Oncolytic immunotherapeutic regimens, such as the oncolytic virus RP1 plus nivolumab (Opdivo), may offer a clinically meaningful option for patients with melanoma experiencing primary resistance to anti–PD-1 therapy, with the added advantage of preserving eligibility for future tumor-infiltrating lymphocyte (TIL)–based therapeutic approaches, according to Nikhil Khushalani, MD. Successful integration of this strategy into clinical practice, however, will depend on multidisciplinary coordination and patient-specific treatment planning, he noted.

Topline results from the phase 2 IGNYTE trial (NCT03767348), released in June 2024, demonstrated that RP1 combined with nivolumab elicited an objective response rate (ORR) of 33.6% by modified RECIST 1.1 criteria and 32.9% by RECIST 1.1 criteria per independent central review in patients with melanoma who progressed on prior anti–PD-1 therapy (n = 156).

 All responses lasted over 6 months, with a median duration of response (DOR) exceeding 35 months. These findings expanded on investigator-assessed data presented at the 

, in which the overall study population (n = 156) achieved an ORR of 32.7%, including a complete response (CR) rate of 14.7%.

for patients with advanced melanoma after anti–PD-1 therapy in January 2025.

“This approach certainly opens up an important avenue, particularly when there is demonstrable clinical benefit for patients with difficult-to-treat tumors,” Khushalani stated in an interview with 

. “If we can do more to treat these [patients] after [they develop] anti–PD-1 refractoriness and potentially convert immunologically ‘cold’ tumors into ‘hot’ tumors that are more responsive to immunotherapy, then we’ve done well. We have to keep an open mind when trying to identify best practices for incorporating this into the clinic.”

In the interview, Khushalani, vice chair of the Department of Cutaneous Oncology at Moffitt Cancer Center in Tampa, Florida, discussed the limited efficacy and availability of third-line treatment options for patients with melanoma and primary or acquired resistance to anti–PD-1–based therapy; recent findings from the phase 2 IGNYTE trial; and key considerations for administering and sequencing RP1-based oncolytic immunotherapy, including the need for multidisciplinary coordination.

: What are some current treatment challenges experienced by patients with advanced melanoma?

:Melanoma has come a long way relative to where we were [approximately] 8 to 10 years ago. With the advent of immune checkpoint inhibitors, we have dramatically [improved] the outlook for patients with advanced or unresectable melanoma, shifting median survival from typically less than 1 year to now potentially exceeding 3 years, particularly when patients receive checkpoint inhibition combinations.

The greater challenge, however, is for patients whose disease is refractory to anti–PD-1–based therapy. [These cases are categorized as] either primary resistance or secondary or acquired resistance, and we have very limited treatment options for those patients, [representing a] huge unmet need.

Some options are available [for this patient population]. For example, in patients whose tumors harbor a 

V600 mutation, targeted MAP kinase inhibitors can be utilized. [However,] these therapies tend to have a finite duration of efficacy. Beyond that, in the third-line setting, treatment choices are again very limited.

TIL therapies [like lifileucel (Amtagvi)], which 

 are another option that may be considered for select patients. As many clinicians are aware, this is a demanding treatment approach. It requires patients to be fit, with adequate cardiopulmonary reserve and sufficient tumor tissue for harvest and resection. Following tumor excision, the TILs must be expanded—a process that takes several weeks—and patients must be eligible to receive lymphodepleting chemotherapy prior to TIL infusion. For those with biologically aggressive or rapidly progressive disease, the time required for manufacturing and the overall treatment burden may render them ineligible.

The response rate with TIL therapy is approximately 30%. Some of these responses are durable, but this benefit [is not seen] in all patients.

What is the mechanism of action of RP1, and how do oncolytic immunotherapy agents differ from T-VEC and other melanoma agents?

Oncolytic immunotherapeutics have been explored for a long time and are one way to target tumors directly, because systemically administered immunotherapy or other agents may not adequately penetrate the tumor microenvironment.

