Gibney Breaks Down the Evolving Treatment Landscape of Melanoma

Geoffrey T. Gibney, MD

A lack of approved treatment options exist for patients with melanoma who have progressed on an anti–PD-1 therapy in later lines of treatment, according to Geoffrey T. Gibney, MD. However, new clinical trials evaluating agents such as tumor infiltrating lymphocyte (TIL) therapy, TLR-9 agonists, and combination therapies are working to address this unmet need.
“We look at the melanoma field, and we see a lot of exciting developments. This is clearly changing the course for patients. The treatment decisions are getting more complex, and this requires more of a multidisciplinary, integrated approach. This is particularly [true] when patients have multiple options that include surgery, radiation, or systemic therapy,” Gibney said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on melanoma.

In the interview, Gibney, who chaired the event, reviewed the topics from the meeting including current treatment options for patients with melanoma, clinical trials that have explored different agents and combinations, and developing treatment options in uveal melanoma. Gibney is a co-leader of the Melanoma Disease Group at the Georgetown Lombardi Comprehensive Cancer Center and the MedStar Cancer Network, and a member of the Developmental Therapeutics (Phase I) program.

OncLive^®: What has been the most exciting advance in uveal melanoma in the past year?

Gibney: [At] the [IPC] meeting, we discussed advanced melanoma, looking at both frontline [treatment], as well as the second- or third-line [treatment]. We then did a deeper dive into newer data for uveal melanoma, where there’s still a very large unmet need. Fortunately, we now have approval of the new immunotherapy, tebentafusp-tebn [(Kimmtrak) for the treatment of HLA-A*02:01–positive adult patients with unresectable or metastatic uveal melanoma], but still clearly a lot more work needs to be done.

Michael B. Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center, discussed newly diagnosed metastatic melanoma. How does the presence of a BRAF mutation affect how immunotherapy is sequenced?

My colleague, Michael Atkins, MD, presented on frontline data, and we fortunately have a number of frontline therapies to offer patients, particularly if there’s a BRAF mutation that’s present in the tumor.

Dr Atkins led a national study called the phase 3 DREAMseq study [NCT02224781] that set the bar for immunotherapy first in this population. We then saw an improvement in the 2-year overall survival [OS] from that data. This has now set the standard for using combination immunotherapy with nivolumab [Opdivo] and ipilimumab [Yervoy] in the frontline setting in this population.

We now have another immunotherapy combination that has been FDA approved: nivolumab and relatlimab-rmbw [(Opdualag), based on findings from the phase 2/3 RELATIVITY-047 trial (NCT03470922)]. These combinations have not been compared head-to-head, but the data look equally impressive. [Relatlimab plus nivolumab] also has benefit in patients with BRAF mutations. The safety profile looks a little more favorable compared with nivolumab plus ipilimumab, but we don’t have any long-term data yet, nor do we have brain metastases data. We don’t have all the pieces we would like for utilizing nivolumab and relatlimab. That said, it’s still a good option to offer patients, particularly in those who may have been hesitant for the ipilimumab toxicity, where we would just offer just [nivolumab] monotherapy. That would be a great patient to offer nivolumab and relatlimab to.

At the meeting, you presented on novel approaches for relapsed/refractory melanoma. What current novel approaches are utilized in this setting?

I spoke on the salvage setting in patients who progressed on an anti–PD-1 monotherapy. This could be a patient who received therapy in the adjuvant setting and relapsed, and also in the setting where a patient has active disease or stage IV disease and either did not respond or had a good response [before progressing]. Unfortunately, we see this often, and there’s an unmet need of treating patients in the second and third line.

There have now been 2 studies looking at nivolumab/ipilimumab or pembrolizumab [Keytruda]/ipilimumab in the second-line setting. We’re fortunate to have the data, and it lined up well, showing similar results where we have a response rate of almost 30%. Many of those responses look durable.

We saw in the phase 2 SWOG S1616 trial [NCT03033576] with nivolumab/ipilimumab that greater efficacy [is observed] when using the nivolumab/ipilimumab combination compared with ipilimumab monotherapy. Now that we have that data, it’s settled the discussion that patients in the salvage setting should receive a combination of a PD-1 drug, such as nivolumab/ipilimumab.

What salvage regimens are under study that are generating excitement for these patients?

There are several agents that are in clinical investigations and some of them are far along. One [regimen] that we spent time talking about was adoptive T-cell therapy, or TIL therapy. Data from a phase 2 trial [NCT03645928] are probably the most mature, and we are hoping to have an FDA approval soon for this. This is a technique that has been around since the 1980s and now has become more of a commercialized product. We are excited to be able to offer this treatment to patients, hopefully soon, as a standard therapy.

