Adding Coxsackievirus to Ipilimumab Displays Durable Antitumor Activity in Advanced Melanoma

Brendan D. Curti, MD

Adding a formulation of the Coxsackievirus A21 (CVA21; CAVATAK^®) to ipilimumab (Yervoy) yielded an overall response rate (ORR) of 50% and was well-tolerated in immunotherapy-naïve and pretreated patients with advanced melanoma. The results offer an encouraging early signal that the combination may provide a new treatment option for patients in this setting 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, MD, reported that 4 patients had a complete response to the combination and 7 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-ipilimumab 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 Ib 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, MD, 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.

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% in the 4 patients who had received prior checkpoint inhibitor therapy and 64% in the 7 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 2 cohorts.

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

In addition to the 4 patients who had a complete response (CR) and the 7 who had a partial response (PR), 6 patients had stable disease (SD), resulting in a disease control rate of 77% (CR+PR+SD).In patients with and without prior checkpoint therapy, the disease control rate was 82% and 73%, respectively.

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

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 grade >3 adverse events (AEs) were attributable to CVA21, and just 2 patients experienced these (fatigue and elevated liver enzymes) due to ipilimumab.

With an overall grade 3/4 treatment-related AE rate of 8%, Curti added that although involving a small patient group, “this represents fewer side effects than we would associate with ipilimumab monotherapy in clinical practice.” Historically, about 25% of ipilimumab -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).

Curti B, Richards J, Hallmeyer S, et al. The MITCI (phase Ib) study: a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients with or without previous immune checkpoint therapy treatment. Presented at the 2017 AACR Annual Meeting; April 2-5, Washington, DC. Abstract CT114.

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In this trial, which is ongoing, 26 patients with stage IIIC and IV melanoma received intralesional injections of CVA21 into melanoma nodal deposits on days 1, 3, 5, 8, and 22, when ipilimumab was added to the regimen at the standard FDA-approved dose of 3 mg/kg every 3 weeks for a total of 4 infusions. Patients also continued to receive CVA21 every 3 weeks. After completion of the ipilimumab therapy, patients can continue to receive intralesional CVA21 up to a total of 19 doses.