RP1 Plus Nivolumab Represents the Next Frontier of Oncolytic Virus–Based Therapy for Melanoma

Anna C. Pavlick, BSN, MSc, DO, MBA

RP1 combined with nivolumab (Opdivo) has yielded durable responses in patients with advanced melanoma after prior immune checkpoint inhibition, offering a promising therapeutic option for those with limited treatment alternatives, according to Anna C. Pavlick, BSN, MSc, DO, MBA.

The phase 1/2 IGNYTE trial (NCT03767348) is investigating RP1 in combination with nivolumab in patients with cutaneous melanoma who have progressed on prior anti–PD-1 therapy. Data presented at the 2024 SITC Annual Meeting showed that among 140 evaluable patients, the overall response rate (ORR) per modified RECIST 1.1 criteria was 33.6%, including respective complete response (CR) and partial response (PR) rates of 15.0% and 18.6%.1 Furthermore, the 12-month duration of response (DOR) rate was 70.5%, and the median DOR was 21.6 months (range, 1.2+ to 43.5+).

Notably, in January 2025, the FDA granted priority review to RP1 plus nivolumab for the treatment of patients with advanced melanoma following anti–PD-1 therapy based on findings from IGNYTE.2

“We still need to do clinical trials because we don't cure 100% of our patients yet,” Pavlick said in an interview with OncLive®. “However, advances and innovations with oncolytic viruses in conjunction with different types of immunotherapy are expanding our armamentarium to manage metastatic melanoma.”

In the interview, Pavlick discussed the need to enhance the melanoma treatment paradigm for patients who do not respond to immunotherapy or cellular therapies; how the mechanism of action of RP1 positions this oncolytic virus as an effective, feasible, and safe treatment option for this patient population; and the importance of multidisciplinary collaboration for delivering effective treatment with this therapy.

Pavlick is a professor of medicine in the Division of Hematology & Medical Oncology at Weill Cornell Medicine in New York, New York; as well as the founding director of the Cutaneous Oncology Program at Weill Cornell Medicine and NewYork-Presbyterian.

OncLive: What unmet needs exist for patients with advanced melanoma?

Pavlick: In 2025, patients with metastatic melanoma have good options, including immunotherapy and targeted therapies, as well as cellular therapies with tumor-infiltrating lymphocyte [TIL] cell infusions. However, that doesn't mean that all patients are going to be cured of their metastatic disease. What happens when patients progress after immunotherapy, don't have a BRAF mutation, or are not physically capable of undergoing a TIL cell process, which takes a lot of planning and requires that patients are well to undergo lymphodepleting chemotherapy and then high-dose interleukin-2 following their TIL infusion? What do we do with that population of patients, which [comprises approximately] 30% to 40% of metastatic melanoma patients? That's where research comes in. This is why our goal is still to continue to put patients onto research studies and to look for good treatment options for them.

What is the mechanism of action of RP1, and how is this agent unique compared with other oncolytic immunotherapy agents?

All oncolytic agents are born from talimogene laherparepvec [T-VEC; Imlygic], so they use an attenuated herpes simplex virus backbone connected to granulocyte-macrophage colony–stimulating factor, [with the hope] to trigger a better immune response. Although it has that same backbone structure, RP1 is different from T-VEC because it also expresses a fusogenic protein that will trigger a broader immune response and cell death through immunogenic mechanisms.

What was the rationale and design of the IGNYTE trial?

The IGNYTE trial was for patients with tumors that had progressed through anti–PD-1 therapy with or without another agent like ipilimumab [Yervoy]. These patients had also been treated with targeted therapy if they had a [BRAF mutation].

IGNYTE was a clinical trial that required a tumor to be injected with RP1, [and patients] also received concurrent nivolumab or continued on PD-1–directed therapy. One of the prerequisites of the trial was that patients needed to [enroll] immediately after they were treated with immunotherapy. Their immune systems were primed, their tumors were injected with RP1, and they then continued with anti–PD-1 therapy. The goal was to evaluate the localized response of the tumors that were injected and to see if, by injecting a local tumor, we could also generate a broader immune response and get distant tumors to respond as well.

What recent efficacy findings have been presented?

This trial enrolled 156 patients [who] really did not have any other options for treatment. They were enrolled onto this clinical trial in the hopes that since they were progressing on immunotherapy, the addition of RP1 may get them to respond again. We saw that [33.6%] of patients had a response. That, to us, was surprising because we were hoping to get some response; however, this was a nice, vigorous response [rate].

Of those patients, [15.0%] had CRs, meaning their disease completely resolved, which we also never expected to see. The other nice outcome was even if patients didn't have CRs, if they had PRs or stable disease, those responses were long term, meaning that responders were likely still responding at 2 years. At the 6-month time point, [most] patients who had a response were still responding.

What safety findings have been observed in this trial?

[RP1 was] exceedingly safe. Our concern was that there may be toxicities [associated with] using an oncolytic virus that we saw with T-VEC, where some patients may experience fever or chills the evening after the tumor injection. However, [among the patients in IGNYTE who received the] intratumoral oncolytic virus injection in conjunction with immunotherapy, we [predominantly] saw grades 1 and 2 toxicities, which made us happy because we weren't making patients sick. We were seeing responses without [patients paying] for them with a toxicity increase.

If RP1 plus nivolumab receives FDA approval for patients with PD-1 inhibitor–exposed melanoma, what would be the significance of the addition of this combination to the treatment armamentarium?

[This combination is] a nice option for patients. [For] the 30% to 40% of patients [in the metastatic melanoma population] whose tumors will progress after immunotherapy and targeted therapies and are not candidates to undergo TIL therapy, [we would] have an FDA-approved option that [is associated with] a [33.6%] ORR and minimal toxicity. [That would be] a game changer.

What is the importance of collaborating with interventional radiologists and other members of a multidisciplinary team when using RP1?

In the IGNYTE trial, we injected visceral tumors like lung or liver metastases directly with RP1 with the assistance of our interventional radiology colleagues. Knowing that it's a safe virus to inject made it easy for our interventional radiologists to want to participate and work with us. We saw that for patients who didn't have easily accessible cutaneous lesions, injecting visceral lesions that were easily accessible for the interventional radiologist was an option for those patients to be treated.

What is your main message regarding the future of oncolytic immunotherapies in melanoma?

We need to keep looking [for effective treatments], but we also need to embrace the therapies that are being FDA-approved or considered for approval because they allow patients to have a great quality of life [QOL] and minimal toxicity with significant responses. As we continue research, our goal is to extend patient survival and not inflict patients with a new toxicity that is going to compromise QOL.

References

1. Wong M, Bommareddy PK, Middleton MR, et al. Primary analysis of the registration-intended cohort of patients with anti–PD-1–failed melanoma from the IGNYTE trial of RP1 plus nivolumab, including clinical subgroup and initial biomarker data. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 1504.
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 May 1, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-biologics-license-application-acceptance-and