Pembrolizumab With Talimogene Laherparepvec or Placebo in Unresected Melanoma (MASTERKEY-265)

A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable Stage IIIB to IVM1c Melanoma (MASTERKEY-265)

The primary objectives of the Phase 1b part of the study are to evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in adults with previously untreated, unresectable, stage IIIB to IVM1c melanoma.

The primary objective of Phase 3 are to evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free survival (PFS) (response evaluation by blinded independent central review using modified Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and overall survival (OS).

Study Overview

• Status: Terminated
• Conditions: Melanoma
• Intervention / Treatment: Drug: Talimogene Laherparepvec; Drug: Pembrolizumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 713
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • North Sydney, New South Wales, Australia, 2060
      • Research Site
    • Waratah, New South Wales, Australia, 2298
      • Research Site
    • Wollongong, New South Wales, Australia, 2500
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  • Queensland
    • Southport, Queensland, Australia, 4215
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    • Woolloongabba, Queensland, Australia, 4102
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  • South Australia
    • Woodville South, South Australia, Australia, 5011
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  • Victoria
    • Geelong, Victoria, Australia, 3220
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    • Heidelberg, Victoria, Australia, 3084
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    • Melbourne, Victoria, Australia, 3000
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    • Prahran, Victoria, Australia, 3181
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  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
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• Austria
  • Graz, Austria, 8036
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  • Innsbruck, Austria, 6020
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  • Salzburg, Austria, 5020
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  • Wien, Austria, 1090
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• Belgium
  • Bruxelles, Belgium, 1200
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  • Liege, Belgium, 4000
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• Canada
  • Quebec, Canada, G1R 2J6
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  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
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  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
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    • London, Ontario, Canada, N6A 4L6
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    • Ottawa, Ontario, Canada, K1H 8L6
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    • Toronto, Ontario, Canada, M5G 2M9
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  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
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• Czechia
  • Brno, Czechia, 656 53
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  • Olomouc, Czechia, 775 20
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  • Ostrava-Poruba, Czechia, 708 52
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  • Praha 10, Czechia, 100 34
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  • Praha 2, Czechia, 128 08
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  • Praha 8, Czechia, 180 81
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• Finland
  • Helsinki, Finland, 00290
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• France
  • Bordeaux Cedex, France, 33075
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  • Grenoble Cedex 9, France, 38043
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  • Lille, France, 59037
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  • Lyon cedex 08, France, 69373
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  • Marseille cedex 05, France, 13385
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  • Nantes Cedex 1, France, 44093
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  • Paris, France, 75010
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  • Pierre Benite Cedex, France, 69495
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  • Toulouse cedex 9, France, 31059
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  • Vandoeuvre les Nancy, France, 54511
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• Germany
  • Berlin, Germany, 10117
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  • Dresden, Germany, 01307
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  • Erlangen, Germany, 91054
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  • Essen, Germany, 45147
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  • Hannover, Germany, 30625
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  • Heidelberg, Germany, 69120
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  • Kiel, Germany, 24105
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  • Leipzig, Germany, 04103
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  • Mainz, Germany, 55131
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  • Mannheim, Germany, 68167
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  • München, Germany, 80337
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  • Regensburg, Germany, 93053
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  • Tübingen, Germany, 72076
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  • Würzburg, Germany, 97080
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• Greece
  • Athens, Greece, 11527
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  • Athens, Greece, 18547
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  • Heraklion - Crete, Greece, 71110
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  • Ioannina, Greece, 45500
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  • Thessaloniki, Greece, 54622
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• Hungary
  • Budapest, Hungary, 1122
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  • Pecs, Hungary, 7632
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  • Szeged, Hungary, 6720
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• Italy
  • Bergamo, Italy, 24127
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  • Brescia, Italy, 25123
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  • Meldola FC, Italy, 47014
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  • Milano, Italy, 20141
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  • Milano, Italy, 20133
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  • Siena, Italy, 53100
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• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
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  • Seoul, Korea, Republic of, 05505
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• Netherlands
  • Amsterdam, Netherlands, 1066 CX
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  • Amsterdam, Netherlands, 1081 HV
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  • Groningen, Netherlands, 9713 GZ
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  • Nijmegen, Netherlands, 6525 GA
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• Poland
  • Bielsko-Biala, Poland, 43-300
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  • Bydgoszcz, Poland, 85-796
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  • Gdansk, Poland, 80-952
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  • Konin, Poland, 62-500
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  • Krakow, Poland, 31-501
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  • Poznan, Poland, 60-848
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  • Poznan, Poland, 61-866
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  • Szczecin, Poland, 71-730
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  • Warszawa, Poland, 02-781
