RP1 and Other Oncolytic Viruses Could Pave a New Treatment Pathway in Advanced Melanoma

With immune checkpoint inhibitors established as the standard frontline treatment for patients with advanced melanoma, investigations into other immune-based therapies such as oncolytic viruses aim to bolster the treatment armamentarium for patients in need of subsequent treatments after progression on an anti–PD-1 regimen, according to Bently P. Doonan, MD.

“Melanoma [treatment] has shown a ton of up-front success, but it doesn't have a deep bench. Once those [initial treatments] get tired, we really don't have anything significantly beneficial [in subsequent lines of therapy],” Doonan explained.

Data from the phase 2 IGNYTE trial (NCT03767348) presented at the 2024 SITC Annual Meeting showed that the HSV-1–based oncolytic immunotherapy RP1 (vusolimogene oderparepvec) in combination with nivolumab (Opdivo) generated an overall response rate (ORR) of 33.6% (95% CI, 25.8%-42.0%) per modified RECIST 1.1 criteria in patients with patients with advanced melanoma whose disease progressed on or after prior anti–PD-1 therapy (n = 140). Data showed that these patients achieved a median duration of response (DOR) of 21.6 months (range, 1.2+ to 43.5+) and a 12-month DOR rate of 70.5%.

Most adverse effects (AEs) reported with the combination were grade 1 or 2, and no specific grade 3 AEs occurred in more than 5% of patients. 5 total grade 4 AEs were reported during the study, and no patients experienced fatal AEs.

In an interview with OncLive®, Doonan discussed the rationale for ongoing research with oncolytic viruses in advanced melanoma, expanded on data from IGNYTE, and explained the need to develop additional therapies for patients who progress on or after immune checkpoint inhibition.

Doonan is a clinical assistant professor in the Division of Hematology & Oncology, Department of Medicine, College of Medicine, at the University of Florida in Gainesville.

OncLive: What has driven the interest in the investigation of oncolytic viruses within the melanoma field?

Doonan: Melanoma has always stood out as the testing ground for immunotherapies. The majority of melanomas, thankfully, are very responsive to manipulation of the immune system to try to combat the disease—the most successful of which has been checkpoint inhibition. However, around the same time that checkpoint [inhibition] was being studied, we were studying in parallel things like vaccines and different adaptive treatments like tumor-infiltrating lymphocyte [TIL] therapy as well as oncolytic [viruses]. [This is] partially because viruses can stimulate an immune response, and that immune response that kills infected viral cells is also a similar pattern to how we can kill cancer cells.

There is a lot of synergy between killing a cell by a virus killing it, or our immune system killing it. If you can kill a cell with a virus directly, you get an antigenic spread and release of information that your immune system will pick up. That is our natural default pattern when a cell ruptures, dies, or is killed by those means.

[With oncolytic viruses,] we are leveraging naturally occurring immune mechanisms in a setting where we expect the cancer to be more immune-sensitive than other cancers. If [oncolytic viruses] are going to work, they should work in a setting like melanoma. We have strong historical data now from previous FDA-approved therapeutics, like talimogene laherparepvec [T-VEC; Imlygic], that it can work.

However, some of the limitations have always been [the fact that] melanoma is more heterogeneous than just 1 tumor cell or 1 type [of cancer]. Getting treatment to the tumor, getting it to kill the tumor, and getting it to stimulate that depth of immune response has always been the challenge, but [oncolytic viruses] never went away as a potential therapy. It just couldn't replace or compete against the up-front value that immune checkpoint inhibitors brought us.

What we're seeing now is a full circle, coming back to [this question]: if immune checkpoint inhibitors are very successful, what [treatment options can we have] for those patients who [progress on immune checkpoint inhibitors]? What strategies do we have to try to overcome some of those failure mechanisms? Some of these therapies or techniques that we've been studying or working on for the last 20 years [have] resurfaced with a new place in the timeline.

For patients who experience disease progression after immune checkpoint inhibition, what are some of the current treatment strategies? What are some of the challenges of treating this population?

