The combination of RP1 (vusolimogene oderparepvec) with nivolumab (Opdivo) has shown durable and clinically meaningful antitumor activity with a favorable safety profile in patients with advanced melanoma that progressed on anti–PD-1 therapy. These topline results come from the primary analysis of the IGNYTE clinical trial (NCT03767348).
Findings presented at the 2024 ESMO Congress revealed that among 140 patients with advanced melanoma, the confirmed overall response rate (ORR) by independent central review (ICR) was 33.6% (n = 47; 95% CI, 25.8-42.0) with a 15.0% complete response rate (n = 21) by modified RECIST 1.1 (mRECIST 1.1) and 32.9% (n = 46; 95% CI, 25.2-41.3) by RECIST 1.1. The median duration of response (DOR) by mRECIST 1.1 was 21.6 months (95% CI, 14.5-not reached).
Caroline Robert, MD, PhD, head of the Dermatology Unit at Gustave Roussy and codirector of the Melanoma Research Unit at INSERM 981 Paris-Sud University, noted the significance of these findings: “We have a combination that gives objective responses in one-third of the patients with durable responses, including patients with visceral non-injected lesions. It gives responses even in a very challenging population of patients.”
About RP1 and the IGNYTE Trial
RP1 is an HSV-1–based oncolytic immunotherapy expressing GM-CSF and a fusogenic protein. GM-CSF aims to maximize tumor killing potency, the immunogenicity of tumor cell death, and the activation of a systemic antitumor immune response.
The phase 1/2, open-label, dose-escalation and -expansion IGNYTE clinical trial enrolled patients with confirmed progression while being treated with anti–PD-1 alone or combined with anti–CTLA-4 for at least 8 weeks as the last prior treatment, including as adjuvant treatment. Key eligibility criteria included anti–PD-1 failed advanced melanoma, measurable disease, an ECOG performance status of 0 to 1, and adequate organ function. Patients were required to have not been previously treated with oncolytic therapy.
Patients received RP1 intratumorally at 1 × 106 plaque-forming units (PFU)/mL, then at 1 × 107 PFU/mL once every 2 weeks up to 7 times, given with intravenous (IV) nivolumab at a dose of 240 mg, followed by 240 mg of nivolumab alone once every 2 weeks or IV nivolumab 480 mg once every 4 weeks for up to 2 years. Further RP1 was allowed if indicated.
The primary end points of the trial were to evaluate safety and efficacy, with secondary end points consisting of ORR by ICR using mRECIST 1.1, with assessment also by standard RECIST 1.1, CR rate, DOR, duration of clinical benefit, disease control rate, progression-free survival, and 1- and 2-year overall survival (OS).
The median age of participants was 62 years (range, 21-91), and most patients were male (67.9%). A total of 48.6% had stage IVb/c/d disease, 62.1% of patients had BRAF wild-type status, 65.7% had primary anti–PD-1 resistance, 56.4% were PD-L1 negative, and 43.6% had prior anti–PD-1 with anti–CTLA-4. Responses were observed in patients with advanced disease, including in injected and non-injected visceral lesions.
In patients with primary anti–PD-1 resistance, the ORR was 34.4%. In patients who received prior anti–PD-1 with anti–CTLA-4, this rate was 26.2%. The landmark OS rates at years 1 and 2 were 75.3% (95% CI, 66.9-81.9) and 63.3% (95% CI, 53.6-71.5), respectively. The 3-year survival rate was 54.8%, and the median OS was not reached.
Safety Profile
Treatment-related adverse events (TRAEs) of all grades were observed in 89.4% of patients, with grade 3 or 4 TRAEs seen in 12.8%. The most commonly reported all-grade TRAEs included fatigue (32.6%), chills (31.9%), pyrexia (30.5%), nausea (22.0%), and influenza-like illness (17.7%). Grade 3 or 4 TRAEs included fatigue, diarrhea, asthenia, arthralgia, and decreased appetite (0.7% each). No grade 5 events were reported.
Future Directions
A confirmatory phase 3 trial, IGNYTE-3 (NCT06264180), is actively recruiting patients to further evaluate RP1 plus nivolumab in patients with advanced melanoma that has progressed on anti–PD-1 and anti–CTLA-4. This study will compare RP1 plus nivolumab with physician’s choice of therapy.
Robert concluded, “It is a safe treatment, survival is very promising, and all this was considered sufficiently encouraging to initiate a phase 3 trial, IGNYTE-3, in patients [whose disease progressed following] ipilimumab [Yervoy]/nivolumab.”
