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T-VEC/Pembrolizumab Combination Demonstrates Safety in Melanoma

Published: Sunday, Sep 27, 2015

Dr. Georgina V. Long

Georgina Long, BSc, PhD, MBBS

The combination of the attenuated oncolytic virus talimogene laherparepvec (T-VEC) and the immune checkpoint inhibitor pembrolizumab has passed an early safety evaluation for unresectable melanoma, investigators reported at the 2015 European Cancer Congress (ECC).1

Treatment-related grade 3 adverse events occurred infrequently in a small phase Ib trial of combination therapy with T-VEC and pembrolizumab. No patient discontinued treatment because of adverse events and no treatment-related deaths occurred.

“T-VEC plus pembrolizumab was well tolerated, and we observed no dose-limiting toxicity,” said Georgina V. Long, BSc, PhD, MBBS, associate professor at the University of Sydney in Australia. “Treatment-related adverse events were mostly grade 1/2. The combination of T-VEC and pembrolizumab is feasible and warrants further investigation.”

PD-1/PD-L1 inhibitors, such as pembrolizumab, have demonstrated activity in advanced melanoma, which has stimulated interest in combination strategies to improve outcomes in patients with advanced disease. T-VEC is an oncolytic herpes simplex virus type 1 engineered to replicate selectively in tumor cells and express human granulocyte macrophage-colony stimulating factor (GM-CSF).

A recently reported study showed that T-VEC treatment improved durable response in advanced melanoma.2 An as-yet unpublished phase Ib study showed that the combination of T-VEC and ipilimumab resulted in an overall response rate of 50%, durable response rate of 44%, and tolerable safety profile in patients with advanced melanoma, said Long.

Investigators enrolled 21 patients with unresectable stage III/IV melanoma and no prior treatment. Patients with clinically active brain metastases or active herpetic skin lesions (or a history of complications from herpetic infection) were excluded.

Five weeks prior to initiating pembrolizumab, patients were given intralesional T-VEC injection at doses up to 4 mL per treatment (106 PFU/mL, then 108 PFU/mL every 2 weeks). Pembrolizumab (200) mg was then administered intravenously every 2 weeks at week 0. Dose-limiting toxicity was assessed during weeks 0 to 6.

Treatment continued until disease progression, development of intolerance, injectable tumor disappearance (T-VEC only), or 2 years. The primary endpoint was the incidence of dose-limiting toxicity.

Women accounted for 13 of the 21 patients, and 8 of the 21 had stage III disease at enrollment. About 20% of the patients had BRAF-positive melanoma. All of the patients received one or more doses of T-VEC and pembrolizumab. Median treatment duration was 13.1 weeks and seven infusions for T-VEC and 10.1 weeks and five infusions for pembrolizumab.

The most common adverse events of any grade were rash and pyrexia (each reported in 9 patients); fatigue (8); chills and nausea (7 each); headache and vomiting (5 each); diarrhea, arthralgia, and pruritus (4 each); and influenza-like illness and peripheral edema in 3 patients each.

Six patients had grade 3 adverse events, including four patients who had a total of five treatment-related adverse events (one case each of anemia, hyperglycemia, macular rash, headache, and generalized rash). No treatment-related grade 4 adverse events were reported, said Long.

Analysis of the timing of treatment-related adverse events showed spikes at the start of T-VEC and at the initiation of pembrolizumab.

Serious adverse events consisted of one case of grade 5 hypovolemic shock that was not considered treatment related and one case of grade 1 treatment-related cytokine release syndrome, which occurred early after initiation of pembrolizumab and did not recur.

One case of T-VEC–associated treatment interruption occurred during T-VEC monotherapy and two cases during T-VEC plus pembrolizumab. Four pembrolizumab-related treatment interruptions occurred.

Long said the safety data reported at ECC are as of June 10, and efficacy data are still being analyzed. Even so, a phase III continuation of the trial has been planned, comparing the combination to pembrolizumab alone. Pembrolizumab will be started concurrently with T-VEC, and the dosing interval for pembrolizumab will be increased to every 3 weeks.


  1. Long GV, Drummer R, Ribas A, et al. Safety data from the phase 1b part of the MASTERKEY-265 study combining talimogene laherparepvec (T-VEC) and pembrolizumab for unresectable stage IIIB-IV melanoma.Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract LBA24.
  2. Andtbacka RH, Kaufman HL, Collichio F, et al.Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780-2788.

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