Immunotherapy Combination Demonstrates Benefit in Small, Early Trial of Melanoma

Patients with advanced melanoma saw evidence of clinical benefit with the combination of the oncolytic virus Imlygic (talimogene laherparepvec; T-VEC) and Keytruda (pembrolizumab). The combination also demonstrated an acceptable safety profile when the treatment regimen was administered at full doses, according to the results of a phase 1b study.

The findings of the MASTERKEY-265 (NCT02263508) trial were reported by Georgina V. Long, Melanoma Institute Australia and The University of Sydney, North Sydney, Australia, at a poster session during the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, a gathering of more than 30,000 oncology professionals in Chicago.

“This is a phase 1b trial, and it's only in 21 patients, ” Long said. “Like all phase 1 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 [Keytruda] combined with [Imlygic] versus [Keytruda] combined with a placebo by intralesional injection and that will tell us whether there is truly an additive effect with [Imlygic and Keytruda].”

Imlygicis a genetically modified herpes simplex virus-1 that selectively replicates in tumor cells after intralesional injection. The oncolytic virus also 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 Imlygic with Yervoy (ipilimumab), which targets different cancer immune response pathways, has improved antitumor responses in patients with unresectable stage 3b/4 melanoma. Keytruda, an anti-programmed death receptor-1 (PD-1) antibody, is associated with greater progression-free survival (PFS) and overall survival (OS) than Yervoy, suggesting the combination of Imlygic with Keytruda might be more effective than the combination of Imlygic with Yervoy.

The MASTERKEY-265 trial was designed to determine safety, efficacy and biomarker data in patients with stage 3/4 unresectable melanoma receiving the combination of Imlygic with Keytruda. 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 criteria for the 21 patients who were enrolled included presence of unresectable stage 3b/4 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 four mL Imlygic by injection into cutaneous/nodal lesions. The first dose contained 106 plaque-forming units (PFU) per mL; the second dose at day 22 contained 108 PFU per mL; subsequent doses at 108 PFU/mL were given every two weeks until progressive disease, intolerance, disappearance of all injectable tumors, or at two years of treatment. Keytruda 200 mg was given intravenously every two weeks after the first two Imlygic injections. DLTs were assessed for six weeks from the first Keytruda treatment.

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

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

The phase 3 part of MASTERKEY-265 is a randomized, double-blind, placebo-controlled trial that will recruit 660 patient with unresectable state 3b/4 melanoma. The primary endpoints will be PFS and OS. This trial will assess long-term safety in a follow-up period lasting five years from the date of the last patient randomly assigned to treatment.

Long described the results of the phase 1b portion of MASTERKEY-265 as interesting, calling the combination of Imlygic and Keytruda “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.”