Article

Herpes Simplex-1 Oncolytic Showcases Antitumor Activity Across Heavily Pretreated Solid Tumors

November 13, 2020 - The genetically modified herpes simplex-1 oncolytic RP2 demonstrated encouraging clinical activity and an acceptable safety profile in heavily pretreated patients with advanced solid tumors

Francesca Aroldi, lead study author, and clinical research fellow at the University of Oxford

Francesca Aroldi

November 13, 2020 -The genetically modified herpes simplex-1 (HSV-1) oncolytic RP2 demonstrated encouraging clinical activity and an acceptable safety profile in heavily pretreated patients with advanced solid tumors, according to findings from a phase 1 study (NCT04336241) that were presented during the 2020 SITC Virtual Congress.

Of the 9 patients treated with single agent RP2, 1 patient with esophageal cancer and 1 patient with uveal melanoma had ongoing partial responses at 9 months, and 1 patient with mucoepidermoid carcinoma had an ongoing complete response.

“These data support the hypothesis that anti-CTLA-4 delivered intra-tumorally through oncolytic virus replication, with accompanying antigen release and presentation, can provide potent anti-tumor effects,” wrote Francesca Aroldi, lead study author, and clinical research fellow at the University of Oxford, and co-authors, in the poster presentation.

RP2 is an enhanced potency HSV-1 oncolytic, expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), a fusogenic protein (GALV-GP R-), and an anti-CTLA-4 antibody-like molecule.

The open-label, multicenter,dose-escalation and -expansion study was designed to evaluate the safety and efficacy of RP2 alone and in combination with nivolumab (Opdivo) in patients with advanced solid tumors.

The dose-escalation portion of the study, and focus of the poster presentation, was designed to assess the safety and tolerability of RP2 and establish the recommended phase 2 dose (RP2D) of RP2. The dose-expansion portion of the study will further evaluate the safety of RP2 in combination with nivolumab at the RP2D.

Eligible patients had histologically or cytologically confirmed advanced or metastatic non-neurological solid tumors. Patients had progressed on or could not tolerate standard therapy, or had no standard therapy preferred to enrollment in a clinical trial. Patients also had to have at least 1 measurable and injectable tumor measuring at least 1 cm in longest diameter, adequate hematologic function, and an ECOG performance status (PS) of 0 or 1.

The tumor types represented in the trial consisted of cutaneous melanoma (n = 1; 11.1%), uveal melanoma (n = 3; 33.3%), mucosal melanoma (n = 1; 11.1%), microsatellite stable colorectal adenocarcinoma (n = 1; 11.1%), mucoepidemoid carcinoma (n = 1; 11.1%), squamous cell carcinoma (n = 1; 11.1%), and oesophageal adenocarcinoma (n = 1; 11.1%).

Exclusion criteria comprised prior treatment with an oncolytic therapy and active central nervous system metastases and/or carcinomatous meningitis.

Patients were to treated using a 3 + 3 dose escalation at 2 dose levels of up to 10 mL. RP2 was given every 2 weeks for up to 5 doses. With regard to the first dose level, patients received 105 plaque forming units (PFU)/mL of RP2 followed by 4 doses of 106 PFU/mL; the second dose level consisted of 106 PFU/mL of RP2 followed by 4 doses of 107 PFU/mL.

Between 3 to 6 additional HSV-1 seronegative patients received the RP2D, and a combination cohort of up to 30 patients received up to 8 doses of the RP2D in combination with 240 mg of nivolumab every 2 weeks for 4 months from the second RP2 dose, then 480 mg every 4 weeks for 20 months.

Lesions were injected directly or under imaging guidance used for visceral lesions. Tumor biopsies were collected for biomarker analysis. Viral shedding and anti-HSV antibody titers were also monitored.

The median patient age was 55 years (range, 36-76). The majority of patients were male (n = 8; 88.9%) and had an ECOG PS of 0 (n = 6; 66.7%).

All patients had received prior therapy; 6 had received prior anti–PD-1 therapy (66.7%), 4 had received prior chemotherapy (44.4%), and 3 had received prior radiotherapy (33.3%).

The majority of patients were seropositive (n = 6; 66.7%) vs seronegative (n = 3; 33.3%).

Regarding safety, grade 1 or 2 adverse effects (AEs) occurred in 6 patients (66.7%), and grade 3 AEs occurred in 1 (11.1%). Grade 1 or 2 AEs consisted of pyrexia (n = 6; 66.7%), fatigue (n = 3; 33.3%), hypotension (n = 3; 33.3%), chills (n = 2; 22.2%), hyperhidrosis (n = 1; 11.1%), influenza like symptoms (n = 1; 11.1%), nausea (n = 1; 11.1%), rash (n = 1; 11.1%), vomiting (n = 1; 11.1%), and left groin and thigh pain (n = 1; 11.1%). Grade 3 AEs included cytokine release syndrome (n = 1; 11.1%) and hypocalcemia (n = 1; 11.1%).

No dose-limiting toxicities requiring dose-level expansion were reported (n = 9).

The RP2D was determined to be up to 10 mL of 106 PFU/mL of RP2 followed by multiple doses of 107 PFU/mL every 2 weeks.

“RP2 demonstrated an acceptable safety profile, with most AEs being grade 1/2,” wrote the study authors. “Both direct injection of superficial and nodal tumors, and imaging guided injection of deep/visceral tumors were well tolerated and practical.”

Ten patients have been enrolled into the dose-expansion portion of the trial, with preliminary data indicating that the combination of RP2 and nivolumab is well tolerated.

Reference

Aroldi F, Sacco JJ, Olsson-Brown A, et al. Initial results of a phase 1 trial of RP2, a first in class, enhanced potency, anti-CTLA-4 antibody expressing, oncolytic HSV as single agent and combined with nivolumab in patients with solid tumors. Presented at: SITC Virtual Congress; November 9-14, 2020. Poster: 421.

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