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

NCT03950674 | Completed Phase 3 Results DMC FDA Drug

• 4 other identifiers: 3475-189 Japan Extension163421MK-3475-189KEYNOTE-189
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 10

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.

Conditions

Non-Small-Cell Lung Carcinoma

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging

  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.

  Up to approximately 31 months

• Overall Survival (OS)

  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.

  Up to approximately 31 months

Secondary Outcomes (4)

• Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging

  Up to approximately 31 months

• Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging

  Up to approximately 31 months

• Number of Participants Who Experienced an Adverse Event (AE)

  Up to approximately 24 months

• Number of Participants Who Discontinued Any Study Drug Due to an AE

  Up to approximately 21 months

Other Outcomes (1)

• Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria

  Up to approximately 31 months

Study Arms (2)

Pembrolizumab with Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed

EXPERIMENTAL

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. Participants who receive pembrolizumab 200 mg IV Q3W for up to 2 years, but experience disease progression, are eligible to receive a second course of pembrolizumab monotherapy 200 mg IV Q3W, at the investigator's discretion, for up to another year.

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

Placebo with Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed

ACTIVE COMPARATOR

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. Participants who receive saline placebo, but experience disease progression, can switch over to pembrolizumab monotherapy 200 mg IV Q3W, at the investigator's discretion, for up to 2 years. The participants who switch over to pembrolizumab 200 mg IV Q3W, but experience disease progression, are eligible to receive a second course of pembrolizumab monotherapy 200 mg IV Q3W, at the investigator's discretion, for up to another year.

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

Interventions

Pembrolizumab 200 mg BIOLOGICAL

IV infusion

Pembrolizumab with Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed

Cisplatin DRUG

IV infusion

Pembrolizumab with Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed; Placebo with Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed

Carboplatin DRUG

IV infusion

Pembrolizumab with Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed; Placebo with Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed

Pemetrexed DRUG

IV infusion

Pembrolizumab with Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed; Placebo with Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed

Folic acid 350-1000 μg DIETARY_SUPPLEMENT

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.

Pembrolizumab with Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed; Placebo with Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed

Vitamin B12 1000 μg DIETARY_SUPPLEMENT

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.

Pembrolizumab with Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed; Placebo with Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed

Dexamethasone 4 mg DRUG

For prophylaxis; orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.

Pembrolizumab with Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed; Placebo with Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed

Saline solution DRUG

IV infusion

Placebo with Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (10)

National Hospital Organization Nagoya Medical Center ( Site 0324)

Nagoya, Aichi-ken, 460-0001, Japan

Location

Kurume University Hospital ( Site 0326)

Kurume, Fukuoka, 830-0011, Japan

Location

Hyogo Cancer Center ( Site 0325)

Akashi, Hyōgo, 673-8558, Japan

Location

Kanazawa University Hospital ( Site 0328)

Kanazawa, Ishikawa-ken, 920-8641, Japan

Location

Kansai Medical University Hospital ( Site 0313)

Hirakata, Osaka, 573-1191, Japan

Location

Shizuoka Cancer Center Hospital and Research Institute ( Site 0322)

Sunto-gun, Shizuoka, 411-8777, Japan

Location

National Hospital Organization Shikoku Cancer Center ( Site 0303)

Matsuyama, 791-0280, Japan

Location

Okayama University Hospital ( Site 0327)

Okayama, 700-8558, Japan

Location

National Cancer Center Hospital ( Site 0301)

Tokyo, 104-0045, Japan

Location

The Cancer Institute Hospital of JFCR ( Site 0323)

Tokyo, 135-8550, Japan

Location

Related Publications (3)

• 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.

  PMID: 34036692 RESULT

• Cheng Y, Yang JC, Okamoto I, Zhang L, Hu J, Wang D, Hu C, Zhou J, Wu L, Cao L, Liu J, Zhang H, Sun H, Wang Z, Gao H, Yan Y, Xiao S, Lin J, Pietanza MC, Kurata T. Pembrolizumab plus chemotherapy for advanced non-small-cell lung cancer without tumor PD-L1 expression in Asia. Immunotherapy. 2023 Sep;15(13):1029-1044. doi: 10.2217/imt-2023-0043. Epub 2023 Jul 19.

  PMID: 37465924 DERIVED

• 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.

  PMID: 35930972 DERIVED

Related Links

• Merck Clinical Trials Information

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab; Cisplatin; Carboplatin; Pemetrexed; Folic Acid; Vitamin B 12; Dexamethasone; Saline Solution

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Coordination Complexes; Organic Chemicals; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Pterins; Pteridines; Corrinoids; Tetrapyrroles; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds, 4 or More Rings; Macrocyclic Compounds; Polycyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 13, 2019
• First Posted: May 15, 2019
• Study Start: February 22, 2016
• Primary Completion: May 20, 2019
• Study Completion: June 22, 2023
• Last Updated: June 10, 2024
• Results First Posted: June 11, 2020

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share

Locations

JP (10)