Combining T-VEC with Pembrolizumab Promising in Late-Stage Melanoma

Georgina V. Long, PhD, MBBS

In a phase Ib study, combining talimogene laherparepvec (T-VEC), an oncolytic virus, with pembrolizumab at full doses had an acceptable safety profile, with evidence of clinical benefit in patients with advanced melanoma.

The results of this small trial in 21 patients was reported by Georgina V. Long, PhD, MBBS, Melanoma Institute Australia and The University of Sydney, North Sydney, Australia, at a poster session at the 2016 ASCO Annual Meeting.

T-VEC is a genetically modified herpes simplex virus-1 that selectively replicates in tumor cells after intralesional injection. T-VEC causes tumor cell lysis and the release of tumor-derived antigens, and stimulates the production of granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF enhances antigen presentation and stimulates antitumor immune responses in patients with melanoma.

Combining T-VEC with ipilimumab, which targets different cancer immune response pathways, has improved antitumor responses in patients with unresectable stage IIIb/IV melanoma. Pembrolizumab, an anti-programmed death receptor-1 (PD-1) antibody, is associated with greater progression-free survival (PFS) and overall survival (OS) than ipilimumab, suggesting the combination of T-VEC with pembrolizumab might be more effective than the combination of T-VEC with ipiliumumab.

MASTERKEY-265 (NCT02263508), a phase Ib study, was designed to determine safety, efficacy, and biomarker data in patients with stage III/IV unresectable melanoma receiving the combination of T-VEC with pembrolizumab. The primary endpoint of this study was the incidence of dose-limiting toxicities (DLTs), evaluated by a dose level review team. Secondary endpoints included the incidence of adverse events (AEs), objective response rate (ORR) by immune-related response criteria, duration of response (DOR), and PFS.

Key inclusion criterial for the 21 patients who were enrolled included presence of unresectable stage IIIb/IV melanoma with injectable lesions, no prior systemic therapy and no active herpetic skin lesions or prior complications from a prior herpetic infection.

Patients received up to 4 mL T-VEC by injection into cutaneous/nodal lesions. The first dose contained 10⁶plaque-forming units (PFU) per mL; the second dose at day 22 contained 10⁸PFU per mL; subsequent doses at 10⁸PFU/mL were given every 2 weeks until progressive disease, intolerance, disappearance of all injectable tumors, or at 2 years of treatment. Pembrolizumab 200 mg was given intravenously every 2 weeks after the first 2 T-VEC injections. DLTs were assessed for 6 weeks from the first pembrolizumab treatment.

No DLTs were observed. The safety profile of the combination of full doses of T-VEC and pembrolizumab was as expected for the agents as monotherapies. One patient died of progressive disease. AEs resulted in interruption of T-VEC in 6 patients and of pembrolizumab in 7 patients. Two patients discontinued therapy because of pembrolizumab-related AEs.

The confirmed ORR was 57.1%, with 23.8% confirmed complete responses (CR). The unconfirmed ORR was 66.7%, and the unconfirmed CR rate was 28.8%. The median follow-up time was not indicated. The disease control rate (including stable disease, partial response, and complete response) was 71.4%. Median PFS was not reached.

Biomarker analysis included characterization of T-cell subsets, expression of markers of proliferation, activation, and checkpoint. Circulating cytotoxic T-cells (CD3+/CD8+) increased, and PD-1 and TIM-3 on these cells were upregulated following initiation of T-VEC monotherapy. After the start of combination therapy, the proliferation marker Ki-67 increased in circulating cytotoxic T-cells; however, TIM-3 and BTLA were not upregulated after initiation of combination therapy.

“This is a phase Ib trial,” Dr. Long said, “and it’s in only 21 patients. Like all phase I trials it’s interesting but it’s not going to change practice. We need to wait for randomized [trial] results. There’s a trial now ongoing looking at pembrolizumab combined with T-VEC versus pembrolizumab combined with a placebo by intralesional injection and that will tell us whether there is truly an additive effect with T-VEC and pembrolizumab.”

The phase III part of MASTERKEY-265 is a randomized, double-blind, placebo-controlled trial that will recruit 660 patient with unresectable state IIIb/IV melanoma. The primary endpoints will be PFS and OS. This trial will assess long-term safety in a follow-up period lasting 5 years from the date of the last patient randomly assigned to treatment.

Dr. Long described the results of the phase Ib portion of MASTERKEY-265 as interesting, calling the combination of T-VEC and pembrolizumab “a very well-tolerated combination with no unusual adverse events.” Noting that these are “exciting early data,” she cautioned, “but let’s wait for the randomized data.”

Long GV, Dummer R, Ribase A, et al. Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma.J Clin Oncol34, 2016 (suppl; abstr 9568).