[Treatment following immune checkpoint inhibition] continues to be an unmet need within the disease. We're fortunate that with up-front immune checkpoint inhibition in patients who are candidates for it, we effectively will only give that therapy to approximately 50% of patients or more, depending on the therapy that we pick. Sometimes [this rate] can be as high as 60% of patients will only receive [checkpoint inhibition]. However, this also tells us that 30% to 40% or more of patients will [need subsequent treatment]. There is a massive need for interventions and strategies for either patients who have no second-line options or those with very limited second-line options.

Currently, the standard would be to look for another pathway of treatment, specifically a molecularly targeted treatment in those patients who are BRAF-mutated; however, that [represents] only 40% to 50% of melanomas. When you look for [BRAF mutations] in the second-line and you don’t find them, you're lacking other options. At times, depending on what a patient’s response to immune checkpoint inhibition was, there are some patients who can either be rechallenged or strengthened in terms of the total immune checkpoint exposure they get. For example, for patients who got single-agent checkpoint [inhibition,] you can consider increasing to dual-agent [treatment]; others who had an initial robust response to checkpoint inhibition or maybe even entered a stable period of remission but had their disease recur— depending on the timeline—you can often rechallenge. For those who develop resistance [to checkpoint inhibition], are resistant while receiving therapy, or showed no response to treatment, you're out of options other than a recently approved cellular therapy, the TIL therapy lifileucel [Amtagvi]. This is approved in the third line for BRAF-mutated patients and in the second line for all other melanoma comers. It's realistically the only FDA-approved therapy in that space.

If patients can't get TIL therapy or are not candidates for it, we're looking for clinical trials or combination therapies, meaning taking pembrolizumab [Keytruda] and adding lenvatinib [Lenvima], which is done in some situations, or using molecularly targeted drugs outside of BRAF inhibitors to try to target those cancers, like in the setting of NRAS, NF1, or some of the new molecular targets that we're finding more commonly in melanomas, [where we can potentially] 'steal' drugs from other cancers. Outside of that, there isn't any other therapy to offer them.

At the 2024 SITC Annual Meeting, we saw some data with the combination of the oncolytic virus RP1 plus nivolumab in patients with advanced melanoma who progressed following prior anti–PD-1 therapy. What were some of the key findings from this study?

These are important data because [RP1] is now a player in the post–PD-1 failure setting where we didn't have effective therapies to meet that demand. As a melanoma community, we probably reference an ORR above 25% or 30% once [patients have progressed] on checkpoint inhibitors. [This is the standard benchmark] to try to say that your therapy likely has an effective possibility of helping these patients. Any [ORR] less than that doesn't mean that [a therapy] can't be helpful, it just means broadening it or making it a more standard approach to use in that setting is more difficult.

The first important thing [about the data for RP1 plus nivolumab] was that it hit that [ORR] threshold [at 33.6%]. That is also the threshold shared by [data for lifileucel]. In terms of new approvals, that is what we need: at least approximately one-third of the patients showing a response to the new therapy. [RP1 plus nivolumab] met that first measure.

One of the next most important markers that you have is how long patients stay on the therapy. How long is their response? We run into trouble if we solely focus on things like progression-free survival vs DOR] or median duration of efficacy of a therapy. What matters much more clinically is [the timing of when] a person needs a new [subsequent] therapy, not necessarily when a scan shows a new lump or when there's some potential change to deviate from what our current treatment plan is. In clinical practice, a little bit of disease somewhere else that has a separate management plan doesn't always take you away from the therapy you're on. Often, the median DOR can be a better indication of how much longer patients experience melanoma-specific survival.

Importantly, the median DOR in those responders [in the IGNYTE trial] was quite long [at 21.6 months]. However, this is a small sample size of patients, and we're talking about patients who potentially have a different form of disease than [those enrolled in] some of the other studies that have been done in the post–PD-1 [setting]. One of the troubles with any study that studies this patient population is that there is a distinct difference between [types of] progression. For example, patients who have not been on a checkpoint inhibitor for 1.5 years have technically recurred and have second-line disease at that point. That's very different than patients who have been on dual-agent immune checkpoint inhibition with ipilimumab [Yervoy] and nivolumab for 4 months and had their tumors keep growing. These are 2 different biologies, but they both will look the same if you only strip them down to patient characteristics.

