Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma

Jason A Chesney, Antoni Ribas, Georgina V Long, John M Kirkwood, Reinhard Dummer, Igor Puzanov, Christoph Hoeller, Thomas F Gajewski, Ralf Gutzmer, Piotr Rutkowski, Lev Demidov, Petr Arenberger, Sang Joon Shin, Pier Francesco Ferrucci, Andrew Haydon, John Hyngstrom, Johannes V van Thienen, Sebastian Haferkamp, Josep Malvehy Guilera, Bernardo Leon Rapoport, Ari VanderWalde, Scott J Diede, James R Anderson, Sheryl Treichel, Edward L Chan, Sumita Bhatta, Jennifer Gansert, Frank Stephen Hodi, Helen Gogas, Jason A Chesney, Antoni Ribas, Georgina V Long, John M Kirkwood, Reinhard Dummer, Igor Puzanov, Christoph Hoeller, Thomas F Gajewski, Ralf Gutzmer, Piotr Rutkowski, Lev Demidov, Petr Arenberger, Sang Joon Shin, Pier Francesco Ferrucci, Andrew Haydon, John Hyngstrom, Johannes V van Thienen, Sebastian Haferkamp, Josep Malvehy Guilera, Bernardo Leon Rapoport, Ari VanderWalde, Scott J Diede, James R Anderson, Sheryl Treichel, Edward L Chan, Sumita Bhatta, Jennifer Gansert, Frank Stephen Hodi, Helen Gogas

Abstract

Purpose: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma.

Methods: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis.

Results: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm.

Conclusion: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

Trial registration: ClinicalTrials.gov NCT02263508.

Conflict of interest statement

Jason A. Chesney

Research Funding: Amgen, Replimune, Iovance Biotherapeutics, Bristol Myers Squibb

Patents, Royalties, Other Intellectual Property: University of Louisville US Patents

Antoni Ribas

Leadership: PACT Pharma, Arcus Biosciences, Lutris

Stock and Other Ownership Interests: Compugen, CytomX Therapeutics, Advaxis, Arcus Biosciences, Tango Therapeutics, PACT Pharma, Merus, ImaginAb, Lutris, Highlight Therapeutics, MapKure, 4c Biomed, Kite/Gilead, Isoplexis, Appia Bio, Synthekine, Pluto Immunotherapeutics, Inspirna, RAPT Therapeutics, ImmPACT-Bio

Honoraria: Merck Sharp & Dohme, Novartis, Amgen, Chugai/Roche, Genentech/Roche, Sanofi, Vedanta Biosciences, AstraZeneca

Consulting or Advisory Role: Merck, Amgen, Novartis, Chugai Pharma, Sanofi

Research Funding: Agilent (Inst), Bristol Myers Squibb (Inst)

Patents, Royalties, Other Intellectual Property: Non-viral gene editing to Arsenal Bio

Georgina V. Long

Honoraria: BMS, Pierre Fabre

Consulting or Advisory Role: Agenus, Amgen, Array BioPharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion Biotech, Hexal AG (Sandoz Company), Highlight Therapeutics, Innovent Biologics USA Inc, Merck Sharp & Dohme, Novartis, OncoSec Medical Australia, PHMR Limited, Pierre Fabre, Provectus, QBiotics, Regeneron

John M. Kirkwood

Honoraria: Bristol Myers Squibb

Consulting or Advisory Role: Novartis, Amgen, Harbor BioMed, Istari Oncology, Scopus BioPharma, Pfizer, AXIO Research, Immunocore, Natera, DermTech, Ankyra Therapeutics, Becker Pharmaceutical Consulting, Fenix Group International, IQVIA, Merck, Replimune, SR One Capital Management, Iovance Biotherapeutics, Checkmate Pharmaceuticals, OncoSec, OncoCyte, Cancer Network, Takeda, Applied Clinical Intelligence

Research Funding: Amgen (Inst), Bristol Myers Squibb (Inst), Checkmate Pharmaceuticals (Inst), Immunocore (Inst), Iovance Biotherapeutics (Inst), Novartis (Inst), ImmVira (Inst), Harbor BioMed (Inst), Takeda (Inst), Verastem (Inst)

Reinhard Dummer

Honoraria: Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator Bioscience, MaxiVax, TouchIME, T3 Pharmaceuticals, Pfizer

