NCT03950674

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

Completed Phase 3 Results posted Last updated 10 June 2024

What this trial tests

Phase 3 trial testing Pembrolizumab 200 mg in Non-Small-Cell Lung Carcinoma in 40 participants. Completed in 22 June 2023.

Timeline

22 February 2016

Primary endpoint
20 May 2019

22 June 2023

Quick facts

Lead sponsor	Merck Sharp & Dohme LLC
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	treatment
Enrollment	40
Start date	22 February 2016
Primary completion	20 May 2019
Estimated completion	22 June 2023
Sites	10 locations across Japan

Drugs / interventions tested

• Pembrolizumab 200 mg
• Cisplatin (cisplatin) — full drug profile →
• Carboplatin (Carboplatin) — full drug profile →
• Pemetrexed — full drug profile →
• Folic acid 350-1000 μg
• Vitamin B12 1000 μg
• Dexamethasone 4 mg
• Saline solution

Conditions studied

• Non-Small-Cell Lung Carcinoma — all drugs for Non-Small-Cell Lung Carcinoma →

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

18 and older, any sex, with Non-Small-Cell Lung Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging Primary · Up to approximately 31 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.

Group	Value	95% CI
Pembrolizumab With Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed	16.5	8.8 – 21.1
Placebo With Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed	7.1	4.7 – 21.4

Overall Survival (OS) Primary · Up to approximately 31 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.

Group	Value	95% CI
Pembrolizumab With Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed	NA	NA – NA
Placebo With Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed	25.9	11.9 – 29.0

Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging Secondary · Up to approximately 31 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.

Group	Value	95% CI
Pembrolizumab With Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed	56.0	34.9 – 75.6
Placebo With Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed	33.3	11.8 – 61.6

Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging Secondary · Up to approximately 31 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:

Group	Value	95% CI
Pembrolizumab With Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed	13.6	5.9 – 19.6
Placebo With Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed	9.7	3.4 – NA

Number of Participants Who Experienced an Adverse Event (AE) Secondary · Up to approximately 24 months

An adverse event was defined as any untoward medical occurrence in a clinical study participant administered a pharmaceutical product which did not necessarily have a causal relationship with this treatment. An adverse event was any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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 frequenc

Group	Value	95% CI
Pembrolizumab With Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed	25
Placebo With Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed	15

Number of Participants Who Discontinued Any Study Drug Due to an AE Secondary · Up to approximately 21 months

An adverse event was defined as any untoward medical occurrence in a clinical study participant administered a pharmaceutical product which did not necessarily have a causal relationship with this treatment. An adverse event was any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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 frequenc

Group	Value	95% CI
Pembrolizumab With Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed	9
Placebo With Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed	3

Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria Secondary · Up to approximately 31 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 progres

Group	Value	95% CI
Pembrolizumab With Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed	13.7	6.4 – 22.0
Placebo With Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed	7.6	2.6 – 11.9

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to approximately 80 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Pembrolizumab With Pemetrexed and Platinum Chemotherapy Followed by Pembrolizumab and Pemetrexed

Serious: 9/25 (36%)

Deaths: 15/25

Placebo With Pemetrexed and Platinum Chemotherapy Followed by Placebo and Pemetrexed

Serious: 6/15 (40%)

Deaths: 11/15

Placebo Switched Over to Pembrolizumab Monotherapy

Serious: 1/4 (25%)

Deaths: 4/4

Second Course Treatment for the Pembrolizumab With Pemetrexed and Platinum Chemotherapy Arm

Serious: 0/1 (0%)

Deaths: 1/1

Second Course Treatment for the Placebo Switched Over to Pembrolizumab Monotherapy Arm

Serious: 0

Deaths: 0

Serious adverse events (19 terms)