[The post–PD-1] population has been difficult to tease out in terms of patients with pure, first-line refractory [disease] vs patients with seventh-line melanoma. This was true for lifileucel, as well. You had patients coming from receiving 1 line of single-agent checkpoint inhibition all the way up to patients who received 7 lines of experimental therapy and had been on some form of treatment for 6.5 years; all [these patients] were clumped together as part of that study cohort. It's interesting that in this same trial, they carried patients with advanced metastatic disease, those with distant sites or visceral sites of disease, those with high lactate dehydrogenase [levels], and those who have the more progressive, more difficult forms of melanoma that we would be more concerned with treating. Sometimes you can skim the cream off the top when you're picking patients with a low burden of disease and show that [a treatment benefited] them. Maybe you were just seeing [the benefit of] rechallenge with checkpoint inhibition in those patients.

Realistically, the population [from IGNYTE] was representative of what we see clinically, so it's a fair comparison to what we look at, but that's just the lens [used] to look at all of these data. Ultimately, the patients who we're going to treat might be quite different than the study population.

Regarding the safety of oncolytic viruses, what is known about adding them to other standard agents?

One of the things that we've noticed in the development of other immunotherapies is that there are 2 different groups of newer treatments. There are those that induce very potent, severe, immune-based AEs and also have strong efficacy when they work. These are more like our BiTE therapies, TIL therapies, or modified immune cells that carry [risks of] things like cytokine release syndrome. They can be strong and potent [treatments], but they carry those associated risks.

On the opposite side of the spectrum are things like oncolytic viruses or some of the nanoparticle-based vaccine approaches that are currently being studied where we’re really not seeing any significant additional toxicities to what we would expect with just the backbone of immune checkpoint inhibitors. We are not seeing any unique features other than localized injection-site pain or reactions.

What you would always look for when you're injecting, for example, a modified herpes virus, is if we gave this person some event that then requires treatment or an intervention. Thankfully, we haven't seen that in any of the clinical data or any of the practical use of T-VEC. We haven't really seen issues in people who are severely immunocompromised.

Notably, they're studying RP1 specifically in patients [who received a prior solid organ transplant] without seeing any new AEs, so that can help tell you what the overall risk to the average population would be. If somebody who's chronically immunosuppressed and received a renal transplant can get RP1 without getting a disseminated herpes infection, [the average population] probably has a low risk if they only have melanoma. Both vaccines and oncolytic viruses carry a significant advantage in the practical use where they can be given in the clinic and by the fact that they're not going to add significant toxicity [beyond] what you'd expect from just being on nivolumab.

As research with oncolytic viruses continues, what is your hope for how they could affect the melanoma treatment paradigm?

There's a lot of hope in this space. If you go to a major national meeting, you're going to have a couple standout presentations that bring some light to [oncolytic viruses]. There is more work being done, and work on other non-immune therapy–based molecular targets of disease will help with different subsets of patients. We need a broader understanding of all of the PD-1 failures in order to not group all [patients] together. We have an effective second-line therapy [with lifileucel] that is relatively difficult for some patients to get, if not impossible. It's very user-dependent, meaning you need a facility that's trained and equipped to do it.

With breakthroughs and things like RP1, as well as other agents that are coming, it gives the potential for [treatments] that can stay in the clinic in a routine environment without added toxicities for our older melanoma population, or patients who don't qualify [for other treatments]. [Emerging treatments] shouldn't be viewed as competition to each other—they should be viewed as options for patients who don't have options otherwise. If we feel like everybody has to get [a specific treatment], then that's at the detriment to other [treatments]. We need to understand who needs what, when they need it, and how we work with all [treatments] to get a patient the best outcome. Frankly, everybody doesn't need every [treatment], and a whole lot of people still only need a single-agent immune checkpoint inhibitor.

Reference

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.