[One option is to] utilize the ability of an oncolytic virus, [such as] herpes simplex virus type 1 [HSV-1], which forms the backbone of several oncolytic viruses, including talimogene laherparepvec [T-VEC] as well as RP1, RP2, and RP3. This gives us the ability to directly inject [drugs] into the tumor and take advantage of the replicative potential of that virus, which selectively multiplies or replicates within the tumor cells and causes local destruction of tumor cells through a variety of mechanisms.

Importantly, through the incorporation of a granulocyte-macrophage colony-stimulating factor [GM-CSF] transgene, they can also induce a systemic immune response. What differentiates RP1 from T-VEC, for instance, is the inclusion of a fusogenic glycoprotein derived from GALV, along with deletion of the ICP47 protein. [This modification] enhances the oncolytic activity of RP1 at the local injection site and may augment the systemic antitumor immune response, including responses in uninjected tumors. That’s what sets it apart [from other options].

Several clinical trials have investigated these agents, including the IGNYTE study, which evaluated RP1 in combination with nivolumab.

What were the rationale and design of the IGNYTE trial?

IGNYTE was strategically designed to address a significant unmet need by focusing on patients with melanoma whose disease had progressed following prior PD-1 therapy. The trial specifically targeted patients with either primary or secondary resistance to anti–PD-1 therapy. Eligibility criteria required patients to have received an anti–PD-1 agent for a minimum of 8 weeks to reduce the likelihood of enrolling individuals experiencing pseudoprogression followed by response. This ensured the inclusion of patients with true disease progression.

Importantly, the trial also included patients who had received adjuvant anti–PD-1 therapy, such as pembrolizumab [Keytruda] or nivolumab, for resected high-risk stage II or stage III melanoma, provided disease progression occurred while patients were still on adjuvant treatment. This broadened the applicability of the trial to a population increasingly encountered in clinical practice.

The study evaluated the combination of intralesional RP1 and systemic nivolumab. RP1 was administered initially as monotherapy at a lower loading dose, followed by combination treatment with nivolumab beginning 2 weeks later. At this point, the RP1 dose was escalated and continued biweekly for a total of 8 doses. Following completion of RP1, patients could continue nivolumab monotherapy for a prespecified duration.

This was a phase 2 study with primary [end points] of safety and efficacy…in a refractory melanoma population. Secondary end points included toxicity, progression-free survival, and overall survival.

What were some of the most recent findings from IGNYTE?

[Data from IGYNTE were] first presented at the 2024 ASCO Annual Meeting. An additional 16 patients from other cohorts, including patients with refractory melanoma, were also included in the dataset.

It is important to consider the trial population, which represented a real-world, treatment- refractory cohort. Nearly 50% of patients had distant metastatic disease, [defined as] M1a or higher, not limited to localized, in-transit, or nodal unresectable melanoma. [Moreover,] approximately one-third of patients had elevated serum lactate dehydrogenase levels, a known poor prognostic factor in advanced melanoma.

[A notable aspect] of the study was the inclusion of both superficial and deep lesions for intralesional injection. Unlike earlier oncolytic virus trials that focused primarily on accessible cutaneous or nodal lesions, the IGNYTE trial permitted injection of deeper lesions, such as liver or soft tissue metastases, when accessible via image guidance and interventional radiology. This approach expands the potential applicability of RP1-based therapy beyond superficially located tumors.

Among the 156 patients [in the overall population], the ORR was [32.7%], with [14.7% of patients] achieving a CR. At the time of initial presentation, DOR was a key finding, with responses measured at 35 months. The median follow-up was approximately 16 months, and many responses were ongoing at the time of analysis, underscoring the potential for long-term benefit.

Additionally, many enrolled patients had received prior combination immune checkpoint inhibition—most commonly ipilimumab [Yervoy] plus nivolumab. This subgroup represents a particularly challenging population, yet an ORR of 27% was observed. Notably, responses were also seen among patients with primary resistance to anti–PD-1 therapy, further supporting the potential utility of this therapeutic approach in difficult-to-treat populations.

If this combination were to become approved by the FDA, what would be the significance of this decision?

Any time a new therapeutic agent receives regulatory approval, it is critical to define the appropriate patient population to maximize clinical benefit. As previously discussed, this regimen expands the treatment armamentarium for patients with treatment-refractory melanoma—particularly those who reflect real-world clinical presentations. Patients with injectable lesions, whether superficial and accessible in the clinic or deep and accessible via image-guided intervention, could be candidates for this approach. This highlights the need for strong multidisciplinary coordination, particularly with interventional radiology, to optimize treatment delivery.

The Prescription Drug User Fee Act date for this regimen is anticipated in the third week of July 2025. If approved, the combination of RP1 and nivolumab may offer an important new option for patients who are ineligible for TIL therapy. As previously noted, TIL therapy has stringent eligibility criteria, often limited by cardiopulmonary status, functional reserve, or age-related considerations that preclude the use of lymphodepleting chemotherapy or high-dose IL-2.

This regimen could also be used as a treatment option prior to TIL therapy. It doesn’t necessarily need to be deferred to a later time, and it does not [preclude] future TIL-based approaches. [Ultimately,] treatment selection in this setting depends on the patient in front of us. All of us making decisions not just based on the science but also the art of medicine. We must weigh the clinical profile and treatment goals of the patient to determine whether to go down the path of RP1 plus nivolumab or whether the patient is an appropriate candidate for TIL therapy.

What is the importance of working with interventional radiologists and other multidisciplinary team members when using RP1 in clinical practice?

That cannot be understated. Close collaboration across multidisciplinary teams is critically important for the successful administration of this regimen. Within the clinic, identifying the appropriate patient is the first step, but subsequent coordination with advanced practice professionals is essential, particularly for procedures conducted in the clinic’s procedure room. These providers are integral to administration workflows.

Where is the drug going to be stored? How long is the shelf life once it is thawed? All of those are very practical considerations. It’s not just simply [a matter of] getting the drug and infusing it like we typically do for systemic immunotherapy. Utilizing our colleagues in interventional radiology, making them part of our team, and knowing ahead of time how we are going to coordinate with them [is vital].

Because this therapy is administered biweekly, aligning the schedules for intralesional injection, imaging guidance, and concurrent nivolumab infusion demands a coordinated effort with the infusion clinic. [Instituting a] standard operating procedure at each individual treatment site could [also help streamline implementation].

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

From a practical standpoint, in busy oncology practices where we see patients every 20 to 30 minutes, interrupting workflow to go perform an injection can be disruptive. Defining how we’re going to do that in our workflow by having a defined time slot–perhaps every 2 weeks–and utilizing or training advanced practice professionals [to perform the injections] could [be helpful].

To that end, education is also important. When patients are first informed that they will be injected with a virus, their eyes may widen, and they [often] become worried. However, there are a tremendous amount of safety data established with prior agents such as T-VEC, and [emerging] safety data from RP1 showing that [this therapy] is safe and the toxicities are mild. [Reinforcing the fact] that administration occurs in a controlled clinical environment can improve patient comfort. As long as patients receive adequate education on what to expect and what their post-procedure precautions are, it’s fairly easy to navigate [their concerns].

Primary analysis of the IGNYTE registrational cohort in anti-PD1 failed melanoma. Replimune Group, Inc. June 6, 2024. Accessed May 28. 2025. https://ir.replimune.com/static-files/2137036f-c2da-405c-b661-7f557bbdc781

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 28, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-biologics-license-application-acceptance-and

Articles

Nikhil Khushalani, MD, discusses the clinical potential of RP1 plus nivolumab in patients with PD-1–refractory melanoma as well as considerations regarding its use. 

Oncolytic Immunotherapy Approaches Open Up Alternative Treatment Avenues After Progression on Anti–PD-1 Therapy in Melanoma

! I’m your host today, Ashling Wahner.


, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, OncLive covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, supported by Replimune, we had the pleasure of speaking with Anna C. Pavlick, BSN, MSc, DO, MBA, about the use of RP1 plus nivolumab (Opdivo) for the treatment of patients with advanced melanoma. Dr 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.

In our exclusive interview, Dr Pavlick discussed the rationale for investigating this combination in patients with advanced melanoma who have received prior immune checkpoint inhibition, key efficacy and safety findings from the phase 1/2 IGNYTE trial (NCT03767348), and where the future may be headed regarding the use of oncolytic viruses in melanoma.

That’s all we have for today! Thank you for listening to this episode of 

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Podcasts

Dr Pavlick discusses the investigation of RP1 plus nivolumab in patients with advanced melanoma who have received prior immune checkpoint inhibition.

RP1 Plus Nivolumab Delivers Durable Responses in PD-1–Exposed Melanoma: With 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.

 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 

 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%.

 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+).

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.

“We still need to do clinical trials because we don't cure 100% of our patients yet,” Pavlick said in an interview with 

®. “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.

: What unmet needs exist for patients with advanced melanoma?

: 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 

 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 [

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.

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.

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

Anna C. Pavlick, BSN, MSc, DO, MBA, discusses data for RP1 plus nivolumab and the evolving treatment landscape in advanced melanoma.

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

Dr Pavlick on RP1 Plus Nivolumab in PD-1 Inhibitor–Pretreated Melanoma

“What we saw was that [33.6%] of patients actually had a response. That, to us, was very surprising because we were hoping to get some response, but this was a really nice, vigorous response [rate].”

Anna C. Pavlick, BSN, MSc, DO, MBA, a professor of medicine in the Division of Hematology & Medical Oncology at Weill Cornell Medicine; as well as the founding director of the Cutaneous Oncology Program at Weill Cornell Medicine and NewYork-Presbyterian, discussed key findings from the phase 2 IGNYTE trial (NCT03767348) investigating the efficacy and safety of RP1 plus nivolumab (Opdivo) in patients with melanoma who had progressed on prior PD-1–directed therapy.

IGNYTE enrolled 156 patients with cutaneous melanoma who had previously progressed on a PD-1 inhibitor. Pavlick noted that this patient population has limited treatment options beyond clinical trials. The investigators hypothesized that the addition of RP1 to an immunotherapy agent may bolster the efficacy of the checkpoint inhibitor in patients who had progressed on immunotherapy alone, Pavlick stated.

Among 140 evaluable patients in the overall population, the overall response rate (ORR) was 33.6%. Among patients who had previously received single-agent PD-1 inhibition (n = 82), the ORR was 38.7%. Pavlick noted that these ORRs were surprising because although she and colleagues had anticipated a relatively high ORR with this combination, they had not anticipated one as robust. In these respective populations, the complete response rates were 15.05% and 21.3%, which was another surprising finding, Pavlick said. Furthermore, the partial response (PR) and stable disease (SD) rates were 18.6% and 29.3% in the overall population, respectively, and 17.3% and 26.7% in the single agent–pretreated population, respectively.

Additionally, among patients who achieved best responses of PR or SD, these outcomes were durable, she explained. Overall, the median duration of response was 21.6 months (range, 1.2+ to 43.5+), and the 1-year response rate was 70.5%.

Videos

Anna C. Pavlick, BSN, MSc, DO, MBA, discusses efficacy data with RP1 plus nivolumab in patients with melanoma who had progressed on PD-1–directed therapy.

Furthering Treatment With Novel Therapies and Multidisciplinary Care in Advanced Melanoma After PD-1 Inhibition | Supplements and Featured Publications

Oncolytic Immunotherapy Approaches Open Up Alternative Treatment Avenues After Progression on Anti–PD-1 Therapy in Melanoma

RP1 Plus Nivolumab Delivers Durable Responses in PD-1–Exposed Melanoma: With Anna C. Pavlick, BSN, MSc, DO, MBA

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

Dr Pavlick on RP1 Plus Nivolumab in PD-1 Inhibitor–Pretreated Melanoma