Clinical trial NCT02220894: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Keywords: PD-1
PD1
PD-L1
PDL1
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2014-08-20
Enrollment: 1274
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Eligibility 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

Primary outcomes:
measure: Overall Survival (OS) in Participants With a Tumor Proportion Score (TPS) of ≥50%
timeFrame: Up to approximately 44 months
measure: Overall Survival (OS) in Participants With a Tumor Proportion Score (TPS) of ≥20%
timeFrame: Up to approximately 44 months
measure: Overall Survival (OS) in Participants With a Tumor Proportion Score (TPS) of ≥1%
timeFrame: Up to approximately 44 months
Secondary outcomes:
measure: 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%
timeFrame: Up to approximately 44 months
measure: 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%
timeFrame: Up to approximately 44 months
measure: 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%
timeFrame: Up to approximately 44 months
measure: 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%
timeFrame: Up to approximately 44 months
measure: 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%
timeFrame: Up to approximately 44 months
measure: 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%
timeFrame: Up to approximately 44 months
measure: Number of Participants Who Experienced At Least One Adverse Event (AE)
timeFrame: Up to approximately 38 months
measure: Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to approximately 35 months
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.