Study of Pemetrexed+Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Participants With First Line Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-3475-189/KEYNOTE-189)-Japan Extension Study

• ClinicalTrials.gov Identifier: NCT03950674
• Recruitment Status: Active, not recruiting
• First Posted: May 15, 2019
• Results First Posted: June 11, 2020
• Last Update Posted: January 26, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

Brief Summary:

This is a Japan Extension Study of Global Study MK-3475-189 (NCT02578680). This is an efficacy and safety study of pembrolizumab (MK-3475) combined with pemetrexed/platinum chemotherapy versus pemetrexed/platinum chemotherapy alone in adult Japanese participants with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have not previously received systemic therapy for advanced disease. Participants will be randomly assigned to receive pembrolizumab combined with pemetrexed/platinum (Investigators choice of cisplatin or carboplatin), OR pemetrexed/platinum (Investigators choice of cisplatin or carboplatin).

With Amendment 11 (effective date 31-Jan-2022), once the study objectives have been met or the study has ended, participants will be discontinued from this study and will be enrolled in an extension study to continue protocol-defined assessments and treatment.

The primary hypothesis is that pembrolizumab in combination with pemetrexed/platinum chemotherapy prolongs Progression-Free Survival (PFS) and Overall Survival (OS) compared to pemetrexed/platinum chemotherapy alone.

Condition or disease	Intervention/treatment	Phase
Non-Small-Cell Lung Carcinoma	Biological: Pembrolizumab 200 mg; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed; Dietary Supplement: Folic acid 350-1000 μg; Dietary Supplement: Vitamin B12 1000 μg; Drug: Dexamethasone 4 mg; Drug: Saline solution	Phase 3

Detailed Description:

The MK-3475-189-Japan Extension Study will be identical to the global study (e.g. inclusion and exclusion criteria, study primary and secondary outcome measures and study procedures).

The MK-3475-189-Japanese Extension Study enrolled a total of 30 participants and the analyses included 10 participants (pembrolizumab =4; control = 6) that had been previously enrolled in the MK-3475-189 global study (NCT02578680), resulting in a total of 40 participants.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Phase III Study of Platinum+Pemetrexed Chemotherapy With or Without Pembrolizumab (MK-3475) in First Line Metastatic Non-squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-189)
• Actual Study Start Date: February 22, 2016
• Actual Primary Completion Date: May 20, 2019
• Estimated Study Completion Date: May 25, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pembrolizumab; Participants receive pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression (up to 35 treatment administrations; up to approximately 2 years).	Biological: Pembrolizumab 200 mg; IV infusion; Drug: Cisplatin; IV infusion; Drug: Carboplatin; IV infusion; Drug: Pemetrexed; IV infusion; Dietary Supplement: Folic acid 350-1000 μg; Orally; at least 5 doses of folic acid must be taken during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed.; Dietary Supplement: Vitamin B12 1000 μg; Intramuscular injection in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed administration.; Drug: Dexamethasone 4 mg; For prophylaxis; orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.
Active Comparator: Control; Participants receive saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurs, participants may be able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression (up to 35 treatment administrations; up to approximately 2 years).	Drug: Cisplatin; IV infusion; Drug: Carboplatin; IV infusion; Drug: Pemetrexed; IV infusion; Dietary Supplement: Folic acid 350-1000 μg; Orally; at least 5 doses of folic acid must be taken during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed.; Dietary Supplement: Vitamin B12 1000 μg; Intramuscular injection in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed administration.; Drug: Dexamethasone 4 mg; For prophylaxis; orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.; Drug: Saline solution; IV infusion

Outcome Measures

Primary Outcome Measures :

1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging [ Time Frame: Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months) ]
   PFS was defined as the time from randomization to the first documented progressive disease (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, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 is presented.
2. Overall Survival (OS) [ Time Frame: Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months) ]
   OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The OS is presented.

Secondary Outcome Measures :

1. Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging [ Time Frame: Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months) ]
   ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The percentage of participants who experienced a CR or PR is presented.
2. Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging [ Time Frame: From time of first documented evidence of CR or PR through database cutoff date of 20-May-2019 (Up to approximately 31.2 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 PD or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. 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 is presented.
3. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months) ]
   An AE was defined as any untoward medical occurrence in a study participant administered study drug and which does not necessarily have to have a causal relationship with this study drug. The number of participants who experienced an AE is presented.
4. Number of Participants Who Discontinued Any Study Drug Due to an AE [ Time Frame: Up to approximately 24 months ]
   The number of participants who discontinued any randomized study drug due to an AE is presented.

Other Outcome Measures:

1. Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria [ Time Frame: Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months) ]
   PFS was defined as the time from randomization to the first documented immune-related progressive disease (irPD) or death due to any cause, whichever occurred first. Per irRECIST, irPD was confirmed if any of the following are observed in 2 scans performed at least 4 weeks apart: target lesion sum of diameters remains ≥20 % and at least 5 mm absolute increase compared to nadir; non-target disease resulting in initial PD is qualitatively worse; new lesion resulting in initial irPD is qualitatively worse; additional new lesion(s) since last evaluation; or additional new non-target lesion progression since last evaluation. The PFS per irRECIST 1.1 is presented.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Has a histologically-confirmed or cytologically confirmed diagnosis of stage IV nonsquamous NSCLC.
• Has confirmation that epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-directed therapy is not indicated.
• Has measurable disease.
• Has not received prior systemic treatment for their advanced/metastatic NSCLC.
• Can provide tumor tissue.
• Has a life expectancy of at least 3 months.
• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
• Has adequate organ function
• If female of childbearing potential, is willing to use adequate contraception for the course of the study through 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents.
• If male with a female partner(s) of child-bearing potential, must agree to use adequate contraception starting with the first dose of study medication through 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents.

Exclusion Criteria:

• Has predominantly squamous cell histology NSCLC.
• Is 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 prior to administration of pembrolizumab.
• Before the first dose of study medication: a) Has received prior systemic cytotoxic chemotherapy for metastatic disease, b) Has received antineoplastic biological therapy (e.g. erlotinib, crizotinib, cetuximab), c) Had major surgery (<3 weeks prior to first dose)
• Received radiation therapy to the lung that is >30 Gray (Gy) within 6 months of the first dose of study medication.
• Completed palliative radiotherapy within 7 days of the first dose of study medication.
• Is expected to require any other form of antineoplastic therapy while on study.
• Received a live-virus vaccination within 30 days of planned start of study medication.
• Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, peritoneal carcinomatosis.
• Known history of prior malignancy except if participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy, except for successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb).
• Known sensitivity to any component of cisplatin, carboplatin or pemetrexed.
• Has active autoimmune disease that has required systemic treatment in past 2 years.
• Is on chronic systemic steroids.
• Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
• Is unable or unwilling to take folic acid or vitamin B12 supplementation.
• Had prior treatment with any other anti-programmed cell death-1 (PD-1), or PD-ligand 1 (PD-L1) or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms. Has participated in any other pembrolizumab study and has been treated with pembrolizumab.
• Has an active infection requiring therapy.
• Has known history of Human Immunodeficiency Virus (HIV).
• Has known active Hepatitis B or C.
• Has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.
• Is a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
• Has symptomatic ascites or pleural effusion.
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.

Contacts and Locations

Locations

Japan

National Hospital Organization Nagoya Medical Center ( Site 0324)

Nagoya, Aichi, Japan, 460-0001

Kurume University Hospital ( Site 0326)

Kurume, Fukuoka, Japan, 830-0011

Hyogo Cancer Center ( Site 0325)

Akashi, Hyogo, Japan, 673-8558

Kanazawa University Hospital ( Site 0328)

Kanazawa, Ishikawa, Japan, 920-8641

Kansai Medical University Hospital ( Site 0313)

Hirakata, Osaka, Japan, 573-1191

Shizuoka Cancer Center Hospital and Research Institute ( Site 0322)

Sunto-gun, Shizuoka, Japan, 411-8777

National Hospital Organization Shikoku Cancer Center ( Site 0303)

Matsuyama, Japan, 791-0280

Okayama University Hospital ( Site 0327)

Okayama, Japan, 700-8558

National Cancer Center Hospital ( Site 0301)

Tokyo, Japan, 104-0045

The Cancer Institute Hospital of JFCR ( Site 0323)

Tokyo, Japan, 135-8550

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

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

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme LLC:

Study Protocol  [PDF] November 6, 2017

Statistical Analysis Plan  [PDF] November 16, 2017

More Information

Additional Information:

Merck Oncology Clinical Trials Information 

Publications of Results:

Horinouchi H, Nogami N, Saka H, Nishio M, Tokito T, Takahashi T, Kasahara K, Hattori Y, Ichihara E, Adachi N, Noguchi K, Souza F, Kurata T. Pembrolizumab plus pemetrexed-platinum for metastatic nonsquamous non-small-cell lung cancer: KEYNOTE-189 Japan Study. Cancer Sci. 2021 Aug;112(8):3255-3265. doi: 10.1111/cas.14980. Epub 2021 Jun 15.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Rolfo C, Hess LM, Jen MH, Peterson P, Li X, Liu H, Lai Y, Sugihara T, Kiiskinen U, Vickers A, Summers Y. External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer. ESMO Open. 2022 Aug;7(4):100551. doi: 10.1016/j.esmoop.2022.100551. Epub 2022 Aug 2.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03950674
• Other Study ID Numbers: 3475-189 Japan Extension; 163421 ( Registry Identifier: JAPIC-CTI ); MK-3475-189 ( Other Identifier: Merck ); KEYNOTE-189 ( Other Identifier: Merck )
• First Posted: May 15, 2019
• Results First Posted: June 11, 2020
• Last Update Posted: January 26, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme LLC:

Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1); Non-Small-Cell Lung Cancer (NSCLC); PD1; PD-1; PDL1; PD-L1; Non-Small-Cell Lung Cancer

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Folic Acid; Vitamin B 12; Dexamethasone; Carboplatin; Pembrolizumab; Pemetrexed; Vitamins; Micronutrients; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Antineoplastic Agents, Immunological