Multidisciplinary Consideration of Frontline Modalities Should Guide Decisions in Melanoma With In-Transit Metastases

Danielle K. DePalo, MD

Selecting between isolated limb infusion/perfusion (ILI/P), immune checkpoint inhibition (ICI), and intratumoral therapy (IT) in the first-line setting for patients with surgically unresectable melanoma in-transit metastases necessitates multidisciplinary collaboration and consideration of the risks and benefits of each modality, according to Danielle K. DePalo, MD.

Findings from a retrospective chart review of these 3 modalities were presented at the 2023 ASCO Annual Meeting and showed that ICI therapy (n = 121) was associated with greater short-term toxicity necessitating pharmacological intervention vs IT (n = 86) and ILI/P (n = 353), at 44.1% vs 18.0% and 20.4%, respectively. ICI therapy was also associated with increased toxicities requiring hospitalization (22.1%) vs IT (1.4%) and ILI/P (9.2%).

Regarding efficacy, ILI/P elicited the highest overall response rate (ORR) of 82.2%, followed by IT at 72.1% and ICI therapy at 63.6% (IT vs ILI/P, P = .047; ILI/P vs ICI, P < .001; ICI vs IT, P = .231). ICI therapy resulted in greater overall melanoma-specific survival (MSS) vs IT or ILI/P, at 148 patients vs 15 and 13 patients, respectively (P = .003).

“The treatment of patients with in-transit metastases is still a patient-specific decision that we need to be making,” said DePalo, who is a general surgeon at Moffitt Cancer Center in Tampa, Florida. “It seems like IT therapy is a promising option, as well as ICIs, but we shouldn’t rule out ILI/P until we look more closely at the most contemporary, recently treated patients to see whether these survival benefits still hold.”

In an interview with OncLive^®, DePalo explained how this study addresses the lack of research directly comparing first-line treatment options for patients with unresectable in-transit metastases, expanded on the safety and efficacy of these 3 modalities, and underscored the need for more data to inform the management of these patients.

OncLive: Please describe the rationale for comparing first-line systemic, regional, and IT modalities therapies in surgically unresectable melanoma with in-transit metastases. How did you compare these modalities?

DePalo: When it metastasizes, melanoma can spread through the lymphatics to regional nodal basins. Metastases en route to the nodal basin are called in-transit metastases. There are now a few different treatment options for these: locoregional therapy with IT therapies, ILI/P, and checkpoint inhibitors. At this point, there are multiple options to choose from, and we don’t know which one is the best option in the first-line setting for the treatment of patients with in-transit metastases; it varies by institution and physician discretion.

To compare these different modalities, we did a retrospective chart review from 1990 to 2022, at 12 international institutions. [We assessed] patients with stage III melanoma and surgically unresectable in-transit metastases who were treated in the first-line setting with talimogene laherparepvec [Imlygic] IT therapy, ILI/P, or ICI therapy with anti–PD-1 with or without anti-CTLA-4 antibodies. We excluded patients with regional nodal involvement or distant metastatic disease at the time that the in-transit metastases were being treated.

What findings from this study were presented at this year’s meeting?

We identified 551 patients. Of those, 70 received IT therapy, 356 received ILI/P, and 25 were treated with ICI therapy. The IT patients were a bit older, and the checkpoint inhibitor patients were a bit younger. We saw that the limb infusions were used to treat a slightly higher number of patients; the median was 4 as opposed to 3 with the other modalities. The overall largest size of in-transit metastases did not vary among treatment modalities. When we looked at toxicity, it followed patterns that we would expect for each regimen. For ILI/P, we saw higher rates of lymphedema.

Patients who received checkpoint inhibitors had higher rates of toxicity requiring pharmacological therapy and hospitalization. The median follow-up was longest for those who are treated with limb infusions. This is consistent with what we know, as limb infusions and perfusions have been around much longer than IT therapies and ICIs.

When we looked at ORR, the locoregional therapies did the best, that’s IT and ILI/P compared with the ICIs. When we looked at the local progression-free survival [PFS], patients [treated with] IT did better than [those treated with] the checkpoint inhibitors, and [those treated with] limb infusions did a little bit worse. [Additionally], when we looked at distant PFS, the locoregional therapies did better. However, we saw that the IT therapies and the ICIs didn’t differ in [terms of] median PFS, but [patients who received] ILI/P did a bit worse. The pattern held up on multivariable analysis, and we saw the same patterns for both melanoma-specific survival and overall survival.

Were any of these findings particularly interesting or surprising to you?

What might have surprised me about this research is that the [patients treated with] ILI/P did do a bit worse regarding melanoma-specific survival. One thing that might contribute to that is the fact that ILI/P has been in use for a lot longer than IT therapy and checkpoint inhibitors. When patients progressed on ILI/P years ago, they didn’t have the options that they have today. That’s probably contributing to some of the survival difference. We are in the process of looking at a much more contemporary cohort of patients treated within the past decade who are using the same modalities to see whether this difference still holds.

How do these findings emphasize the importance of multidisciplinary decision-making when determining treatment plans for patients in this population?

This project is very much multidisciplinary. IT therapy is often given by a surgical oncologist, and sometimes medical oncologists administer it, too. However, ILI/P is performed by a surgical oncologist, and the checkpoint inhibitors are administered by a medical oncologist. For patients coming in with in-transit metastases, it often seems like [the choice of modality] just depends on who they’re seeing first. We’re trying to [identify] the most appropriate first-line modality and [see] whether we can find a more evidence-based approach to treating patients with in-transit metastases.

At this point, we haven’t found enough convincing data to say we need to change our management of in-transit metastases. We need cleaner data before we can draw any conclusions about which option is the most appropriate first-line therapy. It is certainly still a multidisciplinary decision in that some patients are better candidates for limb infusions and that’s usually determined by the surgeon, whereas some might not be the best candidates for checkpoint inhibitors, which is usually decided by medical oncologists. The patient benefits from everyone working together and communicating to decide on the most appropriate treatment regimen.

Does this research open any future avenues of investigation?

We had only looked at these 3 categories of treatments as monotherapies. Something that we need to look at going forward, because there are a lot more therapies in use, is exploring these options as combination regimens. We also [need to] look at the sequencing of the regimens [to figure out] which one is [the optimal] first-line [therapy] and which is the most appropriate regimen to follow that. Those are additional questions that we need to answer in the future.

Reference

DePalo E, Naqvi S, Ollila DW, et al. Intralesional therapy, limb infusion/perfusion, and immune checkpoint inhibitors as first-line therapy in surgically unresectable melanoma in-transit metastases. J Clin Oncol. 2023;41(suppl 16):9574. doi:10.1200/JCO.2023.41.16_suppl.9574