RP1 Plus Nivolumab Demonstrates Durable Antitumor Activity in Advanced Melanoma

The addition of RP1 (vusolimogene oderparepvec) to nivolumab (Opdivo) led durable and clinically meaningful responses with a manageable safety profile in patients with advanced melanoma that had progressed on prior anti–PD-1 therapy, based data from the primary analysis of the phase 2 IGNYTE trial (NCT03767348) shared at the 2024 ESMO Congress.

140 patients with advanced melanoma enrolled, 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 [NR]).

For safety, most treatment-related adverse events (TRAEs) were grade 1 or 2. The grade 3 or higher TRAE rate was 12.8%, and no RP1-related deaths were reported.

“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,” said 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, during a presentation of the data.

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.

Enrollment in the phase 1/2, open-label, dose-escalation and -expansion clinical trial was open to patients with confirmed progression while being treated with anti–PD-1 alone or combined with anti–CTLA-4 for greater than or equal to 8 weeks as the last prior treatment, including as adjuvant treatment.2 Key eligibility criteria included having anti–PD-1 failed advanced melanoma, measurable disease, an ECOG performance status of 0 to 1, and adequate organ function. Patients also were required to have not been previously treated with oncolytic therapy.

Patients received RP1 given 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, 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. If indicated, further RP1 was allowed.

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, 1- and 2-year overall survival (OS).¹

Of those included in the trial, the median age 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.

Additional findings presented at ESMO showed that 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%. In years 1 and 2, the landmark OS rates were 75.3% (95% CI, 66.9-81.9) and 63.3% (95% CI, 53.6-71.5). The 3-year survival rate was 54.8%. Further, the median OS was not reached.

TRAEs of all grades were observed in 89.4% of patients and grade 3 or 4 TRAEs were seen in 12.8%. For all-grade TRAEs, the most commonly reported included fatigue (32.6%), chills (31.9%), pyrexia (30.5%), nausea (22.0%), and influenza-like illness (17.7%). TRAEs deemed grades 3 or 4 included fatigue, diarrhea, asthenia, arthralgia, decreased appetite (0.7% each). No grade 5 events were reported.

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. The study will compare RP1 plus nivolumab with physician’s choice of therapy.

“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,” concluded Robert.

References

1. Robert C, Milhem MM, Sacco JJ, et al. Primary efficacy, safety, and survival data from the registration-intended cohort of patients with anti-PD-1-failed melanoma from the IGNYTE clinical trial with RP1 combined with nivolumab. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA46.
2. Study of RP1 monotherapy and RP1 in combination with nivolumab (IGNYTE). ClinicalTrials.gov. Updated August 2, 2023. Accessed September 15, 2024. https://clinicaltrials.gov/study/NCT03767348?tab=table