[TIL therapy has produced a] response rate of 36%, and a large portion of the responses are durable, and we hope permanent. Past studies with TIL therapy have shown durable and long-lasting responses with a single course of treatment, and we anticipate that will be the same in the salvage setting. We are still waiting for long-term follow up on that data, but this is an exciting therapy to be able to offer patients, particularly after they’ve progressed through anti–PD-1 and anti–CTLA-4 therapy.

We also touched on other evolving data, such as with the TLR-9 agonist, vidutolimod [CMP-001]. This has shown activity in patients as monotherapy and in combination with anti–PD-1 therapy. We’ve seen a response rate of approximately 20% with both regimens, and it is more durable when you have a PD-1 drug in combination. We’re hopeful that this will become another approved regimen for patients, which is currently only available in clinical trials.

There is a range of other options that look very exciting, and we are waiting for more mature data. Looking at the NCCN guidelines, there’s a number of other regimens that can be offered to patients, although we’re still looking for even more effective therapies.

How is TIL therapy utilized as a post–PD-1 treatment?

When patients have been treated with an anti–PD-1 regimen and develop either relapse or progression, it is a challenge for those in the clinic. We see in the adjuvant setting that more than one-third of patients relapse after anti–PD-1 therapy, and in terms of patients with active disease, over half of patients won’t respond up front, or will respond and then progress. This is an area where we need more therapy.

Adoptive T-cell therapy, or TIL therapy has been around for over 20 years, initially studied in patients that were not exposed to anti–PD-1 drugs. We now have data in the population where patients have previously been treated and had progression on anti–PD-1 therapy. This has now become an exciting area where we have seen objective responses in patients who have now progressed on an anti–PD-1 regimen.

We discussed data from the phase 2 trial [mentioned above] in anti–PD-1 refractory melanoma. In that study, using a standard TIL therapy technique of harvesting a tumor, TIL is manufactured in a laboratory, a patient is brought into the hospital, given lymphodepleting chemotherapy, their TIL therapy, and then a course of IL-2.

We’ve seen a response rate of 36% in that data set. This is one of the highest response rates seen in patients who have progressed on an anti–PD-1 therapy before being treated with another immunotherapy. This is very exciting. We have seen that many of these responses are durable with that single course of treatment. Potentially, these patients may not need any further therapy for their melanoma, and they can go on with the rest of their lives. Having this available as a salvage regimen, we’re expecting and hoping that we will have FDA approval in this upcoming year, and we will be able to offer TIL therapy to patients as standard-of-care therapy.

Suthee Rapisuwon, MD, of Georgetown Lombardi Comprehensive Cancer Center, discussed the management of uveal melanoma. What unmet needs remain in this space?

We see uveal melanoma as an area that still needs much more clinical development. It is a rare melanoma, and it does have different biology than cutaneous melanomas, as well some of the other subtypes. We see some activity with anti–PD-1 and anti­–CTLA-4 therapies, but it’s at a much lower rate. Unfortunately, those therapies work well in skin melanomas but not so well in uveal melanoma.

Dr Rapisuwon covered some of the biology in uveal melanoma, discussing how this is an unmet need both in the adjuvant setting, where there’s a high risk of relapse, as well as in patients with active disease. One of the focal points in the discussion was on a new approval of the immunotherapy called tebentafusp. This is a T-cell–engager therapy, which a novel treatment class that engages patients’ T cells, when the antibody binds to it, allowing them to identify and react against tumor cells that are presenting the glycoprotein 100 antigen. This has been an effective strategy with trials showing improvement in OS for patients with uveal melanoma compared with the standard of care therapy.

In a phase 2 trial [NCT03070392], most patients received pembrolizumab [as investigator’s choice in the control arm], and we saw what looks like an improvement over immune checkpoint therapy with this new class of therapy. With that said, we’re happy to have the therapy, but we want more. We want to have better outcomes for patients. While the survival is improved, the response rate was not very high, and patients would end up receiving weekly therapy for tebentafusp. There is clearly a need for further development of novel therapeutics, and a number of these strategies are under investigation.

What remains to be addressed in the future of melanoma?

We see the need for further trials. We need to optimally sequence therapies to improve outcomes, and we need more therapy options in patients that have rare subtypes, such as uveal melanoma, as well as in the salvage setting. Once we have these options, we clearly will see better outcomes with patients. We are seeing this already. Hopefully we get to a point where most patients with advanced disease will have durable responses and long-term survival.