Administration of RP1 Through Intratumoral Injection Offers Unique Advantages in Melanoma Treatment

Nikhil Khushalani, MD

Oncolytic immunotherapy with talimogene laherparepvec (T-VEC; Imlygic) and vusolimogene oderparepvec (RP1) has the potential to provide unique clinical benefits in patients with melanoma through direct intratumoral administration, according to Nikhil Khushalani, MD.

Building on innovations in T-VEC therapy, RP1, in combination with immune checkpoint inhibitors (ICIs), has been shown to enhance cytotoxic death in tumor cells while sparing healthy tissue. Now, ongoing clinical trials such as the phase 2 IGNYTE (NCT03767348) and CERPASS (NCT04050436) trials are examining the efficacy of RP1 in combination with the ICIs nivolumab (Opdivo) and cemiplimab-rwlc (Libtayo), respectively.

“In the IGNYTE trial, [for patients with] cutaneous squamous cell carcinoma (CSCC), RP1 in combination with nivolumab provided response rates of over 60%,” Khushalani, vice chair of the Department of Cutaneous Oncology at Moffitt Cancer Center, said. “More impressively, at least at early reads, there were high percentages of complete response [CR] rates. Although we don’t know whether CR rates in CSCC necessarily translate into improved outcomes, like we’ve seen in melanoma, that may be the case, and hopefully time will tell us that.”

In an interview with OncLive^®, Khushalani discussed the variety of opportunities for RP1 and other novel agents, as well as how RP1 may fit into the melanoma treatment landscape in patients who receive skin grafts.

OncLive^®: What are some unique elements of oncolytic immunotherapies that distinguish them from other agents?

Khushalani: Oncolytic immunotherapy, [commonly referred to] as oncolytic virotherapy, is unique because it is typically administered intratumorally, directly into the tumor itself. What is unique about that [administration] is that it can [stimulate] an antitumor effect where it’s injected.

[Additionally], because of the genetic engineering that has occurred with that oncolytic virus, it can potentially elicit an immune effect that has a bystander effect in other areas of tumor that were not injected. We call that the abscopal effect. We’ve seen this with some of the oncolytic viral therapies that have already been developed, one of which is already in commercial use with regulatory approval.

Could you elaborate on some of the data that we’ve seen with some of these other oncolytic viruses?

Oncolytic viral therapy has been around for a while. It essentially takes the backbone of an existing virus [and] genetically [modifies it], preferentially expanding or expressing certain immune molecules.

The most common [oncolytic virus] that is currently in utilization is granulocyte macrophage stimulating factor [GM-CSF]. [There’s also] T-VEC, which was built on a herpes simplex virus 1 [HSV-1] modification and received regulatory approval from the FDA primarily in cutaneous melanoma for patients with unresected or unresectable in-transit metastases, cutaneous or subcutaneous [metastases], or nodal metastases.

This [approval] was based on data from the phase 3 OPTiM trial [NCT00769704], which compared intratumoral T-VEC versus systemic GM-CSF. The primary end point in that study was durable responses, which was seen in approximately 20% of patients treated with T-VEC versus less than 5% [treated] with GM-CSF.

At Moffitt Cancer Center, where I practice with a very large multidisciplinary group, we have a wealth of experience utilizing T-VEC. Our surgeons administer this intratumorally and have participated in the registration trials [with carefully chosen patients who have] limited in-transit disease. We’ve seen some impressive responses and durable responses. Most importantly, the patients tend to tolerate this therapy well, with minimal or no systemic adverse effects [AEs].

Several other oncolytic viruses or injectable targeted therapies are currently in investigation and in development. Another one that has been utilized is Cavatak [CVA21], which utilizes a coxsackievirus backbone. [Other therapies] use adenovirus backbones. [Much of] that data is still maturing.

Turning to RP1, what is the mechanism of action of this oncolytic virus? What is the rationale for evaluating it with nivolumab in clinical trials?

RP1 is the next generation of T-VEC. It is a selectively replication-competent or replication-specific HSV-1 for intratumoral injection. [A few traits set it apart. RP1] has a construct of HSV-1, [where] the neurovirulence factor gene [has been deleted]. That allows this virus to preferentially replicate within the tumor cells and spare normal cells [relatively well. Usually,] there’s no significant bystander effect on normal tissue.

