Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma

Jason Chesney, Igor Puzanov, Frances Collichio, Parminder Singh, Mohammed M. Milhem, John Glaspy, Omid Hamid, Merrick Ross, Philip Friedlander, Claus Garbe, Theodore F. Logan, Axel Hauschild, Celeste Lebbé, Lisa Chen, Jenny J. Kim, Jennifer Gansert, Robert H.I. Andtbacka, Howard L. Kaufman

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Abstract

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, # 4 mL 3 106 plaque-forming units/mL; after 3 weeks, # 4 mL 3 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade $ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Original languageEnglish (US)
Pages (from-to)1658-1667
Number of pages10
JournalJournal of Clinical Oncology
Volume36
Issue number17
DOIs
StatePublished - Jun 10 2018

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Melanoma
Safety
ipilimumab
Oncolytic Viruses
Chills
Therapeutics
Autoimmunity
Immunosuppression
Fatigue
Diarrhea
Odds Ratio
Research Personnel

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. / Chesney, Jason; Puzanov, Igor; Collichio, Frances; Singh, Parminder; Milhem, Mohammed M.; Glaspy, John; Hamid, Omid; Ross, Merrick; Friedlander, Philip; Garbe, Claus; Logan, Theodore F.; Hauschild, Axel; Lebbé, Celeste; Chen, Lisa; Kim, Jenny J.; Gansert, Jennifer; Andtbacka, Robert H.I.; Kaufman, Howard L.

In: Journal of Clinical Oncology, Vol. 36, No. 17, 10.06.2018, p. 1658-1667.

Research output: Contribution to journalArticle

Chesney, J, Puzanov, I, Collichio, F, Singh, P, Milhem, MM, Glaspy, J, Hamid, O, Ross, M, Friedlander, P, Garbe, C, Logan, TF, Hauschild, A, Lebbé, C, Chen, L, Kim, JJ, Gansert, J, Andtbacka, RHI & Kaufman, HL 2018, 'Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma', Journal of Clinical Oncology, vol. 36, no. 17, pp. 1658-1667. https://doi.org/10.1200/JCO.2017.73.7379
Chesney, Jason ; Puzanov, Igor ; Collichio, Frances ; Singh, Parminder ; Milhem, Mohammed M. ; Glaspy, John ; Hamid, Omid ; Ross, Merrick ; Friedlander, Philip ; Garbe, Claus ; Logan, Theodore F. ; Hauschild, Axel ; Lebbé, Celeste ; Chen, Lisa ; Kim, Jenny J. ; Gansert, Jennifer ; Andtbacka, Robert H.I. ; Kaufman, Howard L. / Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 17. pp. 1658-1667.
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abstract = "Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, # 4 mL 3 106 plaque-forming units/mL; after 3 weeks, # 4 mL 3 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39{\%}) in the combination arm and 18 patients (18{\%}) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95{\%} CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52{\%} of patients in the combination arm and 23{\%} of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59{\%}; ipilimumab alone, 42{\%}), chills (combination, 53{\%}; ipilimumab alone, 3{\%}), and diarrhea (combination, 42{\%}; ipilimumab alone, 35{\%}). Incidence of grade $ 3 AEs was 45{\%} and 35{\%}, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.",
author = "Jason Chesney and Igor Puzanov and Frances Collichio and Parminder Singh and Milhem, {Mohammed M.} and John Glaspy and Omid Hamid and Merrick Ross and Philip Friedlander and Claus Garbe and Logan, {Theodore F.} and Axel Hauschild and Celeste Lebb{\'e} and Lisa Chen and Kim, {Jenny J.} and Jennifer Gansert and Andtbacka, {Robert H.I.} and Kaufman, {Howard L.}",
year = "2018",
month = "6",
day = "10",
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TY - JOUR

T1 - Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma

AU - Chesney, Jason

AU - Puzanov, Igor

AU - Collichio, Frances

AU - Singh, Parminder

AU - Milhem, Mohammed M.

AU - Glaspy, John

AU - Hamid, Omid

AU - Ross, Merrick

AU - Friedlander, Philip

AU - Garbe, Claus

AU - Logan, Theodore F.

AU - Hauschild, Axel

AU - Lebbé, Celeste

AU - Chen, Lisa

AU - Kim, Jenny J.

AU - Gansert, Jennifer

AU - Andtbacka, Robert H.I.

AU - Kaufman, Howard L.

PY - 2018/6/10

Y1 - 2018/6/10

N2 - Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, # 4 mL 3 106 plaque-forming units/mL; after 3 weeks, # 4 mL 3 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade $ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

AB - Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, # 4 mL 3 106 plaque-forming units/mL; after 3 weeks, # 4 mL 3 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade $ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

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