Pembrolizumab With Talimogene Laherparepvec or Placebo in Unresected Melanoma

Melanoma Clinical Trial

— MASTERKEY-265  

Official title:

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02263508
• Other study ID #: 20110265
• Secondary ID: 2014-000185-22KE
• Status: Terminated
• Phase: Phase 3
• Start date: December 8, 2014
• Est. completion date: March 11, 2021

Study information

• Verified date: November 2022
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 713
• Est. completion date: March 11, 2021
• Est. primary completion date: March 11, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 95 Years

Eligibility

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.

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Talimogene Laherparepvec
Talimogene laherparepvec administered by intratumoral injection
• Pembrolizumab
Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.
• Placebo
Administered by intratumoral injection

Locations

Country	Name	City	State
Australia	Research Site	Geelong	Victoria
Australia	Research Site	Heidelberg	Victoria
Australia	Research Site	Melbourne	Victoria
Australia	Research Site	Murdoch	Western Australia
Australia	Research Site	North Sydney	New South Wales
Australia	Research Site	Prahran	Victoria
Australia	Research Site	Southport	Queensland
Australia	Research Site	Waratah	New South Wales
Australia	Research Site	Wollongong	New South Wales
Australia	Research Site	Woodville South	South Australia
Australia	Research Site	Woolloongabba	Queensland
Austria	Research Site	Graz
Austria	Research Site	Innsbruck
Austria	Research Site	Salzburg
Austria	Research Site	Wien
Belgium	Research Site	Bruxelles
Belgium	Research Site	Liege
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Kingston	Ontario
Canada	Research Site	London	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Toronto	Ontario
Czechia	Research Site	Brno
Czechia	Research Site	Olomouc
Czechia	Research Site	Ostrava-Poruba
Czechia	Research Site	Praha 10
Czechia	Research Site	Praha 2
Czechia	Research Site	Praha 8
Finland	Research Site	Helsinki
France	Research Site	Bordeaux Cedex
France	Research Site	Grenoble Cedex 9
France	Research Site	Lille
France	Research Site	Lyon cedex 08
France	Research Site	Marseille cedex 05
France	Research Site	Nantes Cedex 1
France	Research Site	Paris
France	Research Site	Pierre Benite Cedex
France	Research Site	Toulouse cedex 9
France	Research Site	Vandoeuvre les Nancy
Germany	Research Site	Berlin
Germany	Research Site	Dresden
Germany	Research Site	Erlangen
Germany	Research Site	Essen
Germany	Research Site	Hannover
Germany	Research Site	Heidelberg
Germany	Research Site	Kiel
Germany	Research Site	Leipzig
Germany	Research Site	Mainz
Germany	Research Site	Mannheim
Germany	Research Site	München
Germany	Research Site	Regensburg
Germany	Research Site	Tübingen
Germany	Research Site	Würzburg
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Heraklion - Crete
Greece	Research Site	Ioannina
Greece	Research Site	Thessaloniki
Hungary	Research Site	Budapest
Hungary	Research Site	Pecs
Hungary	Research Site	Szeged
Italy	Research Site	Bergamo
Italy	Research Site	Brescia
Italy	Research Site	Meldola FC
Italy	Research Site	Milano
Italy	Research Site	Milano
Italy	Research Site	Siena
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Groningen
Netherlands	Research Site	Nijmegen
Poland	Research Site	Bielsko-Biala
Poland	Research Site	Bydgoszcz
Poland	Research Site	Gdansk
Poland	Research Site	Konin
Poland	Research Site	Krakow
Poland	Research Site	Poznan
Poland	Research Site	Poznan
Poland	Research Site	Szczecin
Poland	Research Site	Warszawa
Poland	Research Site	Wroclaw
Portugal	Research Site	Almada
Portugal	Research Site	Lisboa
Portugal	Research Site	Lisboa
Portugal	Research Site	Porto
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Saint-Petersburg
South Africa	Research Site	Groenkloof	Gauteng
South Africa	Research Site	Johannesburg	Gauteng
South Africa	Research Site	Kraaifontein
South Africa	Research Site	Parktown	Gauteng
South Africa	Research Site	Pretoria
South Africa	Research Site	Pretoria
Spain	Research Site	Badalona	Cataluña
Spain	Research Site	Barcelona	Cataluña
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Pamplona	Navarra
Spain	Research Site	San Sebastian	País Vasco
Spain	Research Site	Valencia	Comunidad Valenciana
Switzerland	Research Site	Bellinzona
Switzerland	Research Site	Bern
Switzerland	Research Site	Geneva 14
Switzerland	Research Site	Lausanne
Switzerland	Research Site	Zürich
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Guildford
United Kingdom	Research Site	Leeds
United Kingdom	Research Site	Leicester
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Oxford
United Kingdom	Research Site	Preston
United Kingdom	Research Site	Southampton
United States	Research Site	Atlanta	Georgia
United States	Research Site	Baltimore	Maryland
United States	Research Site	Beverly Hills	California
United States	Research Site	Birmingham	Alabama
United States	Research Site	Boston	Massachusetts
United States	Research Site	Buffalo	New York
United States	Research Site	Chicago	Illinois
United States	Research Site	Chicago	Illinois
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Cleveland	Ohio
United States	Research Site	Dallas	Texas
United States	Research Site	Detroit	Michigan
United States	Research Site	Duarte	California
United States	Research Site	Encinitas	California
United States	Research Site	Fridley	Minnesota
United States	Research Site	Germantown	Tennessee
United States	Research Site	Hackensack	New Jersey
United States	Research Site	Knoxville	Tennessee
United States	Research Site	La Jolla	California
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	Louisville	Kentucky
United States	Research Site	Miami	Florida
United States	Research Site	Miami Beach	Florida
United States	Research Site	Mobile	Alabama
United States	Research Site	Murray	Utah
United States	Research Site	Nashville	Tennessee
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	Orlando	Florida
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Riverside	California
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Salt Lake City	Utah
United States	Research Site	San Francisco	California
United States	Research Site	San Francisco	California
United States	Research Site	Santa Monica	California
United States	Research Site	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Amgen	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  Finland,  France,  Germany,  Greece,  Hungary,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Portugal,  Russian Federation,  South Africa,  Spain,  Switzerland,  United Kingdom, 

References & Publications (3)

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. [Epub ahead of print] — View Citation

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. Review. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).
Primary	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.
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.

External Links

•   AmgenTrials clinical trials website