Study of Pembrolizumab (MK-3475) Versus Platinum-Based Chemotherapy for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Advanced or Metastatic Non-Small Cell Lung Cancer (MK-3475-042/KEYNOTE-042)

• ClinicalTrials.gov Identifier: NCT02220894
• Recruitment Status: Completed
• First Posted: August 20, 2014
• Results First Posted: March 15, 2019
• Last Update Posted: October 10, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

Brief Summary:

In this study, participants with programmed cell death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) will be randomized to receive single agent pembrolizumab for up to 35 treatments or standard of care (SOC) platinum-based chemotherapy (carboplatin + paclitaxel or carboplatin + pemetrexed for 4 to 6 21-day cycles). Participants in the platinum-based chemotherapy arms with non-squamous tumor histologies may receive pemetrexed maintenance therapy after the 4 to 6 cycles of chemotherapy. The primary study hypothesis is that pembrolizumab prolongs overall survival (OS) compared to SOC chemotherapy.

Condition or disease	Intervention/treatment	Phase
Non-small Cell Lung Cancer	Biological: pembrolizumab; Drug: carboplatin; Drug: paclitaxel; Drug: pemetrexed	Phase 3

Detailed Description:

Pembrolizumab-treated participants, who attain a confirmed complete response (CR) or who stop trial treatment after 35 administrations of study medication for reasons other than disease progression or intolerability, may consider stopping trial treatment. These participants may be eligible for re-treatment with pembrolizumab monotherapy after they have experienced radiographic disease according to protocol-defined criteria. Response or progression in the Second Course Phase will not count towards the objective response rate (ORR) and progression free survival (PFS) endpoints in this trial.

The global study for MK-3475-042 enrolled 1274 participants. Of the 1274 total participants enrolled in the global study, 92 were also enrolled in the China extension study for MK-3475-042 (NCT03850444).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1274 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open Label, Phase III Study of Overall Survival Comparing Pembrolizumab (MK-3475) Versus Platinum Based Chemotherapy in Treatment Naïve Subjects With PD-L1 Positive Advanced or Metastatic Non-Small Cell Lung Cancer (Keynote 042)
• Actual Study Start Date: October 30, 2014
• Actual Primary Completion Date: September 4, 2018
• Actual Study Completion Date: September 12, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pembrolizumab; Participants receive pembrolizumab 200 mg intravenous (IV) on Day 1 of every 21-day cycle (every 3 weeks, or Q3W) for up to 35 treatments.	Biological: pembrolizumab; Other Names: MK-3475; KEYTRUDA®
Active Comparator: SOC Treatment; Participants receive carboplatin target dose Area Under Curve (AUC) 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 IV on Day 1 of every 21-day cycle (Q3W) for a maximum of 6 cycles OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 IV on Day 1 Q3W for a maximum of 6 cycles; participants with non-squamous histologies may go on to receive optional treatment with pemetrexed 500 mg/m^2 IV on Day 1 Q3W.	Drug: carboplatin; Other Name: PARAPLATIN®; Drug: paclitaxel; Other Name: TAXOL®; Drug: pemetrexed; Other Name: ALIMTA®

Outcome Measures

Primary Outcome Measures :

1. Overall Survival (OS) in Participants With a Tumor Proportion Score (TPS) of ≥50% [ Time Frame: Up to approximately 44 months ]
   OS was determined for participants with a TPS of ≥50% and was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow-up. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was OS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The OS for participants with a TPS ≥50% is presented.
2. Overall Survival (OS) in Participants With a Tumor Proportion Score (TPS) of ≥20% [ Time Frame: Up to approximately 44 months ]
   OS was determined for participants with a TPS of ≥20% and was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow-up. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was OS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The OS for participants with a TPS ≥20% is presented.
3. Overall Survival (OS) in Participants With a Tumor Proportion Score (TPS) of ≥1% [ Time Frame: Up to approximately 44 months ]
   OS was determined for participants with a TPS of ≥1% and was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow-up. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was OS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The OS for participants with a TPS ≥1% is presented.

Secondary Outcome Measures :

1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥50% [ Time Frame: Up to approximately 44 months ]
   PFS was determined for participants with a TPS of ≥50% and 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. The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was PFS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The PFS for participants with a TPS ≥50% is presented.
2. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥20% [ Time Frame: Up to approximately 44 months ]
   PFS was determined for participants with a TPS of ≥20% and 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. The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was PFS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The PFS for participants with a TPS ≥20% is presented.
3. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥1% [ Time Frame: Up to approximately 44 months ]
   PFS was determined for participants with a TPS of ≥1% and 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. The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was PFS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The PFS for participants with a TPS ≥1% is presented.
4. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥50% [ Time Frame: Up to approximately 44 months ]
   ORR was determined for participants with a TPS of ≥50%. ORR was determined per RECIST 1.1 and 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 efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was ORR in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The percentage of participants who had a TPS ≥50% and who experienced a CR or PR is presented.
5. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥20% [ Time Frame: Up to approximately 44 months ]
   ORR was determined for participants with a TPS of ≥20%. ORR was determined per RECIST 1.1 and 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 efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was ORR in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The percentage of participants who had a TPS ≥20% and who experienced a CR or PR is presented.
6. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With a Tumor Proportion Score (TPS) of ≥1% [ Time Frame: Up to approximately 44 months ]
   ORR was determined for participants with a TPS of ≥1%. ORR was determined per RECIST 1.1 and 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 efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was ORR in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The percentage of participants who had a TPS ≥1% and who experienced a CR or PR is presented.
7. Number of Participants Who Experienced At Least One Adverse Event (AE) [ Time Frame: Up to approximately 38 months ]
   An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment 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 study treatment, was also an AE. The number of participants who experienced at least one AE is presented.
8. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 35 months ]
   An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment 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 study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE 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:

