RP1/Nivolumab Combo Shows Responses in Advanced Pretreated Melanoma

“Overall, these data support the safety and efficacy of deep/visceral injections and demonstrate the development of a robust systemic antitumor response following RP1 treatment,” according to the study authors.

Patients with advanced melanoma who had progressed on previous PD-1 inhibitor therapy experienced responses following treatment with vusolimogene oderparepvec (RP1) plus nivolumab (Opdivo), with numerically higher response rates observed in deep or visceral injections vs superficial injections alone, according to findings from the phase 2 IGNYTE trial (NCT03767348) presented during the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.1

RP1 injections to patients with lung and liver lesions were feasible and resulted in responses. Specifically, in 7 patients with lung injections, pneumothorax events were observed in 5.8% (n = 3/52) of injections at grade 1 (n = 1) and grade 2 (n = 2), which were self-resolved. Additionally, the 2 grade 2 events were resolved within days. One lung injection led to pneumothorax and required invasive intervention with chest tube insertion, which occurred within 7 days following RP1 injection.

In the overall population (n = 140), the objective response rate (ORR) by blinded independent central review (BICR) per RECIST 1.1 criteria was 32.9%, with 15.0% and 38.6% of patients achieving complete response (CR) and partial response (PR), respectively. Notably, patients treated with deep/visceral plus superficial injections (n = 14) achieved an ORR of 42.9%, with CR and PR comprising 0% and 21.4%, respectively. Those with superficial injections only (n = 104) had an ORR of 29.8%, with CR and PR rates of 17.3% and 12.5%, respectively. Patients who received deep/visceral injections only (n = 22) experienced an ORR of 40.9%, including CR and PR rates of 13.6% and 27.3%, respectively.

“Liver and lung injections had a tolerable safety profile, with no bleeding events reported after liver injection, and lung injections were associated with low rates of pneumothorax events, which were typically of low grade and manageable,” lead study author Gino Kim In, MD, a medical oncologist at Keck Medicine of the University of Southern California (USC) in Los Angeles, and colleagues wrote in a poster presentation of the data. “Patients experienced numerically higher ORRs after receiving deep/visceral injections [with or without] superficial injections compared with superficial injections only. Deep responses were observed in injected and non-injected, including visceral lesions.”

IGNYTE Study Design and Baseline Patient Characteristics

RP1 is a selectively replication-competent herpes simplex virus type 1–based oncolytic immunotherapy. Based on prior data from IGNYTE, the FDA granted priority review to a biologics license application (BLA) seeking the approval of RP1 in combination with nivolumab for the treatment of adult patients with advanced melanoma who have received prior treatment with a PD-1 inhibitor–containing regimen.2

The open-label, dose-escalation and -expansion study evaluated RP1 plus nivolumab for the treatment of patients with advanced melanoma who experienced progression on anti–PD-1 therapy and had measurable disease and adequate organ function.1 Patients on the study did not previously receive oncolytic therapy and had an ECOG performance status of 0 or 1.

In cycle 1, patients received RP1 at the first dose of 106 PFU/mL, and after 2 weeks, went on to receive RP1 at the subsequent dose of 107 PFU/mL plus nivolumab at 240 mg once every 2 weeks from cycles 2 to 8. Following 2 weeks, patients were treated with nivolumab at 240 mg in cycle 9, then 2 weeks later, received nivolumab at 480 mg once every 4 weeks from cycles 10 to 30. At 100 days, a safety follow-up was performed.

Of note, RP1 was injected into superficial and/or deep/visceral lesions, in which superficial tumors were defined as those that could be visualized and accessed via standard needle and syringe sizes. Deep/visceral tumors could not be directly observed and required imaging guidance prior to injection. Both superficial and deep/visceral lesions could receive the injections on the same day, with the volume dependent on lesion size.

The primary end points were safety and efficacy per modified RECIST 1.1 criteria by BICR and RECIST 1.1 criteria. Secondary end points included investigator-assessed ORR, duration of response, CR rate, central and investigator-assessed progression-free survival, and 1- and 2-year overall survival.

At the data cutoff date of March 8, 2024, the median age in the overall population was 62 years (range, 21-91), and the group went through a median follow-up of 15.5 months (range, 0.5-47.6) at the time of primary analysis. Moreover, 48.6% of patients had stage IVM1b–d disease, and lactate dehydrogenase levels were above the upper limit of normal in 33.6% of patients. Prior anti–PD-1 plus anti–CTLA-4 was received by 43.6% of patients, in which 2.9% received the treatments sequentially. The majority of patients had primary resistance to anti–PD-1 therapy (65.7%).

Additional Efficacy and Safety Data With RP1/Nivolumab

In RECIST 1.1 criteria responders (n = 46), patients from both the injected and non-injected lesion groups had robust responses. Of note, a reduction of at least 30% was observed in 93.6% (n = 73/78) of injected lesions, and 79.0% (n = 94/119) of non-injected lesions. Among non-injected lesions in responding patients, 96.2% (n = 50/52) demonstrated reduction from baseline, and 65.4% reduced by at least 30%. Of the measured lesions for RECIST 1.1 responders with CRs and PRs, no reductions were observed in patients with injected lesions (1.3%) and non-injected lesions (3.4%). Any reductions occurred in 98.7% and 96.6% of patients in those with injected and non-injected lesions, respectively. Notably, the best reduction of 100% was reported in 53.8% and 39.5% of patients with injected and non-injected lesions, respectively.

Responses in non-injected visceral lesions from RECIST 1.1 criteria responders (n = 46) included 56 sites, which comprised the lung (lesion, 29), liver (14), spleen (6), pleura (2), and brain (1).

The most common all-grade treatment-related adverse effects (TRAEs) related to RP1 plus nivolumab in the superficial only (n = 104), deep/visceral plus superficial (n = 14), and deep/visceral only included fatigue (n = 22) groups included fatigue (89.4%; 85.7%; 95.5%), pyrexia (29.8%; 21.4%; 40.9%), chills (28.8%; 35.7%; 45.5%), nausea (21.2%; 21.4%; 27.3%), diarrhea (13.5%; 14.3%; 18.2%), vomiting (13.5%; 7.1%; 18.2%), headache (12.5%; 7.1%; 18.2%), influenza-like illness (12.5%; 14.3%; 45.5%), and injection site pain (12.5%; 21.4%; 22.7%).

“Overall, these data support the safety and efficacy of deep/visceral injections and demonstrate the development of a robust systemic antitumor response following RP1 treatment,” study authors concluded in the poster.

References

1. In GK, Wong MKK, Sacco JJ, et al. Response analysis for injected and non-injected lesions and of the safety and efficacy of superficial and deep/visceral RP1 injection in the registrational cohort of anti–PD-1–failed melanoma patients of the IGNYTE trial. J Clin Oncol. 2025;43(suppl 16):9537. doi: 10.1200/JCO.2025.43.16_suppl.9537
2. Replimune announces biologics license application acceptance and priority review for RP1 for the treatment of advanced melanoma.News release. Replimune. January 21, 2025. Accessed June 5, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-biologics-license-application-acceptance-and