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

NCT ID: NCT03950674

Last Updated: 2024-06-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-22
• Study Completion Date: 2023-06-22

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.

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.

Conditions

Non-Small-Cell Lung Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Pembrolizumab with Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed

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.

Group Type: EXPERIMENTAL

Pembrolizumab 200 mg

Intervention Type: BIOLOGICAL

IV infusion

Cisplatin

Intervention Type: DRUG

IV infusion

Carboplatin

Intervention Type: DRUG

IV infusion

Pemetrexed

Intervention Type: DRUG

IV infusion

Folic acid 350-1000 μg

Intervention Type: 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.

Vitamin B12 1000 μg

Intervention Type: 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.

Dexamethasone 4 mg

Intervention Type: DRUG

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

Placebo with Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed

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.

Group Type: ACTIVE_COMPARATOR

Cisplatin

Intervention Type: DRUG

IV infusion

Carboplatin

Intervention Type: DRUG

IV infusion

Pemetrexed

Intervention Type: DRUG

IV infusion

Folic acid 350-1000 μg

Intervention Type: 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.

Vitamin B12 1000 μg

Intervention Type: 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.

Dexamethasone 4 mg

Intervention Type: DRUG

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

Saline solution

Intervention Type: DRUG

IV infusion

Interventions

Pembrolizumab 200 mg

IV infusion

Intervention Type: BIOLOGICAL

Cisplatin

IV infusion

Intervention Type: DRUG

Carboplatin

IV infusion

Intervention Type: DRUG

Pemetrexed

IV infusion

Intervention Type: DRUG

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.

Intervention Type: 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.

Intervention Type: DIETARY_SUPPLEMENT

Dexamethasone 4 mg

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

Intervention Type: DRUG

Saline solution

IV infusion

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

Locations

National Hospital Organization Nagoya Medical Center ( Site 0324)

Nagoya, Aichi-ken, Japan

Kurume University Hospital ( Site 0326)

Kurume, Fukuoka, Japan

Hyogo Cancer Center ( Site 0325)

Akashi, Hyōgo, Japan

Kanazawa University Hospital ( Site 0328)

Kanazawa, Ishikawa-ken, Japan

Kansai Medical University Hospital ( Site 0313)

Hirakata, Osaka, Japan

Shizuoka Cancer Center Hospital and Research Institute ( Site 0322)

Sunto-gun, Shizuoka, Japan

National Hospital Organization Shikoku Cancer Center ( Site 0303)

Matsuyama, , Japan

Okayama University Hospital ( Site 0327)

Okayama, , Japan

National Cancer Center Hospital ( Site 0301)

Tokyo, , Japan

The Cancer Institute Hospital of JFCR ( Site 0323)

Tokyo, , Japan

Countries

Japan

References

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.

Reference Type: RESULT

PMID: 34036692 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37465924 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35930972 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.merckclinicaltrials.com/

Merck Clinical Trials Information

Other Identifiers

163421

Identifier Type: REGISTRY

Identifier Source: secondary_id

MK-3475-189

Identifier Type: OTHER

Identifier Source: secondary_id

KEYNOTE-189

Identifier Type: OTHER

Identifier Source: secondary_id

3475-189 Japan Extension

Identifier Type: -

Identifier Source: org_study_id