Injecting Oncolytic Viruses in Melanoma: Durable Responses

Walter Alexander

October 10, 2014

MADRID — Injecting melanoma lesions with specific common cold or herpes simplex viruses destroys tumor cells and induces systemic immune responses, according to research presented here at the European Society for Medical Oncology Congress 2014.

A phase 2 study of a product that uses coxsackievirus A21 (CVA21) (Cavatrack) won the best poster award, and clinical data from a phase 3 trial were presented for talimogene laherparepvec (T-VEC).

The injection of oncolytic viruses directly into lesions is an active area of research in melanoma, said Sanjiv S. Agarwala, MD, professor of medicine at St. Luke's University Hospital in Bethlehem, Pennsylvania and Temple University in Philadelphia, who was not involved in either study.

Oncolytic intralesional therapy has the potential to produce responses in both injected and noninjected lesions that are durable, with a low and manageable toxicity profile, he told Medscape Medical News. It's true potential, however, is "in combination with currently approved systemic immunotherapies, such as ipilimumab and nivolumab." Trial results from these combinations are highly anticipated, he added.

Virus Found in Common Cold

The CVA21 used in Cavatrak is a naturally occurring common cold RNA virus that targets surface intracellular adhesion molecule (ICAM)-1, which is upregulated in a number of cancers, including melanoma. In early research, CVA21 displayed potent oncolytic activity, and lysed tumor cells induced a secondary systemic host-generated antitumor immune response.

The clinical data presented come from the phase 2 CAVATAK in Late-Stage Melanoma (CALM) trial, which involved 57 patients with stage IIIC and IV melanoma. All had at least one injectable dermal, cutaneous, subcutaneous, or lymph node lesion. Patients received 10 series of multi-intratumoral CVA21 injections.

The primary end point, immune-related progression-free survival, was defined as the proportion of patients who, 6 months after the initiation of treatment, demonstrated a complete response, partial response, or stable disease (measured with immune-related RECIST 1.1).

The immune-related progression-free survival rate was "favorable," at 38.6%, said lead investigator Robert Andtbacka, MD, from the Huntsman Cancer Institute at the University of Utah in Salt Lake City. He noted that responses were observed in both injected and noninjected lesions.

The secondary end point was objective response rate (complete response plus partial response), which was achieved by 28.1% of patients.

Median time to response was 2.8 months, and the 1-year survival rate was 73.3%.

CVA21 was well tolerated, with no grade 3/4 treatment-related adverse events, the researchers report.

Dr. Andtbacka emphasized that tumor responses were observed in injected lesions, noninjected lesions, and noninjected visceral lesions. They occurred when levels of anti-CVA21 neutralizing antibody were high, and in the absence of circulating infectious CVA21.

In earlier research, neutralizing antibodies to CVA21 were lacking in at least 85% of patients. In the CALM trial, "we found that after the fifth injection, around day 22, virtually all patients had developed neutralizing antibodies," Dr. Andtbacka reported. "Yet even in the presence of these neutralizing antibodies, we saw objective responses, indicating to us that the response is likely immune-mediated rather than caused by the virus itself."

Dr. Andtbacka explained that before the trial, he and his colleagues had hoped that at least 10 patients would meet the primary end point. The fact that 22 patients actually achieved sustained immune-related progression-free survival has bolstered the conviction that CVA21 should be evaluated in combination with other immunotherapeutic agents, he said.

He noted that in addition to combining an oncolytic virus injection with an immune checkpoint inhibitor, it would be interesting to test combinations of the injection and targeted small molecules like BRAF and MEK kinase inhibitors, such as dabrafenib (Tafinalar), trametinib (Mekinist), and vemurafenib (Zelboraf).

"This study met its modest end point; immune-related progression-free survival was 22.5% at 24 weeks, and it clearly has clinical activity when injected locally," said Jeffrey S. Weber, MD, PhD, director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa, Florida, who was not involved in the study.

"Some distant metastases could even regress after its use locally," Dr. Weber told Medscape Medical News. "Such drugs have a potential use as an immune primer prior to the use of checkpoint protein inhibitors, and should be evaluated in combination with those drugs," he added.

New Data on T-VEC

Also presented at the meeting were data from an extension of the phase 3 OPTiM trial that compared intralesional T-VEC with subcutaneous granulocyte macrophage colony stimulating factor (GM-CSF).

T-VEC is a herpes simplex virus (HSV)-1-derived oncolytic immunotherapy designed to selectively replicate in tumors and produce GM-CSF, enhancing systemic antitumor immune responses.

Early results from OPTiM were presented last year, and the final results just missed being statistically significant.

Patients in the original study had unresected stage IIIB to IV melanoma and had received either the maximum treatment permitted in OPTiM with no clinically relevant progressive disease or had a complete response but developed a new lesion in the 12 months after their last treatment. Overall survival was better with T-VEC than with GM-CSF, and just failed to meet statistical significance (23.3 vs 18.9 months; P = .051).

In the study extension, randomized treatment was continued in 28 patients in the T-VEC group and three patients in the GM-CSF group.

The overall response rate improved with continued T-VEC treatment, but not GM-CSF treatment, reported Kevin Harrington, MD, professor of biological cancer therapies at the Institute of Cancer Research in London, United Kingdom.

In fact, in the T-VEC group, best overall responses improved in seven patients. Five patients who had a partial response in the original trial achieved a complete response, as did two patients who had stable disease in the original trial. A quarter of patients had a complete resolution, and 86% maintained at least stable disease.

One patient who received T-VEC had a new durable response, defined as a partial or complete response beginning at any point in the 12 months after the initiation of therapy and lasting continuously for at least 6 months.

The subset of patients was small, Dr. Harrington acknowledged, but "these data suggest that if you need to continue dosing with T-VEC, even in patients who have relapsed, rechallenging them is safe and efficacious."

The CALM study was funded by Viralytics Ltd (Australia), the developer of Cavatak. The OPRiM study was funded by AMGEN, the developer of T-VEC.

European Society for Medical Oncology (ESMO) Congress 2014: Abstracts 1103P and 1102P. Presented September 28, 2014.


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