Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma

Abstract

BackgroundWhile programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation.MethodsAn open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections.ResultsPVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months.ConclusionIntratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients.Trial registration numberNCT03712358

Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy

“…All AEs were of G1/2 severity, with pruritis (50.0%) and erythema (33.3%) being the most common trAEs. Around 33% of patients achieved a response ( 87 ).…”

Combinatorial Approaches for Cancer Treatment Using Oncolytic Viruses: Projecting the Perspectives through Clinical Trials Outcomes

“…The efficacy of monotherapy using either CAVATAK or PVS-RIPO has been evaluated in six clinical trials (NCT03564782, NCT02986178, NCT03712358, NCT04577807, NCT03043391, NCT01491893). The main cancer types, which have been treated with enteroviruses are melanoma, malignant glioma and glioblastoma [ 94 , 115 ]. Remarkably, none of these clinically-tested enteroviruses carried any transgene.…”

Search for effective treatments in patients with advanced refractory melanoma continues: can novel intratumoral therapies deliver?

“…In a recent edition of JITC, Beasley et al 24 present the results of a small (n=12), single-center, phase 1 trial of PVSRIPO therapy in patients with unresectable anti-PD-1-refractory melanoma. Key inclusion criteria included the presence of injectable disease.…”