Meeting NewsPerspective

Combined immunotherapy shows early promise in advanced melanoma

Patients with advanced melanoma derived benefit from a combination of ipilimumab and Coxsackievirus A21, according to a phase 1b clinical trial presented at the American Association for Cancer Research Annual Meeting.

“Before our study commenced, we knew that oncolytic viruses, and specifically Coxsackievirus A21 (CVA21 [Cavatak, Viralytics]), could prime immune responses, had single-agent activity and could upregulate T-cell checkpoints, including CTLA-4 and PD-1 in melanoma deposits,” Brendan D. Curti, MD, director of the clinical biotherapy program and co-director of the melanoma program at the Earle A. Chiles Research Institute of Providence Cancer Center, told HemOnc Today.

Brendan D. Curti
Louis M. Weiner

“We also knew that anti–CTLA-4, or ipilimumab (Yervoy, Bristol-Myers Squibb), could induce clinically significant immune responses,” Curti added. “The clinical benefit of each of these components given as monotherapy is modest, in my opinion. The surprising finding was the degree of clinical activity combining these agents, especially in patients who had disease progression after prior checkpoint treatment.”

CVA21 is a bioselected, nongenetically altered common cold RNA virus and can directly infect a variety of cancer cells, which boosts immune responses.

Curti and colleagues began their trial with 25 patients with advanced melanoma and, based on promising preliminary data, expanded the trial to include up to 70 patients.

The current analysis included data from 25 patients, 22 of whom were evaluable for both safety and response.

Safety and achieving four or more complete or partial responses among the first 12 patients served as primary endpoints.

All patients — those who had and had not received prior immune checkpoint inhibitors — received CVA21 injections (3 x 108 TCID50) directly into melanoma lesions. IV–administered ipilimumab (3 mg/kg) began on day 22.

The overall response rate was 50%. Four patients achieved a complete response, and seven patients achieved a partial response. The median duration of response had not been reached, but researchers noted some responses of longer than 6 months, with some ongoing.

Among the 11 patients who had disease progression despite prior immune checkpoint inhibitor therapy, four had a response with the combined therapy. The other seven patients who had a response had not been previously treated with immune checkpoint inhibitors.

“The preliminary overall response rate of 50% is very positive because previous reports indicate an 11% overall response rate for ipilimumab alone and an approximately 28% overall response rate for CVA21 alone,” Curti said.

Among the 25 patients evaluable for safety, two had grade 3 or worse adverse events related to ipilimumab. CVA21 did not lead to any adverse events worse than grade 2.

Curti noted those data were encouraging when measured against previous data that showed 25% of patients treated with ipilimumab experienced grade 3 or worse adverse events.

“In my view, one of the greatest challenges in clinical immunotherapy is finding agents or combinations that help patients after cancer progression on checkpoint therapy including anti–CLTA-4 and anti–PD-1,” Curti said. “If we confirm our preliminary findings of overall response, clinical benefit and good tolerability in a larger group of patients with melanoma after checkpoint failure, then our efforts will be clinically useful to a large number of patients.”

These data illustrate the ability to prime the immune response to make a self-populating tumor that has been resistant to therapy become sensitive again to a checkpoint antibody therapy, according to Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center.

“For many years, scientists like myself were a little skeptical about these strategies for manipulating local tumor immunity to get a broader antitumor effect,” said Weiner, who was not associated with the study. “We all hoped it would happen, but the evidence to support it was really rather sparse. I think this study has relevance, not only for patients who have refractory disease, but also for those who have earlier-stage disease. It’s a potentially exciting observation, although it’s obviously still pretty early.” – by Chuck Gormley

Reference:

Curti B, et al. Abstract CT114. Presented at: AACR Annual Meeting; April 1-5, 2017; Washington, D.C.

Disclosure: Viralytics Ltd. Funded this study. Curti reports research funding from Bristol-Myers Squibb, MedImmune, Merck and Prometheus; and consultant roles with AgonOx, Bristol-Myers Squibb, Nektar and Ubivac.

Patients with advanced melanoma derived benefit from a combination of ipilimumab and Coxsackievirus A21, according to a phase 1b clinical trial presented at the American Association for Cancer Research Annual Meeting.

“Before our study commenced, we knew that oncolytic viruses, and specifically Coxsackievirus A21 (CVA21 [Cavatak, Viralytics]), could prime immune responses, had single-agent activity and could upregulate T-cell checkpoints, including CTLA-4 and PD-1 in melanoma deposits,” Brendan D. Curti, MD, director of the clinical biotherapy program and co-director of the melanoma program at the Earle A. Chiles Research Institute of Providence Cancer Center, told HemOnc Today.

Brendan D. Curti
Louis M. Weiner

“We also knew that anti–CTLA-4, or ipilimumab (Yervoy, Bristol-Myers Squibb), could induce clinically significant immune responses,” Curti added. “The clinical benefit of each of these components given as monotherapy is modest, in my opinion. The surprising finding was the degree of clinical activity combining these agents, especially in patients who had disease progression after prior checkpoint treatment.”