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  • Wroclaw, Poland, 50-368
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• Portugal
  • Almada, Portugal, 2801-951
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  • Lisboa, Portugal, 1649-035
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  • Lisboa, Portugal, 1099-023
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  • Porto, Portugal, 4200-072
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• Russian Federation
  • Moscow, Russian Federation, 115478
    • Research Site
  • Saint-Petersburg, Russian Federation, 197758
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• South Africa
  • Kraaifontein, South Africa, 7570
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  • Pretoria, South Africa, 0002
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  • Pretoria, South Africa, 0081
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  • Gauteng
    • Groenkloof, Gauteng, South Africa, 0181
      • Research Site
    • Johannesburg, Gauteng, South Africa, 2196
      • Research Site
    • Parktown, Gauteng, South Africa, 2193
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• Spain
  • Madrid, Spain, 28046
    • Research Site
  • Madrid, Spain, 28009
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  • Madrid, Spain, 28050
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  • Cataluña
    • Badalona, Cataluña, Spain, 08916
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    • Barcelona, Cataluña, Spain, 08036
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  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46014
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  • Navarra
    • Pamplona, Navarra, Spain, 31008
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  • País Vasco
    • San Sebastian, País Vasco, Spain, 20014
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• Switzerland
  • Bellinzona, Switzerland, 6500
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  • Bern, Switzerland, 3010
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  • Geneva 14, Switzerland, 1211
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  • Lausanne, Switzerland, 1011
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  • Zürich, Switzerland, 8091
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• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
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  • Guildford, United Kingdom, GU2 7XX
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  • Leeds, United Kingdom, LS9 7TF
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  • Leicester, United Kingdom, LE1 5WW
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  • London, United Kingdom, SW3 6JJ
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  • London, United Kingdom, SE1 9RT
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  • Manchester, United Kingdom, M20 4BX
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  • Oxford, United Kingdom, OX3 7LJ
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  • Preston, United Kingdom, PR2 9HT
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  • Southampton, United Kingdom, SO16 6YD
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• United States
  • Alabama
    • Birmingham, Alabama, United States, 35243
      • Research Site
    • Mobile, Alabama, United States, 36608
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  • California
    • Beverly Hills, California, United States, 90211
      • Research Site
    • Duarte, California, United States, 91010
      • Research Site
    • Encinitas, California, United States, 92024
      • Research Site
    • La Jolla, California, United States, 92037
      • Research Site
    • Los Angeles, California, United States, 90025
      • Research Site
    • Los Angeles, California, United States, 90024
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    • Riverside, California, United States, 92505
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    • San Francisco, California, United States, 94115
      • Research Site
    • San Francisco, California, United States, 94117
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    • Santa Monica, California, United States, 90404
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  • Florida
    • Miami, Florida, United States, 33136
      • Research Site
    • Miami Beach, Florida, United States, 33140
      • Research Site
    • Orlando, Florida, United States, 32806
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  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Research Site
    • Chicago, Illinois, United States, 60611
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  • Kentucky
    • Louisville, Kentucky, United States, 40202
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  • Maryland
    • Baltimore, Maryland, United States, 21237
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  • Massachusetts
    • Boston, Massachusetts, United States, 02215
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  • Michigan
    • Detroit, Michigan, United States, 48201
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  • Minnesota
    • Fridley, Minnesota, United States, 55432
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110-1093
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  • New Jersey
    • Hackensack, New Jersey, United States, 07601
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  • New York
    • Buffalo, New York, United States, 14263
      • Research Site
    • New York, New York, United States, 10016
      • Research Site
    • New York, New York, United States, 10032
      • Research Site
    • New York, New York, United States, 10065
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  • Ohio
    • Cincinnati, Ohio, United States, 45209
      • Research Site
    • Cleveland, Ohio, United States, 44195
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  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Research Site
    • Philadelphia, Pennsylvania, United States, 19111
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    • Pittsburgh, Pennsylvania, United States, 15232
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  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Research Site
    • Knoxville, Tennessee, United States, 37920
      • Research Site
    • Nashville, Tennessee, United States, 37232
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  • Texas
    • Dallas, Texas, United States, 75246
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  • Utah
    • Murray, Utah, United States, 84107
      • Research Site
    • Salt Lake City, Utah, United States, 84112
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  • Washington
    • Seattle, Washington, United States, 98109-1023
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Age ≥ 18 years with histologically confirmed diagnosis of melanoma and stage IIIB to IVM1c for whom surgery is not recommended.
• Subjects must have measurable disease and be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal lesions.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate hematologic, hepatic, renal, and coagulation function.
• Subjects with serine/threonine protein kinase B-Raf V600 (BRAFV600) wild-type tumors must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant setting for unresectable stage IIIB to IVM1c melanoma.
• Subjects with B-Raf V600 (BRAFV600) mutated tumors who have received prior BRAF inhibitor therapy either alone or in combination with mitogen-activated protein kinase kinase (MEK) inhibitor as their only prior systemic therapy are eligible.
• Subjects who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to, interferon, ipilimumab, limb infusion/perfusion, or use of investigational agents in the adjuvant setting) with the exception that prior adjuvant therapy with inhibitors of programmed cell death-1 (PD-1) or programmed cell death ligand 1 (PD-L1) is not allowed. However, if the subject received adjuvant therapy, the subject must have completed therapy at least 28 days prior to enrollment.
• Subjects must have a tumor sample that is adequate for PD-L1 assessment prior to randomization.