Consulting or Advisory Role: Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Alligator Bioscience, TouchIME, MaxiVax, Regeneron, Pfizer, T3 Pharmaceuticals

Research Funding: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Amgen (Inst)

Igor Puzanov

Stock and Other Ownership Interests: Celldex

Consulting or Advisory Role: Amgen, Iovance Biotherapeutics, Merck, Roche, Nouscom, Seneca Therapeutics, Nektar, Oncorus

Christoph Hoeller

Honoraria: Bristol Myers Squibb Foundation, MSD, Novartis, Sanofi, Pierre Fabre

Consulting or Advisory Role: Almirall Hermal GmbH, Bristol Myers Squibb Foundation, MSD, Novartis, Pierre Fabre, Sanofi, Immunocore

Research Funding: Amgen (Inst), Bristol Myers Squibb Foundation (Inst), MSD (Inst), Nektar (Inst), Novartis (Inst), Pierre Fabre (Inst), Roche (Inst)

Travel, Accommodations, Expenses: Bristol Myers Squibb Foundation (Inst), MSD (Inst), Pierre Fabre (Inst), Sanofi (Inst)

Thomas F. Gajewski

Stock and Other Ownership Interests: Jounce Therapeutics, Evelo Therapeutics, Pyxis

Consulting or Advisory Role: Merck, Jounce Therapeutics, Adaptimmune, FogPharma, Allogene Therapeutics, Pyxis, Trillium Therapeutics, MAIA Biotechnology, Bicara Therapeutics, CatalYm, Samyang

Research Funding: Bristol Myers Squibb (Inst), Merck (Inst), Roche/Genentech (Inst), Incyte (Inst), Seattle Genetics (Inst), Ono Pharmaceutical (Inst), Aduro Biotech (Inst), Pyxis (Inst), Bayer (Inst)

Patents, Royalties, Other Intellectual Property: Licensing to Evelo (Inst), Licensing to Aduro (Inst), Licensing to BMS (Inst), Licensing to Pyxis (Inst)

Ralf Gutzmer

Honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Merck Serono, Almirall Hermal GmbH, Amgen, Sun Pharma, Pierre Fabre, Sanofi/Regeneron, Immunocore

Consulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Almirall Hermal GmbH, 4SC, Amgen, Pierre Fabre, Merck Serono, Sun Pharma, Sanofi, Immunocore

Research Funding: Pfizer (Inst), Novartis (Inst), Johnson & Johnson (Inst), Amgen (Inst), Merck Serono (Inst), Sun Pharma (Inst), Sanofi (Inst)

Travel, Accommodations, Expenses: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma

Piotr Rutkowski

Honoraria: Bristol Myers Squibb, MSD, Novartis, Roche, Pfizer, Pierre Fabre, Sanofi, Merck

Consulting or Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, Amgen

Speakers' Bureau: Pfizer, Novartis, Pierre Fabre

Research Funding: Novartis (Inst), Roche (Inst), Bristol Myers Squibb (Inst)

Travel, Accommodations, Expenses: Orphan Europe, Pierre Fabre

Lev Demidov

Research Funding: Roche/Genentech, Amgen, BMS GmbH & Co KG, Novartis, BIOCAD

Petr Arenberger

Honoraria: AbbVie, Bristol Myers Squibb/Pfizer, Merck, Pierre Fabre, La Roche-Posay, Sanofi/Aventis, Novartis, Janssen

Consulting or Advisory Role: Sanofi/Aventis, AbbVie

Research Funding: Pfizer

Pier Francesco Ferrucci

Expert Testimony: Delcath Systems

Andrew Haydon

Honoraria: Novartis, Merck

Consulting or Advisory Role: Novartis, Merck Sharp & Dohme, Bristol Myers Squibb

Speakers' Bureau: Novartis, Merck, Bristol Myers Squibb

Expert Testimony: BMS

John Hyngstrom

Consulting or Advisory Role: Bristol Myers Squibb

Research Funding: Amgen (Inst), Skyline Diagnostics (Inst), LOKON (Inst), Checkmate Pharmaceuticals (Inst), Philogen (Inst), Iovance Biotherapeutics (Inst), Morphogenesis (Inst), Merck (Inst), Bristol Myers Squibb Foundation (Inst), Takara Bio (Inst), OncoSec (Inst), Signatera (Inst)

