Study of Pembrolizumab (MK-3475) vs Placebo for Participants With Non-small Cell Lung Cancer After Resection With or Without Standard Adjuvant Therapy (MK-3475-091/KEYNOTE-091) (PEARLS)

• ClinicalTrials.gov Identifier: NCT02504372
• Recruitment Status: Active, not recruiting
• First Posted: July 21, 2015
• Results First Posted: February 15, 2024
• Last Update Posted: February 15, 2024
• Sponsor: Merck Sharp & Dohme LLC
• Collaborators: ETOP; European Organisation for Research and Treatment of Cancer - EORTC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: July 20, 2015
• First Posted Date: July 21, 2015
• Results First Submitted Date: January 9, 2024
• Results First Posted Date: February 15, 2024
• Last Update Posted Date: February 15, 2024
• Actual Study Start Date: November 6, 2015
• Actual Primary Completion Date: January 24, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 13, 2024)

• Disease-Free Survival (DFS) [ Time Frame: Up to approximately 84 months ]
  DFS was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.
• DFS in Programmed Death Ligand-1 (PDL-1) Strong Positive Participants With Tumor Proportion Score (TPS) ≥50% [ Time Frame: Up to approximately 84 months ]
  DFS in PDL-1 strong positive participants with TPS ≥50% was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.

• Original Primary Outcome Measures (submitted: July 20, 2015): Disease-free Survival (DFS) [ Time Frame: Up to 100 months ]

Current Secondary Outcome Measures (submitted: February 13, 2024)

• DFS in PDL-1 Strong Positive Participants With TPS ≥1% [ Time Frame: Up to approximately 84 months ]
  DFS in PDL-1 strong positive participants with TPS ≥1% was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.
• Overall Survival (OS) [ Time Frame: Up to approximately 132 months ]
  OS was defined as the time from randomization to the date of death.
• OS in PDL-1 Strong Positive Participants With TPS ≥50% [ Time Frame: Up to approximately 132 months ]
  OS in PDL-1 Strong Positive Participants with TPS ≥50% was defined as the time from randomization to the date of death.
• OS in PDL-1 Strong Positive Participants With TPS ≥1% [ Time Frame: Up to approximately 132 months ]
  OS in PDL-1 Strong Positive Participants with TPS ≥1% was defined as the time from randomization to the date of death.
• Lung Cancer Specific Survival (LCSS) [ Time Frame: Up to approximately 132 months ]
  LCSS was defined as the time from randomization to the date of death (due to lung cancer specifically).
• Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 22 months ]
  An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be 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. The number of participants who experienced an AE were reported.
• Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 19 months ]
  An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be 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. The number of participants who discontinued study treatment due to an AE were reported.

Original Secondary Outcome Measures (submitted: July 20, 2015)

• Overall Survival (OS) [ Time Frame: Up to 100 months ]
• Lung Cancer Specific Survival (LCSS) [ Time Frame: Up to 100 months ]

Current Other Pre-specified Outcome Measures (submitted: February 13, 2024)

DFS at 68 Months [ Time Frame: Up to approximately 68 months ]

DFS was defined as the time from randomization to either the date of disease recurrence or death (whatever the cause) as assessed by the investigator. Recurrence of disease was defined as local regional recurrence, a distant (metastatic) recurrence, or a second primary cancer. Occurrence of a second extra-pulmonary malignancy was considered to be an event.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Pembrolizumab (MK-3475) vs Placebo for Participants With Non-small Cell Lung Cancer After Resection With or Without Standard Adjuvant Therapy (MK-3475-091/KEYNOTE-091)
• Official Title: A Randomized, Phase 3 Trial With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) Versus Placebo for Patients With Early Stage NSCLC After Resection and Completion of Standard Adjuvant Therapy (PEARLS)
• Brief Summary: In this study, participants with Stage IB/II-IIIA non-small cell lung cancer (NSCLC) who have undergone surgical resection (lobectomy or pneumonectomy) with or without adjuvant chemotherapy will be treated with pembrolizumab or placebo. The primary study hypothesis is that pembrolizumab will provide improved disease-free survival (DFS) versus placebo.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Non-small Cell Lung Cancer

Intervention

• Biological: Pembrolizumab
  IV infusion
  Other Names:

  • MK-3475
  • KEYTRUDA®
• Other: Placebo
  IV infusion

Study Arms

• Experimental: Pembrolizumab
  Participants receive pembrolizumab 200 mg, intravenously (IV), every 3 weeks, for one year (expected maximum 18 doses).
  Intervention: Biological: Pembrolizumab
• Placebo Comparator: Placebo
  Participants receive placebo, IV, every 3 weeks, for one year (expected maximum 18 doses).
  Intervention: Other: Placebo

