FDA Grants Orphan Drug Designation to PVSRIPO for Advanced Melanoma

January 11, 2021 — The FDA has granted an orphan drug designation to the novel intratumoral immunotherapy agent PVSRIPO for the treatment of patients with advanced melanoma, specifically those with stage IIIB-IV disease.

The FDA has granted an orphan drug designation to the novel intratumoral immunotherapy agent PVSRIPO for the treatment of patients with advanced melanoma, specifically those with stage IIIB-IV disease.1

The decision follows data from a phase 1 trial (NCT03712358) presented during the 2020 SITC Annual Meeting, which showed that the agent elicited an overall response rate (ORR) of 33% in 12 patients with anti–PD-1 refractory melanoma.2 Among patients who had undergone a full course of treatment with PVSRIPO, the ORR was even higher, at 67%. However, the study investigators noted that it was too early to draw definitive conclusions based on the data because the population was small.

“We are happy to kick off the new year with the announcement that our request for an orphan drug designation has been granted to PVSRIPO for the treatment of advanced melanoma,” Matt Stober, president and chief executive officer at Istari Oncology, stated in a press release. “This is just one of many milestones to come in 2021 as we continue to drive the clinical development of PVSRIPO across multiple indications.”

A novel immunotherapy based on the Sabin Type-1 polio vaccine, PVSRIPO is injected directly into tumors. The recombinant oncolytic poliovirus was developed to infect antigen-presenting cells like macrophages and dendritic cells that express CD155. Often, the poliovirus receptor is expressed on malignant cells of solid neoplasia; it is also expressed in myeloid and endothelial cells. After the tumor is infected, a series of acute inflammatory events permits immune cell invasion and creates an immunogenic microenvironment.3

For the open-label, phase 1 trial, investigators recruited a total of 12 patients with unresectable and/or metastatic melanoma who progressed on at least 1 PD-1–based regimen and those with BRAF V600 mutations who progressed on at least 1 BRAF-targeted therapy.

In the trial, participants were randomized to 1 of 3 arms: cohort 1 was given PVSRIPO injected into 1 lesion on day 1 and second lesion on day 21, cohort 2 received the drug in 3 separate lesions 21 days apart; and cohort 3 was given 3 injections into 1 lesion 21 days apart.

The primary goal of the research was to assess the safety, tolerability, efficacy, and immune activation of PVSRIPO in patients with advanced melanoma. To do this, investigators evaluated responses in tumors that received injections of the agent and those that did not.

Additional results indicated that 33% (n = 4) of patients met the criteria for total ORR; this included 66% (n = 4/6) of the participants who had received the maximum course of treatment with the investigational immunotherapeutic, which was 3 injections over the course of 21 days. Based on the findings, investigators noted that the drug is capable of initiating or rekindling responses in patients who have progressed on previous treatment with a PD-1 inhibitor.

Additionally, half of the patients with in-transit disease (n = 2/4) achieved a pathologic complete response with PVSRIPO. Notably, 50% of patients (n = 6/12) continued to be free of disease progression at a median follow-up of 12 months.

The majority of trial participants, or 83%, went on to receive additional treatment with an immune checkpoint inhibitor after the study completed; these patients achieved a response after subsequent treatment with immune checkpoint inhibitors, which could suggest that combination approaches may yield a stronger response in this population.

Regarding safety, all toxicities reported with the immunotherapy were found to be grade 1 or 2 in severity, and no serious effects were observed. No dose-limiting toxicities were reported, either. Fifty percent of patients experienced grade 1 pruritis, while 33.3% of patients reported erythema.

“We are encouraged by the data from our phase 1 trial presented at the 2020 SITC Annual Meeting,” Garrett Nichols, MD, MS, chief medical officer at Istari Oncology, stated in a press release. “We plan to build upon that success with LUMINOS-102. As those data and the data from our other solid tumor trials emerge, we will continue to work closely with the FDA toward the goal of bringing PVSRIPO to market.”

Based on the findings from the phase 1 trial, investigators have launched the multicenter, open-label, phase 2 LUMINOS-102 trial (NCT04577807).4 In this effort, investigators would like to characterize the safety, tolerability, and efficacy of intratumoral injection with PVSRIPO both alone and paired with a PD-1 inhibitor in patients with advanced, unresectable melanoma who have progressed on anti–PD-1 treatment.

To be eligible for enrollment, patients must be 18 years of age or older; have prior Centers for Disease Control and Prevention–recommended vaccination against poliovirus and have received a boost immunization at least 1 week, but less than 6 weeks, before day 1 of the trial; have unresectable cutaneous or mucosal melanoma per biopsy; have at least 2 measurable lesions; and have confirmed disease progression per RECIST v1.1 criteria. Patients also needed to have an ECOG performance status of 0 or 1, serum lactate dehydrogenase levels of 3 or less x upper limit of normal, a life expectancy of longer than 12 weeks, and acceptable bone marrow, liver, and renal function.

If they had symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that were actively progressing, they could not participate. Additionally, patients with a history of leptomeningeal disease, uncontrolled tumor-associated pain, or uncontrolled pleural effusion, pericardial effusion, or ascites, were excluded from the analysis.

The primary outcome measures of the phase 2 trial include ORR, frequency and severity of treatment-emergent toxicities, frequency and severity of adverse effects determined to be of special interest, and the incidence of treatment discontinuation because of toxicities. Secondary objectives comprised overall survival, duration of response, disease control rate, durable response rate, and progression-free survival.

In the trial, participants on the PVSRIPO-only arm will receive the agent via direct injection to their melanoma lesion at a dose of up to 6 x 108 TCID50, which will be given every 3 weeks. Those in the combination arm will receive the agent at a dose of up to 6 x 108 TCID50 via direct injection to amenable lesions and anti–PD-1 treatment, which will be given every 3 or 4 weeks per the approved package insert for the PD-1 inhibitor used.

The first participant in this trial is expected to be dosed in Q1 2021, according to Istari Oncology, Inc, the drug developer.

Previously, in May 2016, PVSRIPO received a breakthrough therapy designation from the FDA as a potential treatment for patients with recurrent glioblastoma multiforme, which was supported by data from a phase 1 trial which showed that the treatment resulted in an OS rate of 24% at 24 months in a total of 24 patients.5 


  1. Istari Oncology announces FDA grants orphan drug designation for PVSRIPO for the treatment of advanced melanoma. News release. Istari Oncology, Inc. January 10, 2021. Accessed January 11, 2021. http://bit.ly/39qx3qC.
  2. Beasley GM, Farrow NE, Landa K, et al. A phase I trial of intratumoral PVSRIPO in patients with unresectable treatment refractory melanoma. Presented at: 2020 SITC Annual Meeting; November 9-14, 2020; Virtual. Abstract 302.
  3. Jammal MP, Michelin MA, Nomelini RS, Murta EFC. Recombinant poliovirus for cancer immunotherapy. Ann Transl Med. 2018;6(18):368. doi:10.21037/atm.2018.07.19
  4. PVSRIPO with or without immune checkpoint blockade in patient with advanced PD-1 refractory melanoma. ClinicalTrials.gov. Updated November 25, 2020. Accessed January 11, 2021. https://clinicaltrials.gov/ct2/show/NCT04577807.
  5. Desjardins A, Sampson JH, Peters KB, et al. Oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM): optimal dose determination. J Clin Oncol. 2015;33 (suppl 15):2068. doi:10.1200/jco.2015.33.15_suppl.2068