[RP1 is also] impregnated similarly to T-VEC with the codon and coding for GM-CSF. That is the immunotherapy part of the immune moiety of this molecule.

A third distinguishing feature [is that RP1] also has an encoding codon for a glycoprotein, called GALV-GP-R-, [where] the R sequence has been deleted. What that does is promotes cell-to-cell adhesion-related cytotoxicity. Tumor cells that are adjacent to each other, when exposed to this, get lysed, [or, in other words,] undergo cytotoxic death.

That is essentially the premise of the construct of RP1, [which] is given intratumorally. Preclinical data, [which are] primarily murine, or data from mice, have shown that [RP1], in combination with PD-1 or CTLA-4 inhibitors, both checkpoints that are commonly utilized in the management of diseases such as melanoma, enhances cell killing. There’s enhancement within the tumor microenvironment of recruited CD8-positive cells, or cytotoxic T cells, [which] enhances tumor cell kill.

[That synergistic effect was the impetus for moving RP1] into human trials. Currently, several clinical trials, both in cutaneous cancers as well as other cancers, are ongoing with RP1, [as well as with] subsequent generations, which are RP2, and RP3.

The IGNYTE trial is enrolling patients whose disease has progressed on prior PD-1 inhibitors. What does the treatment landscape for that population currently look like, and what unmet need could this agent fill?

The current standard of care for patients with therapy-naïve advanced melanoma is typically an anti–PD-1-based regimen. Previously, it was anti–PD-1 monotherapy, or [PD-1 inhibitors] in combination with the anti–CTLA-4 drug ipilimumab [Yervoy].

This [standard of care] was based on several large, randomized trials, the most prominent being CheckMate 067 [NCT01844505]. We have since heard the trial presentation for RELATIVITY-047 [NCT03470922], which evaluated the combination of nivolumab plus relatlimab [Opdualag], a LAG-3 antibody. [That combination] demonstrated superiority in progression-free survival [PFS] compared with nivolumab alone, leading to FDA approval in March of 2022. That is a potential new standard of care for frontline therapy for a large number of patients.

Ipilimumab plus nivolumab still has a large place in the management of advanced melanoma, particularly given the long-term data that we have with that combination now with over 6 and a half years of median follow-up that has also been presented and published. The bigger problem is: What happens when patients do not respond to these regimens?

We know that at least 50% of patients will not respond to frontline ICIs. Unfortunately, those patients still have a poor prognosis. Patients who are treated with PD-1 monotherapy and antibodies can potentially receive an ipilimumab-based regimen in the second-line setting. We have prospective data suggesting low-dose ipilimumab plus pembrolizumab [(Keytruda) may work] for those patients, where response rates are approximately 28%. 

Similarly at the American Association for Cancer Research [AACR] Annual Meeting 2022, we heard about standard-dose ipilimumab plus nivolumab, which, when compared with ipilimumab alone, again showed a numerically higher response rate, between 25% and 30%.

However, there’s still a huge unmet need. Outside of targeted agents, such as MAP kinase-targeted agents, including BRAF and MEK inhibitors for that subset of patients that are BRAF V600-mutant, we don’t have any other treatment options apart from chemotherapy, which is palliative at best. Although we’ve raised the bar in melanoma, we still have [a long road ahead of us]. Trying to combine, for example, a novel agent such as an intratumorally administered agent to try and overcome either primary or secondary resistance to ICIs is a very novel strategy.

Building off the abscopal effect of intratumoral injections, what are some other advantages of this type of approach?

One of the important [aspects of intratumoral injections] is that you can see where you’re injecting the tumor. It is going right to the scene of the crime. At Moffitt Cancer Center, we are currently participating in the trial that’s evaluating cemiplimab with or without RP1 for patients with advanced, therapy-naïve CSCC.

The toxicity [from this treatment] is manageable because it’s local toxicity, primarily either injection site pain or occasionally bleeding at that site. Some patients have mild constitutional symptoms in the first 24 hours, typically a low-grade fever or flu-like effect, but otherwise, it’s quite well tolerated. In the data presented, there is not any potential for longer-term toxicity.