• Publications *: O'Brien M, Paz-Ares L, Marreaud S, Dafni U, Oselin K, Havel L, Esteban E, Isla D, Martinez-Marti A, Faehling M, Tsuboi M, Lee JS, Nakagawa K, Yang J, Samkari A, Keller SM, Mauer M, Jha N, Stahel R, Besse B, Peters S; EORTC-1416-LCG/ETOP 8-15 - PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022 Oct;23(10):1274-1286. doi: 10.1016/S1470-2045(22)00518-6. Epub 2022 Sep 12.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 15, 2020): 1177
• Original Estimated Enrollment (submitted: July 20, 2015): 1380
• Estimated Study Completion Date: February 2, 2027
• Actual Primary Completion Date: January 24, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Pathological diagnosis of NSCLC confirmed at surgery, any histology. Participants with two synchronous primary non-small cell lung cancers are excluded from the study
• Union for International Cancer Control (UICC) v7 Stage IB with T ≥ 4 cm, II-IIIA NSCLC after complete surgical resection with resection margins proved microscopically free of disease (R0). Carcinoma in situ can be present at the bronchial margin
• Available tumor sample obtained at surgical resection for programmed cell death ligand-1 (PD-L1) Immunohistochemistry (IHC) expression assessment
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
• Adequate organ function performed within 10 days of treatment initiation
• Female participants of childbearing potential must have a negative urine or serum pregnancy test at screening (within 72 hours of first infusion of study medication). If the urine test cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the participant to be eligible
• Female participants of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity starting with the first infusion of study treatment through 120 days after the last infusion of study treatment
• Female participants who are breast feeding must discontinue nursing prior to the first infusion of study medication and until 120 days after the last infusion study treatment
• Male participants must agree to use an adequate method of contraception starting with the first infusion of study treatment through 120 days after the last infusion of study treatment
• Absence of severe comorbidities that in the opinion of the Investigator might hamper the participation to the study and/or the treatment administration
• No prior or planned neo-adjuvant or adjuvant radiotherapy and/or neo-adjuvant chemotherapy for the current malignancy is allowed

Exclusion Criteria:

• Evidence of disease at clinical examination and/or baseline radiological assessment as documented by contrast enhanced chest/upper abdomen CT scan, brain CT/MRI and clinical examination
• More than 4 cycles of adjuvant therapy
• Prior treatment with anti-programmed cell death (anti-PD)-1, anti-PD ligand-1/2, anti-CD137, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) modulators or any other immune-modulating agents
• Live vaccine within 30 days prior to the first infusion of study treatment
• Current participation or treatment with an investigational agent or use of an investigational device within 4 weeks of the first infusion of study treatment
• History of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive). No known active Hepatitis B or C
• Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 3 days prior to the first infusion of study treatment
• History of interstitial lung disease or (non-infectious) pneumonitis that required oral or IV steroids (other than COPD exacerbation) or current pneumonitis
• Active autoimmune disease that has required systemic treatment in past 2 years
• History of a hematologic or primary solid tumor malignancy, unless in remission for at least 5 years with the exception of pT1-2 prostatic cancer Gleason score < 6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix
• Previous allogeneic tissue/solid organ transplant
• Active infection requiring therapy
• Surgery- or chemotherapy-related toxicity (non-hematological) not resolved to Grade 1 with the exception of alopecia, fatigue, neuropathy and lack of appetite /nausea
• Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last infusion of study treatment
• Participant will not be eligible if the participant is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial, unless prospective site Review Board approval is given allowing exception to this criterion for a specific participant

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided
• Removed Location Countries: Australia, Austria, Belgium, Brazil, Canada, Chile, Czechia, Denmark, Estonia, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Latvia, Netherlands, Peru, Poland, Portugal, Russian Federation, Slovenia, Spain, Switzerland, Turkey, United Kingdom

Administrative Information

• NCT Number: NCT02504372
• Other Study ID Numbers: 3475-091; EORTC-1416-LCG ( Other Identifier: EORTC ); 163457 ( Registry Identifier: JAPIC-CTI ); MK-3475-091 ( Other Identifier: Merck ); KEYNOTE-091 ( Other Identifier: Merck ); 2015-000575-27 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

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

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current

Collaborators

• ETOP
• European Organisation for Research and Treatment of Cancer - EORTC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: February 2024