Key Exclusion Criteria:

• Subjects must not have clinically active cerebral metastases.
• Subjects must not have primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states or history of other malignancy within the past 3 years.
• Subjects may not have been previously treated with talimogene laherparepvec, any other oncolytic virus, pembrolizumab, or any other inhibitor of PD-1, PD-L1, or PD-L2.
• Subjects must not have history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, other symptomatic autoimmune disease, documented history of autoimmune disease or syndrome requiring systemic treatment in the past 2 years (ie, with use of disease modifying agents, steroids or immunosuppressive agents) except vitiligo or resolved childhood asthma/atopy, or evidence of clinically significant immunosuppression.
• Subjects must not have active herpetic skin lesions or prior complications of herpetic infection and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1b: Talimogene Laherparepvec + Pembrolizumab; Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.	Drug: Talimogene Laherparepvec; Talimogene laherparepvec administered by intratumoral injection; Other Names: IMLYGIC®; OncoVEX^GM-CSF; T-VEC; Drug: Pembrolizumab; Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.; Other Names: MK-3475; Keytruda®
Placebo Comparator: Phase 3 : Placebo + Pembrolizumab; Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.	Drug: Pembrolizumab; Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.; Other Names: MK-3475; Keytruda®; Drug: Placebo; Administered by intratumoral injection
Experimental: Phase 3: Talimogene Laherparepvec + Pembrolizumab; Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.	Drug: Talimogene Laherparepvec; Talimogene laherparepvec administered by intratumoral injection; Other Names: IMLYGIC®; OncoVEX^GM-CSF; T-VEC; Drug: Pembrolizumab; Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.; Other Names: MK-3475; Keytruda®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)	A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: Grade 4 non-hematologic toxicity.; Grade 3 or higher pneumonitis.; Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care, excluding grade 3 fatigue.; Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for > 1 week.; Febrile neutropenia grade 3 or grade 4.; Thrombocytopenia < 25 x 10^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit.; Grade 5 toxicity (ie, death).; Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab.	The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12).
Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1	PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause. PD: Increase in size of target lesions from nadir by ≥ 20% and ≥ 5 mm absolute increase above nadir, or the appearance of a new lesion. Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020).	From randomization until the data-cut-off date of 02 March 2020; median (range) time on follow-up was 25.5 (0.6, 44.7) months in the Placebo + Pembrolizumab arm and 25.6 (0.3, 45.8) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 3: Overall Survival	Overall survival (OS) is defined as the interval from randomization to death from any cause. Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.	From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Objective Response Rate (ORR)	ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart. Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers.	Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
Phase 1b: Best Overall Response (BOR)	Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.	Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
Phase 1b: Durable Response Rate (DRR)	DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.	Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
Phase 1b: Duration of Response (DOR)	Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.	Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
Phase 1b: Disease Control Rate (DCR)	DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 84 days elapsed after enrollment.	Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
Phase 1b: Progression-free Survival (PFS)	Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment.	From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
Phase 1b: Overall Survival (OS)	Overall survival is defined as the interval from first dose to death from any cause. OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.	From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR)	Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only.	Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS)	PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause. iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection. Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020).	From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 3: Overall Survival Excluding Stage IVM1c Participants	Overall survival is defined as the interval from randomization to death from any cause. Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date.	From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1	ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ.	Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1	BOR is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE per modified RECIST 1.1, evaluated by BICR. CR: Disappearance of all lesions except lymph node short axis < 10 mm; PR: ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required; NN: Persistence of ≥ 1 non-target lesions and/or maintenance of tumor marker level above normal limits; SD: Neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD and ≥ 84 days from randomization; PD: Increase from nadir by ≥ 20% or ≥ 5 mm of target lesions or any new lesion; Missing: No postbaseline assessment, or assessments on or after the start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.	Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1	DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 evaluated by blinded independent central review, with a duration of response of ≥ 6 months. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.	Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1	Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of the first subsequent anticancer therapy. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. PD was defined as an increase from nadir by ≥ 20% or ≥ 5 mm absolute increase above nadir of target lesions or appearance of any new lesion.	From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1	Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization.	Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR)	Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only.	Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST	BOR is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by BICR. iCR: Disappearance of all lesions confirmed by consecutive assessment ≥ 4 weeks from the date first documented. Reduction of any pathological lymph node to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed ≥ 4 weeks after first documentation. iPD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmed ≥ 4 weeks from initial detection. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD and ≥ 84 days from randomization. Missing: No postbaseline assessment, or assessments after start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.	Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR)	Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response ≥ 6 months. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.	Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR)	Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.	From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR)	Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization.	Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score	The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items. The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement. The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section).	Baseline and day 1 of weeks 3, 6, 9, 12, then every 6 weeks until end of study treatment; median (range) duration of treatment was 39.0 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 54.1 (0.1, 109.6) weeks in Talimogene Laherparepvec + Pembrolizumab.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose. A serious adverse event (SAE) is an AE that met at least 1 of the following criteria: fatal; life threatening; required in-patient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier. AEs were graded for severity using CTCAE version 4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.	From first dose to 30 days after last dose (90 days for SAEs); median (range) duration was 48 (5.1, 110.1) weeks in Phase 1b, 39 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 56 (0.1, 109.6) weeks in Phase 3 Talimogene Laherparepvec + Pembrolizumab.

