The combination of the attenuated oncolytic virus talimogene laherparepvec and the immune checkpoint inhibitor pembrolizumab for unresectable melanoma has passed an early safety evaluation.
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A recently reported study showed that T-VEC treatment improved durable response in advanced melanoma.2 An as-yet unpublished phase Ib study showed that the combination of T-VEC and ipilimumab resulted in an overall response rate of 50%, durable response rate of 44%, and tolerable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.