Now, we are combining cemiplimab with RP1 in many of these trials. For example, in the IGNYTE set of studies, or in the CERPASS study, we’re using that combination with ICIs. Inevitably, [it’s not easy to] escape the toxicities unique to ICIs. But if we can do that, potentially by enhancing response rates, overcoming resistance to ICIs, or prolonging duration of response, then that will be a success.

The publicly available data for RP1 appears to suggest good efficacy in combination with anti–PD-1 therapy. For example, in the IGNYTE trial, multiple cohorts of diseases are being studied, some of which are anti–PD-1 or therapy naïve, whereas some are anti–PD-1 refractory. This trial is not limited to cutaneous malignancies but is also looking at patients with microsatellite high or microsatellite unstable cancer, for whom ICIs are an approved option because of defined efficacy.

We don’t have readouts from the CERPASS trial yet. In the anti–PD-1 refractory melanoma cohort, we’re also seeing response rates upwards of 30%. This is an early study, and we’ll need randomized comparisons to what we would consider the current standards of care in refractory melanoma, but that is encouraging activity that can hopefully stand the test of time in a larger study as well.

Do treatment delivery methodologies differ among patients who have superficial lesions vs those with deep visceral tumors?

They absolutely do. The superficial lesions such as skin subcutaneous tissue that is visible or is palpable can certainly be done in the clinic. With the appropriate training of our personnel, we can easily do that in the office setting itself.

The tumors that are deeper, including deeper-seated lymph nodes or liver tumors, are extraordinarily difficult to treat. It’s important to bring up the topic of liver tumors because RP1 is being investigated for patients with hepatic metastatic disease, including a disease that I treat, metastatic uveal melanoma, or melanoma of the eye, which has a high propensity of spreading to the liver.

The immunosuppressive milieu within the hepatic microenvironment tends to affect or impede response to anti–PD-1 therapy for patients with hepatic metastatic disease. Instead, we can directly inject tumors through interventional radiology guidance. That approach certainly requires more planning and a very well-defined workflow. But in many centers, it can absolutely be done with the right skill set, particularly involving image-guided or, typically, ultrasound-guided injections with interventional radiologists.

Based on ongoing trials with RP1, where do you see this drug fitting into the treatment landscape? Will there be multiple niches for it?

The biggest niche is in patients with anti–PD-1 refractory melanoma. RP1 treatment requires injectable disease. It’s certainly easier to treat superficial lesions in the office-based setting than it is to treat the unresectable, in-transit disease that we see in melanoma, Merkel cell carcinoma, and CSCC.

In CSCC, it’s also important to recognize that most of our patients, when they present with unresectable disease, have what we refer to as locally advanced disease: large tumors that are close to vital structures that make curative surgery difficult or impossible. Similarly, [in many of these patients], definitive radiotherapy has already been utilized or is not possible, even though they don’t have distant metastatic disease. An intralesional approach or an intralesional approach plus systemic immunotherapy would be ideal for those patients.

Trials are underway investigating RP1 with direct intratumoral injection in tumors involving the liver, for example, primary hepatocellular carcinoma [HCC]. That requires far more complex coordination. But in the right setting, it can absolutely be done. There will likely be very specific niches [for RP1 such as these].

Now, in the frontline setting, if the CERPASS trial demonstrates significant improvement, as it has hypothesized, and if the primary end points are met, then RP1 could potentially become the new standard of care for CSCC, at least for injectable and locally advanced disease.

In that population, it’s also important to recognize that we have a large number of solid organ transplants done in the United States and worldwide. These patients receiving transplant have a high risk of developing skin cancers, most prominently CSCC. The problem is, because of the allograft, the use of ICIs is relatively contraindicated, or at least if it’s done, it has to be done with great caution and as a shared decision-making process with the patient.

Patients with melanoma or those who receive transplants commonly have multifocal superficial disease, multiple small, CSCCs that arise with great frequency. An intralesional approach or superficial approach would be ideal for those patients as well.

Would you like to further elaborate about any other aspects of oncolytic viruses?

The data have to show us that oncolytic viruses in melanoma are worth pursuing. If the data are simply going to be just as good as our systemic therapy, then, from a practical standpoint, it becomes harder to administer oncolytic viruses in the office-based setting, especially in a medical oncology community office setting. [We must] clearly show that [this treatment] is superior to the existing standards of care. The bar is high, but that doesn't mean it cannot be met or broken.