Intralesional therapy ‘here to stay’ for melanoma

Issue: April 10, 2016

NEW YORK — There are many ongoing monotherapy and combination trials of oncolytic agents, according to a speaker at HemOnc Today Melanoma and Cutaneous Malignancies.

“The idea is, you have a tumor, and if it’s reachable by a needle and unresectable — and arguably, even resectable — can you make the tumor your ally to be able to treat it directly, and then potentially to combine it with other agents?” Sanjiv S. Agarwala, MD, professor of medicine at Temple University School of Medicine, chief of oncology and hematology at St. Luke’s Cancer Center, and a HemOnc Today Editorial Board member, said during his presentation.

Sanjiv S. Agarwala

Monotherapy trials

Ongoing monotherapy trials of oncolytic agents include those for PV-10 (Provectus), interleukin-12 (IL-12) and coxsackievirus type A21 (Cavatak, Viralytics).

Results of a phase 2 trial of PV-10 have shown 51% response rates in target lesions and 33% response rates in nontarget lesions. Further, PFS was 11.4 months in responders and 4.1 months in nonresponders.

A phase 3 trial was initiated in April 2015.

“If we’re going to show monotherapy with PV-10 works, you have to design a randomized trial,” Agarwala said. “It is not easy to design a randomized trial for a monotherapy intralesional agent, when you have all of these drugs available. This trial is designed in a very specific way, and it will be very interesting to see the results of this trial compared to the talimogene laherparepvec [Imlygic, Amgen] trial, because that trial was designed in a different era.”

IL-12 is also being evaluated in a phase 2 trial using injection through electroporation, a technique that uses electrical pulses to improve how the therapy reaches the lesion.

Lastly, the CALM phase 2 study is evaluating the use of the coxsackievirus type A21 in patients with late-stage melanoma. Early results showed 80.6% of patients achieved complete response, partial response or stable disease.

“There is no getting away from the fact that even monotherapy with intralesional agents for the right patient population produces good clinical results,” Agarwala said. “The question is, in what setting are you going to use it? For us, in the medical oncology world, whether we will pick this first or not is a bit of a question.”

Combinations with checkpoint inhibitors

The oncolytic therapies talimogene laherparepvec, PV-10 and HF10 (Takara Bio) — a replication-competent mutant strain of Herpes Simplex Virus type 1 — also are being evaluated in combination with checkpoint inhibitors.

“Combinations will be the future,” Agarwala said. “Why not find a way to combine modalities that have different mechanisms of action and have, very importantly, nonoverlapping toxicities?”

Talimogene laherparepvec, also known as T-VEC, is under evaluation in combination with ipilimumab (Yervoy, Bristol-Myers Squibb). A small trial of 17 patients has shown the combination has the promise to yield long-term responses in patients, Agarwala said.

T-VEC also is being studied with pembrolizumab (Keytruda, Merck) in patients with previously untreated, unresected, stage IIIB to IVM1c melanoma.

So far, safety results have shown a low adverse event profile for this combination, Agarwala said. Preliminary efficacy results showed an overall response rate of 56.3%, which suggests improvement over the T-VEC–ipilimumab combination.

“We’ve been able to now make an intralesional therapy applicable to not only patients with M1a disease, but also to patients with M1b and M1c disease. So, patients with multiple metastatic sites might be able to benefit,” Agarwala said.

The phase 3 MASTERKEY-265 study is comparing T-VEC plus pembrolizumab to placebo plus pembrolizumab, which should definitively prove or disprove the theory that a viral oncolytic agent plus a checkpoint inhibitor will improve outcomes, Agarwala said.

Further, a phase 2 trial is ongoing evaluating PV-10 with pembrolizumab, and another phase 2 trial is evaluating HF10 with ipilimumab.

“We have to realize intralesional therapy is not going anywhere, it is here to stay,” Agarwala said. “It is a new paradigm for potential combinations, and perhaps in the future the ultimate melanoma regimen is going to be with an intralesional therapy with a systemic, checkpoint inhibitor. Monotherapy also is applicable to specific patients.” – by Alexandra Todak

Reference:

Agarwala SS. Current trials with oncolytic agents. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 18-19, 2016; New York.

Disclosure: Agarwala reports no relevant financial disclosures.