Collaborators and Investigators

• Sponsor: Amgen
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ, Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Chen L, Gorski KS, Anderson AA, Diede SJ, Lassman ME, Gansert J, Hodi FS, Long GV. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017 Sep 7;170(6):1109-1119.e10. doi: 10.1016/j.cell.2017.08.027. Erratum In: Cell. 2018 Aug 9;174(4):1031-1032.
• Dummer R, Hoeller C, Gruter IP, Michielin O. Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors. Cancer Immunol Immunother. 2017 Jun;66(6):683-695. doi: 10.1007/s00262-017-1967-1. Epub 2017 Feb 25.
• Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, Hoeller C, Gajewski TF, Gutzmer R, Rutkowski P, Demidov L, Arenberger P, Shin SJ, Ferrucci PF, Haydon A, Hyngstrom J, van Thienen JV, Haferkamp S, Guilera JM, Rapoport BL, VanderWalde A, Diede SJ, Anderson JR, Treichel S, Chan EL, Bhatta S, Gansert J, Hodi FS, Gogas H. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. J Clin Oncol. 2022 Aug 23:JCO2200343. doi: 10.1200/JCO.22.00343. Online ahead of print.
• Watanabe D, Goshima F. Oncolytic Virotherapy by HSV. Adv Exp Med Biol. 2018;1045:63-84. doi: 10.1007/978-981-10-7230-7_4.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2014
• Primary Completion (Actual): March 11, 2021
• Study Completion (Actual): March 11, 2021

Study Registration Dates

• First Submitted: September 26, 2014
• First Submitted That Met QC Criteria: October 9, 2014
• First Posted (Estimate): October 13, 2014

Study Record Updates

• Last Update Posted (Actual): November 14, 2022
• Last Update Submitted That Met QC Criteria: November 10, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: pembrolizumab; Talimogene Laherparepvec; KEYNOTE-034; MASTERKEY-265
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab; Talimogene laherparepvec
• Other Study ID Numbers: 20110265; 2014-000185-22 (EudraCT Number); KEYNOTE-034 (Other Identifier: Merck Sharp & Dohme Corp.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No