Open Payments Link: https://openpaymentsdata.cms.gov/physician/1239581

Sebastian Haferkamp

Honoraria: Novartis, Bristol Myers Squibb, Amgen

Consulting or Advisory Role: Bristol Myers Squibb, Novartis, Amgen, Roche, Pierre Fabre, MSD

Josep Malvehy Guilera

Stock and Other Ownership Interests: Athena Tech, Dermavision

Honoraria: ISDIN, Sun Pharma, Almirall, BMS, Pierre Fabre, Sanofi, Regeneron, Pfizer

Consulting or Advisory Role: Almirall, Sanofi, Pierre Fabre, ISDIN, Roche

Research Funding: ISDIN, Sun Pharma (Inst), Almirall (Inst), Roche (Inst)

Travel, Accommodations, Expenses: Almirall, ISDIN, Roche Posay, Pierre Fabre

Bernardo Leon Rapoport

Honoraria: Lilly, MSD, Janssen, Novartis South Africa

Consulting or Advisory Role: Janssen, Lilly, Novartis South Africa

Speakers' Bureau: Merck, Bristol Myers Squibb, Novartis South Africa, Roche, Lilly, Astellas Pharma, Amgen, Janssen, AstraZeneca, Mylan, ECS Progastrin

Research Funding: Roche, Sandoz, Cancer Association of South Africa, ECS Progastrin, GlaxoSmithKline, HalioDx

Ari Vanderwalde

Employment: Caris Life Sciences

Consulting or Advisory Role: Bristol Myers Squibb, Caris Life Sciences, Compugen, Concerto HealthAI, Elsevier, Inivata

Research Funding: Amgen (Inst), Merck (Inst), Genentech/Roche (Inst), Millennium (Inst), AstraZeneca (Inst), Lilly (Inst), Bristol Myers Squibb (Inst), Replimune (Inst), Caris Life Sciences (Inst), EMD Serono (Inst), Immunomedics/Gilead (Inst)

Scott J. Diede

Employment: Merck Sharp & Dohme

Stock and Other Ownership Interests: Merck Sharp & Dohme

James R. Anderson

Employment: Merck

Stock and Other Ownership Interests: Merck Sharp & Dohme

Travel, Accommodations, Expenses: Merck Sharp & Dohme

Sheryl Treichel

Employment: Amgen

Stock and Other Ownership Interests: Amgen

Edward L. Chan

Employment: Amgen, Arvinas

Stock and Other Ownership Interests: Amgen

Travel, Accommodations, Expenses: Amgen, Arvinas

Sumita Bhatta

Employment: Amgen

Stock and Other Ownership Interests: Amgen

Jennifer Gansert

Employment: Amgen

Stock and Other Ownership Interests: Amgen

Patents, Royalties, Other Intellectual Property: Talimogene laherparepvec patents. No royalties

Helen Gogas

Honoraria: Bristol Myers Squibb, MSD Oncology, Pierre Fabre, Sanofi/Regeneron

Consulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Amgen, Pierre Fabre, Sanofi/Regeneron

Research Funding: Bristol Myers Squibb (Inst), Roche (Inst), MSD Oncology (Inst), Amgen (Inst), Novartis (Inst), Iovance Biotherapeutics (Inst)

Travel, Accommodations, Expenses: Bristol Myers Squibb, MSD, Amgen, Pfizer

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
CONSORT diagram. T-VEC, talimogene laherparepvec.
FIG 2.
FIG 2.
(A) Kaplan-Meier estimate of PFS in the intention-to treat population. Vertical lines indicate censoring. (B) Forest plots for PFS in subgroups. HRs are shown for subgroups as defined by baseline patient and tumor characteristics. BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HSV, herpes simplex virus; IVRS, interactive voice response system; LDH, lactate dehydrogenase; PFS, progression-free survival; SLD, sum of lesion diameters; T-VEC, talimogene laherparepvec; ULN, upper limit of normal.
FIG 3.
FIG 3.
(A) Kaplan-Meier estimate of OS in the intention-to treat population. Vertical lines indicate censoring. (B) Forest plots for OS in subgroups. HRs are shown for subgroups as defined by baseline patient and tumor characteristics. BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HSV, herpes simplex virus; IVRS, interactive voice response system; LDH, lactate dehydrogenase; NE, not estimable; OS, overall survival; SLD, sum of lesion diameters; T-VEC, talimogene laherparepvec; ULN, upper limit of normal.

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