• Histologically- or cytologically-confirmed diagnosis of advanced or metastatic NSCLC
• PD-L1 positive tumor
• Measureable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Life expectancy of at least 3 months
• No prior systemic chemotherapy for the treatment of the participant's advanced or metastatic disease (treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as completed at least 6 months prior to diagnosis of advanced or metastatic disease)
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Adequate organ function
• No 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, or has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy
• Submission of formalin-fixed diagnostic tumor tissue (in the case of participants having received adjuvant systemic therapy, the tissue should be taken after completion of this therapy)
• Female participants of childbearing potential must have a negative urine or serum pregnancy test and must be willing to use two adequate barrier methods of contraception or a barrier method plus a hormonal method starting with the screening visit through 120 days after the last dose of pembrolizumab or 180 days after the last dose of chemotherapeutic agents used in the study
• Male participants with a female partner(s) of child-bearing potential must be willing to use two adequate barrier methods of contraception from screening through 120 days after the last dose of pembrolizumab or 180 days after the last dose of chemotherapeutic agents used in the study

Exclusion criteria:

• Epidermal growth factor receptor (EGFR)-sensitizing mutation and/or is echinoderm microtubule-associated protein-like 4(EML4) gene/anaplastic lymphoma kinase (ALK) gene fusion positive
• Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study therapy
• No tumor specimen evaluable for PD-L1 expression by the central study laboratory
• Squamous histology and received carboplatin in combination with paclitaxel in the adjuvant setting
• Is receiving systemic steroid therapy ≤3 days prior to the first dose of study therapy or receiving any other form of immunosuppressive medication with the exception of daily steroid replacement therapy
• The NSCLC can be treated with curative intent with either surgical resection and/or chemoradiation
• Expected to require any other form of systemic or localized antineoplastic therapy while on study
• Any prior systemic cytotoxic chemotherapy, biological therapy or major surgery within 3 weeks of the first dose of study therapy; received lung radiation therapy >30 Gy within 6 months of the first dose of study therapy
• 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 (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
• Known central nervous system metastases and/or carcinomatous meningitis
• Active autoimmune disease that has required systemic treatment in the past 2 years
• Had allogeneic tissue/solid organ transplantation
• Interstitial lung disease or history of pneumonitis that has required oral or IV steroids
• Has received or will receive a live vaccine within 30 days prior to the first study therapy (seasonal flu vaccines that do not contain live vaccine are permitted)
• Active infection requiring intravenous systemic therapy
• Known history of human immunodeficiency virus (HIV)
• Known active Hepatitis B or C
• Regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol)
• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study

Contacts and Locations

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 and Statistical Analysis Plan  [PDF] March 24, 2021

More Information

Additional Information:

Merck Clinical Trials Information 

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

de Castro G Jr, Kudaba I, Wu YL, Lopes G, Kowalski DM, Turna HZ, Caglevic C, Zhang L, Karaszewska B, Laktionov KK, Srimuninnimit V, Bondarenko I, Kubota K, Mukherjee R, Lin J, Souza F, Mok TSK, Cho BC. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score >/= 1% in the KEYNOTE-042 Study. J Clin Oncol. 2023 Apr 10;41(11):1986-1991. doi: 10.1200/JCO.21.02885. Epub 2022 Oct 28.

Halmos B, Burke T, Kalyvas C, Insinga R, Vandormael K, Frederickson A, Piperdi B. Indirect comparison of pembrolizumab monotherapy versus nivolumab + ipilimumab in first-line metastatic lung cancer. Immunotherapy. 2022 Apr;14(5):295-307. doi: 10.2217/imt-2021-0273. Epub 2022 Jan 25.

Wu YL, Zhang L, Fan Y, Zhou J, Zhang L, Zhou Q, Li W, Hu C, Chen G, Zhang X, Zhou C, Dang T, Sadowski S, Kush DA, Zhou Y, Li B, Mok T. Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non-small-cell lung cancer: KEYNOTE-042 China Study. Int J Cancer. 2021 May 1;148(9):2313-2320. doi: 10.1002/ijc.33399. Epub 2020 Dec 9.

Weng X, Luo S, Lin S, Zhong L, Li M, Xin R, Huang P, Xu X. Cost-Utility Analysis of Pembrolizumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small Cell Lung Cancer With Different PD-L1 Expression Levels. Oncol Res. 2020 Mar 27;28(2):117-125. doi: 10.3727/096504019X15707883083132. Epub 2019 Oct 14.

Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. doi: 10.1016/S0140-6736(18)32409-7. Epub 2019 Apr 4.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02220894
• Other Study ID Numbers: 3475-042; 152877 ( Registry Identifier: JAPIC-CTI ); MK-3475-042 ( Other Identifier: Merck Protocol Number ); KEYNOTE-042 ( Other Identifier: Merck ); 2014-001473-14 ( EudraCT Number )
• First Posted: August 20, 2014
• Results First Posted: March 15, 2019
• Last Update Posted: October 10, 2023
• Last Verified: October 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:

PD-1; PD1; PD-L1; PDL1

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; Paclitaxel; Carboplatin; Pembrolizumab; Pemetrexed; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Enzyme Inhibitors; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors