Study of Two Doses of Pembrolizumab (MK-3475) Versus Docetaxel in Previously Treated Participants With Non-Small Cell Lung Cancer (MK-3475-010/KEYNOTE-010)

• ClinicalTrials.gov Identifier: NCT01905657
• Recruitment Status: Completed
• First Posted: July 23, 2013
• Results First Posted: January 18, 2017
• Last Update Posted: October 6, 2021
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: July 18, 2013
• First Posted Date: July 23, 2013
• Results First Submitted Date: September 15, 2016
• Results First Posted Date: January 18, 2017
• Last Update Posted Date: October 6, 2021
• Actual Study Start Date: August 9, 2013
• Actual Primary Completion Date: September 30, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 13, 2021)

• Overall Survival (OS) [ Time Frame: Through pre-specified database cutoff date of 30 Sep 2015 (Up to approximately 24 months) ]
  OS was defined as the time from randomization to death due to any cause. OS was analyzed using the Kaplan-Meier method and is reported in months. Per protocol, final analysis for this primary outcome measure was performed for the first pembrolizumab course and docetaxel treatment arms, with a protocol-specified analysis data cutoff date of 30 September (Sep) 2015.
• Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Through pre-specified database cutoff date of 30 Sep 2015 (Up to approximately 24 months) ]
  PFS was defined as the time from the first day of study treatment to the first documented disease progression per RECIST 1.1 based on blinded independent central radiologists' review or death due to any cause, whichever occurred first. Using RECIST 1.1, progressive disease was defined as either a 20% relative increase in the sum of diameters of target lesions, taking as reference the smallest sum on study OR an absolute increase of >5 mm in the sum of lesions, OR the appearance of new lesions. PFS was analyzed using the Kaplan-Meier method and is reported in months. Per protocol, final analysis for this primary outcome measure was performed for the first pembrolizumab course and docetaxel treatment arms, with a protocol-specified analysis data cutoff date of 30 Sep 2015.
• Percentage of Participants Experiencing Adverse Events (AEs) [ Time Frame: Through pre-specified database cutoff date of 30 Sep 2015 (Up to approximately 24 months) ]
  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily had to have a causal relationship with this treatment. An AE is 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 medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. Per protocol, final analysis for this primary outcome measure was performed for the first pembrolizumab course and docetaxel treatment arms, with a protocol-specified analysis data cutoff date of 30 Sep 2015.
• Percentage of Participants Discontinuing Study Drug Due to AEs [ Time Frame: Through pre-specified database cutoff date of 30 Sep 2015 (Up to approximately 24 months) ]
  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily had to have a causal relationship with this treatment. An AE is 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 medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. Per protocol, final analysis for this primary outcome measure was performed for the first pembrolizumab course and docetaxel treatment arms, with a protocol-specified analysis data cutoff date of 30 Sep 2015.

Original Primary Outcome Measures (submitted: July 18, 2013)

• Overall Survival (OS) [ Time Frame: Up to 3 years ]
• Progression free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [ Time Frame: Up to 3 years ]
• Number of participants experiencing adverse events [ Time Frame: Up to 3 years ]
• Number of participants discontinuing study drug due to adverse events [ Time Frame: Up to 3 years ]

Current Secondary Outcome Measures (submitted: September 13, 2021)

• Overall Response Rate (ORR) by RECIST 1.1 [ Time Frame: Through pre-specified database cutoff date of 30 Sep 2015 (Up to approximately 24 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 Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) based on blinded independent central radiologists' review using RECIST 1.1. Per protocol, final analysis for this secondary outcome measure was performed for the first pembrolizumab course and docetaxel treatment arms, with a protocol-specified analysis data cutoff date of 30 Sep 2015.
• Duration of Response (DOR) by RECIST 1.1 [ Time Frame: Through pre-specified database cutoff date of 30 Sep 2015 (Up to approximately 24 months) ]
  DOR is measured from the time measurement criteria were first met for CR/PR (whichever was first recorded) until the first date that death or progressive disease was objectively documented (taking as reference for progressive disease the smallest measurements recorded on study). Non-responders were not included in the analysis. DOR was analyzed using the Kaplan-Meier method and is reported in weeks. Per protocol, final analysis for this secondary outcome measure was performed for the first pembrolizumab course and docetaxel treatment arms, with a protocol-specified analysis data cutoff date of 30 Sep 2015.

Original Secondary Outcome Measures (submitted: July 18, 2013)

• Overall response rate (ORR) by RECIST 1.1 [ Time Frame: Up to 3 years ]
• Response duration by RECIST 1.1 [ Time Frame: Up to 3 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Two Doses of Pembrolizumab (MK-3475) Versus Docetaxel in Previously Treated Participants With Non-Small Cell Lung Cancer (MK-3475-010/KEYNOTE-010)
• Official Title: A Phase II/III Randomized Trial of Two Doses of MK-3475 (SCH900475) Versus Docetaxel in Previously Treated Subjects With Non-Small Cell Lung Cancer

Brief Summary

This study compared two doses of pembrolizumab (MK-3475) versus docetaxel in participants with non-small cell lung cancer (NSCLC) who had experienced disease progression after platinum-containing systemic therapy. Participants were assigned randomly to receive either pembrolizumab 2 mg/kg once every three weeks (Q3W), pembrolizumab 10 mg/kg Q3W or docetaxel 75 mg/m^2 Q3W. The total number of participants randomized depended upon demonstration of sufficient objective responses at an interim analysis.

Eligible participants who were allocated to the first course of pembrolizumab (2 mg/kg Q3W or 10 mg/kg Q3W) and experienced disease progression, to be permitted to receive a second course of pembrolizumab as long as Inclusion/Exclusion criteria were met.

Protocol Amendment 12 (effective date: 09 Dec 2015) enabled eligible participants who were allocated to docetaxel and experienced disease progression, to be permitted to switch over to receive pembrolizumab 2 mg/kg Q3W as long as Inclusion/Exclusion criteria were met.

With Protocol Amendment 15 (effective date: 03 Jan 2018), all second course and switch over participants will receive pembrolizumab 200 mg Q3W. Response or progression during the second and switch over pembrolizumab courses will not count towards efficacy outcome measures, and adverse events during the second and switch over pembrolizumab courses will not count towards safety outcome measures.

Also with Amendment 15, once a participant has achieved the study objective or the study has ended, the participant will be discontinued from this study and enrolled in an extension study (Keynote 587; NCT03486873) to continue protocol-defined assessments and treatment. Switch over participants who have not transitioned to pembrolizumab will be considered for the extension study on a case-by-case basis.

The primary study hypotheses are that pembolizumab prolongs Overall Survival (OS) and Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by independent radiologists' review in previously-treated participants with NSCLC in the strongly positive programmed cell death ligand 1 (PD-L1) stratum compared to docetaxel and in participants whose tumors express PD-L1 compared to docetaxel.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non Small Cell Lung Cancer (NSCLC)

Intervention

• Biological: Pembrolizumab
  IV infusion
  Other Names:

  • MK-3475
  • KEYTRUDA®
• Drug: Docetaxel
  IV infusion
  Other Name: TAXOTERE®

Study Arms

• Experimental: Pembrolizumab 2 mg/kg
  Participants received pembrolizumab 2 mg/kg intravenously (IV) over 30 minutes Q3W for up to 2 years.
  Intervention: Biological: Pembrolizumab
• Experimental: Pembrolizumab 10 mg/kg
  Participants received pembrolizumab 10 mg/kg IV over 30 minutes Q3W for up to 2 years.
  Intervention: Biological: Pembrolizumab
• Active Comparator: Docetaxel 75 mg/m^2
  Participants received docetaxel 75 mg/m^2 IV over 1 hour Q3W for up to 2 years.
  Intervention: Drug: Docetaxel

Publications *

• Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19.
• Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A, Lunceford J. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.
• Jemielita T, Li XN, Piperdi B, Zhou W, Burke T, Chen C. Overall Survival With Second-Line Pembrolizumab in Patients With Non-Small-Cell Lung Cancer: Randomized Phase III Clinical Trial Versus Propensity-Adjusted Real-World Data. JCO Clin Cancer Inform. 2021 Jan;5:56-65. doi: 10.1200/CCI.20.00099.
• Lala M, Li TR, de Alwis DP, Sinha V, Mayawala K, Yamamoto N, Siu LL, Chartash E, Aboshady H, Jain L. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020 May;131:68-75. doi: 10.1016/j.ejca.2020.02.016. Epub 2020 Apr 15. Erratum In: Eur J Cancer. 2021 Feb;144:400.
• Herbst RS, Garon EB, Kim DW, Cho BC, Perez-Gracia JL, Han JY, Arvis CD, Majem M, Forster MD, Monnet I, Novello S, Szalai Z, Gubens MA, Su WC, Ceresoli GL, Samkari A, Jensen EH, Lubiniecki GM, Baas P. Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1-Positive, Advanced Non-Small-Cell Lung Cancer in the KEYNOTE-010 Study. J Clin Oncol. 2020 May 10;38(14):1580-1590. doi: 10.1200/JCO.19.02446. Epub 2020 Feb 20.
• van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.
• Barlesi F, Garon EB, Kim DW, Felip E, Han JY, Kim JH, Ahn MJ, Fidler MJ, Gubens MA, de Castro G Jr, Surmont V, Li Q, Deitz AC, Lubiniecki GM, Herbst RS. Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1-Expressing NSCLC. J Thorac Oncol. 2019 May;14(5):793-801. doi: 10.1016/j.jtho.2019.01.016. Epub 2019 Jan 31. Erratum In: J Thorac Oncol. 2019 Jul;14(7):1306.
• Herbst RS, Baas P, Perez-Gracia JL, Felip E, Kim DW, Han JY, Molina JR, Kim JH, Dubos Arvis C, Ahn MJ, Majem M, Fidler MJ, Surmont V, de Castro G Jr, Garrido M, Shentu Y, Emancipator K, Samkari A, Jensen EH, Lubiniecki GM, Garon EB. Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial. Ann Oncol. 2019 Feb 1;30(2):281-289. doi: 10.1093/annonc/mdy545.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 6, 2021): 1034
• Original Estimated Enrollment (submitted: July 18, 2013): 920
• Actual Study Completion Date: September 30, 2020
• Actual Primary Completion Date: September 30, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Life expectancy of at least 3 months
• Histologically- or cytologically-confirmed diagnosis of NSCLC that is anti-programmed cell death ligand 1 (PD-L1) positive per central laboratory review
• At least one bi-dimensional measurable lesion
• Radiographic progression after treatment with at least 2 cycles of a platinum-containing doublet
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

Exclusion Criteria:

• Prior therapy with docetaxel for NSCLC
• Receiving systemic steroid therapy within 3 days prior to the first dose of study treatment or receiving any other form of immunosuppressive medication
• Currently participating or has participated in a study using an investigational antineoplastic agent or device within 30 days of first dose
• Expected to require any other form of systemic or localized antineoplastic therapy while on trial
• History of allogeneic tissue/solid organ transplant
• Prior systemic cytotoxic chemotherapy, antineoplastic biological therapy (e.g., cetuximab), major surgery within 3 weeks of the first dose of study drug; received thoracic radiation therapy of >30 Gy within 6 months of the first dose of study drug; received prior tyrosine kinase inhibitor therapy or completed palliative radiotherapy within 7 days of the first dose of study drug
• Prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-tumor necrosis factor 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), or took part in another pembrolizumab trial
• Known history of prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cervical cancer, and has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Active autoimmune disease, or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents
• Interstitial lung disease, or history of pneumonitis requiring systemic steroids for treatment
• Known history or active human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
• Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial through 120 days after last dose of pembrolizumab or 180 days after last dose of docetaxel

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: Argentina, Australia, Belgium, Brazil, Canada, Chile, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Japan, Korea, Republic of, Lithuania, Netherlands, Portugal, Russian Federation, South Africa, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT01905657
• Other Study ID Numbers: 3475-010; 2012-004391-19 ( EudraCT Number ); 132355 ( Registry Identifier: Japic-CTI ); MK-3475-010 ( Other Identifier: Merck ); KEYNOTE-010 ( Other Identifier: Merck )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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: Not Provided

Investigators

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

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: September 2021