Using a Virus to Boost Immunotherapy Response in Melanoma

Patients with advanced melanoma who are immunotherapy-naïve or pretreated saw a 50 percent overall response rate (ORR) when adding a formulation of the Coxsackievirus A21 (CVA21; CAVATAK^®) to Yervoy (ipilimumab), and the combination was well-tolerated. These encouraging results may point toward a new treatment option for this group of patients who become refractory to immune checkpoint inhibitors.

Of the 22 patients evaluable for response at the time of data cutoff for his presentation April 4 at the 2017 AACR Annual Meeting, Brendan D. Curti, M.D., reported that four patients had a complete response to the combination and seven had a partial response.

“A significant number of patients had regression of their disease,” said Curti, director of the Clinical Biotherapy Program and co-director of the Melanoma Program at the Earle A. Chiles Research Institute of Providence Cancer Center in Portland, Oregon. “While preliminary, these data suggest that a CVA21-Yervoy combination may represent a viable treatment option for an unmet need in advanced melanoma patients.”

The proprietary formulation of CVA21 is a common cold RNA virus that was not genetically modified for use in this phase 1b trial known as MITCI. CVA21 destroys local and metastatic cells by oncolytic and immunotherapeutic activity, and thus has the potential to be deployed across a range of cancer types, alone and in combination with other immunotherapies.

"For me, the take-home point is that one can prime the immune response potentially with this kind of approach and basically make the tumor cell population that has been resistant to therapy become sensitive again to a checkpoint antibody therapy,” said Louis M. Weiner, M.D., director of the Lombardi Comprehensive Cancer Center at Georgetown University, and moderator of the AACR panel where the MITCI results were presented.

“I think this has relevance, not only for patients who have refractory disease to checkpoint antibodies, but also for folks who have earlier-stage disease. It's a potentially exciting observation, but obviously early," he continued.

In this trial, which is ongoing, 26 patients with stage 3C and 4 melanoma received intralesional injections of CVA21 into melanoma nodal deposits on days one, three, five, eight and 22, when Yervoy was added to the regimen at the standard FDA-approved dose of 3 mg/kg every three weeks for a total of four infusions. Patients also continued to receive CVA21 every three weeks. After completion of the Yervoy therapy, patients can continue to receive intralesional CVA21 up to a total of 19 doses.

Fifty percent of the 22 patients evaluable for efficacy achieved an overall response. Of the 11 patients who responded to the combination, the ORR was 36 percent in the four patients who had received prior checkpoint inhibitor therapy and 64 percent in the seven who were checkpoint therapy—naïve. Although not preplanned, the evaluable study population turned out to evenly distributed, with a total of 11 patients in each of these two cohorts.

All response rates with the combination were higher than those previously reported for either Yervoy (11 percent ORR) or CVA21 monotherapy (28 percent ORR) in advanced melanoma, Curti noted.

In addition to the four patients who had a complete response (CR) and the seven who had a partial response (PR), six patients had stable disease (SD), resulting in a disease control rate of 77 percent (CR+PR+SD). In patients with and without prior checkpoint therapy, the disease control rate was 82 percent and 73 percent, respectively.

Among patients with prior checkpoint therapy, 46 percent of their noninjected target lesions regressed 50 percent or more. These include lung, liver and other visceral lesions, Curti explained. In the checkpoint-naïve group, 67 percent of noninjected target lesions regressed by at least 50 percent.

Although the study population evaluated thus far is small, Curti said the investigators have been encouraged by the combination’s tolerability and safety. No dose-limiting toxicities were reported, and only mild, infusion-related reactions were seen with the study agent. No adverse events (AEs) higher than grade 3 were attributable to CVA21, and just two patients experienced these (fatigue and elevated liver enzymes) due to Yervoy.

With an overall grade 3/4 treatment-related AE rate of 8 percent, Curti added that although involving a small patient group, “this represents fewer side effects than we would associate with Yervoy monotherapy in clinical practice.” Historically, about 25 percent of Yervoy -treated patients experience grade 3 or higher AEs, he said.

Based on these promising preliminary data, the MITCI trial is expanding to enroll up to 70 patients (NCT02307149).