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

Nikhil Khushalani, MD

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).1 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 2024 ASCO Annual Meeting, in which the overall study population (n = 156) achieved an ORR of 32.7%, including a complete response (CR) rate of 14.7%.

Notably, RP1 plus nivolumab was granted priority review by the FDA for patients with advanced melanoma after anti–PD-1 therapy in January 2025.2

“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 OncLive®. “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.

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

Khushalani: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 BRAF 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 was approved by the FDA in February 2024, 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].

References

1. 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
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 28, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-biologics-license-application-acceptance-and