CVA21 is a bioselected, nongenetically altered common cold RNA virus and can directly infect a variety of cancer cells, which boosts immune responses.

Curti and colleagues began their trial with 25 patients with advanced melanoma and, based on promising preliminary data, expanded the trial to include up to 70 patients.

The current analysis included data from 25 patients, 22 of whom were evaluable for both safety and response.

Safety and achieving four or more complete or partial responses among the first 12 patients served as primary endpoints.

All patients — those who had and had not received prior immune checkpoint inhibitors — received CVA21 injections (3 x 108 TCID50) directly into melanoma lesions. IV–administered ipilimumab (3 mg/kg) began on day 22.

The overall response rate was 50%. Four patients achieved a complete response, and seven patients achieved a partial response. The median duration of response had not been reached, but researchers noted some responses of longer than 6 months, with some ongoing.

Among the 11 patients who had disease progression despite prior immune checkpoint inhibitor therapy, four had a response with the combined therapy. The other seven patients who had a response had not been previously treated with immune checkpoint inhibitors.

“The preliminary overall response rate of 50% is very positive because previous reports indicate an 11% overall response rate for ipilimumab alone and an approximately 28% overall response rate for CVA21 alone,” Curti said.

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Among the 25 patients evaluable for safety, two had grade 3 or worse adverse events related to ipilimumab. CVA21 did not lead to any adverse events worse than grade 2.

Curti noted those data were encouraging when measured against previous data that showed 25% of patients treated with ipilimumab experienced grade 3 or worse adverse events.

“In my view, one of the greatest challenges in clinical immunotherapy is finding agents or combinations that help patients after cancer progression on checkpoint therapy including anti–CLTA-4 and anti–PD-1,” Curti said. “If we confirm our preliminary findings of overall response, clinical benefit and good tolerability in a larger group of patients with melanoma after checkpoint failure, then our efforts will be clinically useful to a large number of patients.”

These data illustrate the ability to prime the immune response to make a self-populating tumor that has been resistant to therapy become sensitive again to a checkpoint antibody therapy, according to Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center.

“For many years, scientists like myself were a little skeptical about these strategies for manipulating local tumor immunity to get a broader antitumor effect,” said Weiner, who was not associated with the study. “We all hoped it would happen, but the evidence to support it was really rather sparse. I think this study has relevance, not only for patients who have refractory disease, but also for those who have earlier-stage disease. It’s a potentially exciting observation, although it’s obviously still pretty early.” – by Chuck Gormley

Reference:

Curti B, et al. Abstract CT114. Presented at: AACR Annual Meeting; April 1-5, 2017; Washington, D.C.

Disclosure: Viralytics Ltd. Funded this study. Curti reports research funding from Bristol-Myers Squibb, MedImmune, Merck and Prometheus; and consultant roles with AgonOx, Bristol-Myers Squibb, Nektar and Ubivac.

    Perspective
    Sanjiv S. Agarwala

    Sanjiv S. Agarwala

    Interest in intralesional therapies has been fueled by the approval of talimogene laherparepvec (Imlygic, Amgen), commonly called TVEC. This genetically modified oncolytic viral therapy is indicated for the local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery. Other intralesional agents are being investigated as monotherapy or in combination with other immunotherapeutics, such as ipilimumab (Yervoy, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb). The mechanism of action of these agents underlies a common theme of direct oncolytic effects — either viral (TVEC and coxsackievirus A21 [Cavatak, Viralytics]) or nonviral (PV-10 [Provectus]) — and systemic effects that are thought to be immune-mediated. The latter effect makes combinations with systemic immunotherapies rational and attractive.
    Curti and colleagues report on the initial results of a combination of intralesional Cavatak, a novel strain of coxsackievirus A21, and ipilimumab in 23 patients with unresectable stage III and stage IV melanoma. The trial met its primary statistical futility endpoint, with an impressive response rate of 50% in the entire population and 60% in previously untreated patients. Of interest, a robust response of 38% occurred in patients who had previously received immunotherapy. Both injected and noninjected lesions responded, and the durability of response was 3.5 months. Toxicity appeared manageable and was not increased by the combination.
    Although the high response rate is encouraging, it is important to keep in mind that the sample size is small and needs to be validated in a larger study. The researchers plan to expand this trial to up to 70 patients, which will provide useful information. In addition, the true benefit of a second agent can only be definitively proven in a randomized controlled trial. Such a trial is ongoing to compare the addition of pembrolizumab to TVEC in a double blind, placebo-controlled design. The results of this and other trials with multiple intralesional agents are awaited with interest. Although monotherapy with intralesional agents suffers from obvious limitations, it is hoped that innovative combinations as described in this trial may further improve outcomes for patients with advanced melanoma.

    • Sanjiv S. Agarwala, MD
    • HemOnc Today Editorial Board member Temple University School of Medicine St. Luke’s Cancer Center

    Disclosures: Agarwala reports no relevant financial disclosures.

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