or death due to any cause, whichever occurred first. Using RECIST 1.1, progressive disease was defined as either a 20% relative increase in the sum of diameters of target lesions, taking as reference the smallest sum on study OR an absolute increase of >5 mm in the sum of lesions, OR the appearance of new lesions. PFS was analyzed using the Kaplan-Meier method and is reported in months. The median PFS for all PD-L1 positive participants is presented.	Up to 2 years
DOR by RECIST 1.1 in PD-L1 Positive Participants	DOR was measured from the time measurement criteria were first met for CR/PR (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented (taking as reference for progressive disease the smallest measurements recorded on study). DOR was censored at the last tumor assessment date if a responder did not have PD or death. Non-responders were not included in the analysis. The lower and upper limits were estimated at the time of data cutoff. DOR was analyzed using the Kaplan-Meier method and is reported in days. The median DOR for all PD-L1 positive participants with a confirmed response is presented.	Up to 2 years
OS in PD-L1 Positive Participants	OS was defined as the time from the first day of study treatment to death due to any cause. OS is reported for all PD-L1 positive participants in months.	Up to 2 years
ORR Per irRC in PD-L1 Positive Participants	ORR per irRC was defined as the percentage of participants in the analysis population who had a irCR (Complete disappearance of all tumor lesions [whether measureable or not, and no new lesions; irCR must be confirmed by repeated, consecutive assessments made no less than 4 weeks from the date first documented]) or irPR (Decrease in sum of the products of the two largest perpendicular diameters [SPD] of 50% or greater by a consecutive assessment at least 4 weeks after first documentation). The percentage of PD-L1 positive participants who experienced an irCR or irPR is presented.	Up to 2 years
PFS Per irRC in PD-L1 Positive Participants	PFS was defined as the time from the first day of study treatment to the first documented disease progression per irRC or death due to any cause, whichever occurred first. Using irRC, progressive disease was defined as at least a 25% increase in SPD relative to minimum recorded tumor burden. Confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented was required. Median PFS was analyzed using the Kaplan-Meier method and is presented in months for all PD-L1 positive participants.	Up to 2 years
DOR Per irRC in PD-L1 Positive Participants	DOR was measured from the time measurement criteria were first met for irCR/irPR (whichever was first recorded) until the first date that recurrent or progressive disease (PD) was objectively documented (taking as reference for progressive disease the smallest measurements recorded on study). PD was defined as at least a 25% increase in SPD relative to minimum recorded tumor burden. Confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented was required. DOR was censored at the last tumor assessment date if a responder did not have PD or death. Non-responders were not included in the analysis. DOR was analyzed using the Kaplan-Meier method, is reported in days and is presented for all PD-L1 positive participants who experienced an irCR or irPR.	Up to 2 years

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Nishio M, Takahashi T, Yoshioka H, Nakagawa K, Fukuhara T, Yamada K, Ichiki M, Tanaka H, Seto T, Sakai H, Kasahara K, Satouchi M, Han SR, Noguchi K, Shimamoto T, Kato T. KEYNOTE-025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1-positive advanced non-small-cell lung cancer. Cancer Sci. 2019 Mar;110(3):1012-1020. doi: 10.1111/cas.13932. Epub 2019 Feb 16.

Helpful Links

• Merck Oncology Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2014
• Primary Completion (Actual): July 9, 2015
• Study Completion (Actual): March 31, 2017

Study Registration Dates

• First Submitted: December 5, 2013
• First Submitted That Met QC Criteria: December 5, 2013
• First Posted (Estimate): December 10, 2013

Study Record Updates

• Last Update Posted (Actual): May 13, 2020
• Last Update Submitted That Met QC Criteria: April 29, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: PD-1; PD-L1; PD1; PDL1
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: 3475-025; 142500 (Registry Identifier: JAPIC-CTI); MK-3475-025 (Other Identifier: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No