Reaction	System	Pembrolizumab With Pemetre…	Placebo With Pemetrexed an…	Placebo Switched Over to P…	Second Course Treatment fo…	Second Course Treatment fo…
Pyrexia	General disorders	—	—	—	—	—
Interstitial lung disease	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Adrenal insufficiency	Endocrine disorders	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Hepatic function abnormal	Hepatobiliary disorders	—	—	—	—	—
Bacterial infection	Infections and infestations	—	—	—	—	—
Oesophageal infection	Infections and infestations	—	—	—	—	—
Parotitis	Infections and infestations	—	—	—	—	—
Radiation oesophagitis	Injury, poisoning and procedural complications	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Tumour necrosis	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Brain oedema	Nervous system disorders	—	—	—	—	—
Cerebral haemorrhage	Nervous system disorders	—	—	—	—	—
Polyneuropathy	Nervous system disorders	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Toxic epidermal necrolysis	Skin and subcutaneous tissue disorders	—	—	—	—	—
Deep vein thrombosis	Vascular disorders	—	—	—	—	—

Other adverse events (96 terms — click to expand)

Reaction	System	Pembrolizumab With Pemetre…	Placebo With Pemetrexed an…	Placebo Switched Over to P…	Second Course Treatment fo…	Second Course Treatment fo…
Nausea	Gastrointestinal disorders	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
White blood cell count decreased	Investigations	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—	—
Hiccups	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—
Face oedema	General disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Malaise	General disorders	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—
Dysgeusia	Nervous system disorders	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—
Tinnitus	Ear and labyrinth disorders	—	—	—	—	—
Periorbital oedema	Eye disorders	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—
Herpes zoster	Infections and infestations	—	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—	—
Diabetes mellitus	Metabolism and nutrition disorders	—	—	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—	—	—
Peripheral sensory neuropathy	Nervous system disorders	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—
Lymphopenia	Blood and lymphatic system disorders	—	—	—	—	—
Hyperthyroidism	Endocrine disorders	—	—	—	—	—
Dry eye	Eye disorders	—	—	—	—	—

Most-reported serious reactions: Pyrexia, Interstitial lung disease, Adrenal insufficiency, Diarrhoea, Hepatic function abnormal, Bacterial infection, Oesophageal infection, Parotitis.

Data from ClinicalTrials.gov NCT03950674 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer without tumor PD-L1 expression: A pooled analysis of 3 randomized controlled trials.
   Borghaei H, Langer CJ, Paz-Ares L, Rodríguez-Abreu D, et al · · 2020 · cited 95× · PMID 32914866 · DOI 10.1002/cncr.33142
2. Expert consensus on neoadjuvant immunotherapy for non-small cell lung cancer.
   Liang W, Cai K, Chen C, Chen H, et al · · 2020 · cited 79× · PMID 33489828 · DOI 10.21037/tlcr-2020-63
3. Stevens-Johnson syndrome/toxic epidermal necrolysis in patients treated with immune checkpoint inhibitors: A safety analysis of clinical trials and FDA pharmacovigilance database.
   Zhu J, Chen G, He Z, Zheng Y, et al · · 2021 · cited 64× · PMID 34386743 · DOI 10.1016/j.eclinm.2021.100951
4. Immunogenicity of cell death and cancer immunotherapy with immune checkpoint inhibitors.
   Catanzaro E, Beltrán-Visiedo M, Galluzzi L, Krysko DV. · · 2025 · cited 53× · PMID 39653769 · DOI 10.1038/s41423-024-01245-8
5. Pembrolizumab plus pemetrexed-platinum for metastatic nonsquamous non-small-cell lung cancer: KEYNOTE-189 Japan Study.
   Horinouchi H, Nogami N, Saka H, Nishio M, et al · · 2021 · cited 50× · PMID 34036692 · DOI 10.1111/cas.14980
6. Pembrolizumab Plus Chemotherapy for Metastatic NSCLC With Programmed Cell Death Ligand 1 Tumor Proportion Score Less Than 1%: Pooled Analysis of Outcomes After Five Years of Follow-Up.
   Gadgeel SM, Rodríguez-Abreu D, Halmos B, Garassino MC, et al · · 2024 · cited 35× · PMID 38642841 · DOI 10.1016/j.jtho.2024.04.011
7. What is the optimal duration of immune checkpoint inhibitors in malignant tumors?
   Yin J, Song Y, Tang J, Zhang B. · · 2022 · cited 27× · PMID 36225926 · DOI 10.3389/fimmu.2022.983581
8. External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer.
   Rolfo C, Hess LM, Jen MH, Peterson P, et al · · 2022 · cited 11× · PMID 35930972 · DOI 10.1016/j.esmoop.2022.100551