Sullivan Unpacks Breakthroughs, Challenges in the Treatment of Advanced Melanoma

Ryan J. Sullivan, MD

Over the past decade, investigators have worked to expand the treatment landscape for patients with advanced melanoma and finally their efforts are bearing fruit. The addition of immune checkpoint inhibitors and targeted therapies has paved the way for advances in the adjuvant and met-astatic setting with recent data from clinical trials demonstrating significant improvements in overall survival for these patients.

But even with these strides toward improved treatment options, physicians still have safety concerns and patients still have unmet needs in this setting.

“The past decade has been an exciting time for the development of therapies for patients with melanoma,” Ryan J. Sullivan, MD, said. “With that said, we’ve had 1 new approval in 4 years [Table 1¹]. The past several years has been about learning more about how the drugs work, not necessarily about developing new drugs. We’ve had a number of disappointments in terms of randomized phase 3 trials, [but] this year that seems different. And though [the treatment landscape] hasn’t changed the way we [treat] patients right now, there were a few trials that will change management.”

In an interview with OncLive^®, Sullivan, an associate professor of medicine at Harvard Medical School in Boston, Massachusetts, highlighted the key developments in melanoma and the ongoing challenges facing clinicians ahead of his presentation “Individualized Management of Advanced Melanoma: 2021 Updates.”

What does the landscape for melanoma look like?

The development of new therapies for metastatic melanoma in the past decade has been one of the real success stories in oncology. Despite that, we’ve had a bit of a slow period [but] we’re now again seeing trials that are [producing] positive [results] and new therapies that are likely to be rolled out. The point is, there’s been continued progress in trying to identify better therapies in the upfront setting for patients with metastatic melanoma.

Approximately 40% of patients [with melanoma] have BRAF mutations, and there are strategies to target BRAF with small molecule inhibitors or with small molecule emitters plus monoclonal antibodies against PD-1 or PD-L1. One of the major discussion points for the past decade [has been] where do we start first. Should we treat individuals with BRAF inhibitors, or should we treat them with immunotherapy first?

We’ve all migrated to using immunotherapy first because of this potential for long-term durable benefit, and the potential also to be off therapy. Findings from 2 randomized trials that have read out in the past month clearly show that frontline therapy for BRAF-mutated melanoma should be immunotherapy.

Despite the advances in developing therapies, including immunotherapies that can be associated with durable benefit in patients, we are continuing to try to identify why patients develop resistance and develop more effective strategies for that patient population. Immunotherapy resistance is a key problem and developing new therapies in that space is an unmet need [and my presentation] will highlight some of the strategies that are being taken.

For patients with melanoma that has metastasized to the brain, the data are quite clear that dual immune checkpoint inhibitor therapy with ipilimumab [Yervoy] plus nivolumab [Opdivo] is associated with unprecedented survival in that patient population. The key there is that for patients with melanoma with brain metastases, frontline ipilimumab plus nivolumab is the right decision. There has to be a good reason not to use them.

What are the top safety concerns for treatments in advanced melanoma in clinical practice?

I think we’ve learned a lot about the safety of these drugs over the past several years. The major safety concerns are immune- related adverse events from checkpoint inhibitors. By inhibiting these checkpoints, which essentially are the things that keep our immune system in homeostasis, we’re at risk for having terrible things happen.

[I anticipate that we will] learn more about how immune-related adverse events or specific immune-related adverse events are related to a cancer that’s in that organ or [if they are] related to a mechanism related to the way the immune system is attacking cancer. Ideally [we want] to identify what’s different about how the immune system recognizes and attacks cancer vs how the immune system recognizes an attack of itself. In doing that, we’ll be able to identify better therapies that may be effective at helping us prevent and treat immune-related adverse events, while not preventing immune destruction of the tumor.

We’re close to beginning to understand how this works. We’re getting closer to developing better strategies so we’re not just [administer-ing] immune suppressants.

What are the unmet needs for patients with advanced melanoma?

It would be nice to have biomarkers that could help us predict adverse effects. Then at least when we’re talking about treating patients in the adjuvant setting, we could figure out who we should recommend to a therapy and who we shouldn’t. If we had a good marker of toxicity, [it] would also allow us to do studies that could help us sort out what types of therapies can be used to prevent toxicities.

[With the exception of ] trials such as CheckMate 067 [NCT01844505], the results of which showed a median survival rate over 50% and a median 6.5 years of survival, in the immunotherapy-resistant population, despite all our successes, more than half of patients are dying. [The number is] probably significantly greater than that because [patients enrolled in] trials are not representative of all the patients that we see. So having better treatments in the resistance population and then also better treatments upfront is going to be useful.

There are pockets of patients with melanoma that are defined by where their melanoma originates that do less well and [who] probably should be studied for various therapies. We need better therapies in that space. Things are getting a bit better, but we need to see more [point-of-origin] types of trials.

Which large clinical trials have the potential to change the future of care?

The KEYNOTE-716 study [NCT03553836] demonstrated improved relapse-free survival in patients with high-risk stage II melanoma. These results will likely lead to an approval of pembrolizumab [Keytruda] in that setting and to significant use of pembrolizumab in that setting.

We’re not quite there yet, because it hasn’t been approved, although there’s nothing that would stop a provider from utilizing pembrolizumab in a patient with high-risk stage II disease. At this point, there are certainly issues concerning [whether] every patient with high-risk stage II disease should be treated with pembrolizumab. One of the downsides of expanding our use of pembrolizumab in terms of increasing toxicity includes chronic toxicities, which occur at a significant rate.

There are a lot of reasonable arguments around this that can be made. If data from a ran-domized phase 3 trial were positive, they’re good data, and it’s nice to at least have the option to present it to the patients and allow them to be part of the decision-making. [KEYNOTE-716] is the first major randomized phase 3 trial that will likely lead to change in the way we practice in the field.

Another important clinical trial was the RELATIVITY-047 study [NCT03470922], which randomized patients to receive nivolumab or a fixed-dose combination of nivolumab and relatlimab. The primary end point was progression-free survival in patients with previously untreated advanced melanoma. The toxicity [profile] was a bit higher but not dramatically so, particularly when you compare [it with] the toxicity of ipilimumab plus nivolumab in this patient population. [The fixed-dose regimen] seems like it’s a lot safer [and] it’s better than a single agent anti–PD-1 antibody. So we anticipate that when that drug gets approved, most patients with a new diagnosis of melanoma will receive that combination. We haven’t seen response rate data [for this trial] so there are reasons to be skeptical if relatlimab plus nivolumabis the right choice for patients with rapidly progressing disease.

And then the third randomized trial [IMCgp100-202; NCT03070392] is in uveal melanoma, and it’s a trial randomizing patients to either tebentafusp [or investigator’s choice of dacarbazine, ipilimumab, or pembrolizumab]. Tebentafusp is a bispecific molecule that recognizes an antigen in melanoma but does so in the context of the major histocompatibility complex which essentially is the way that our T cells recognize antigens. One thing that’s important there is that only patients [positive for] HLA-A*0201 are eligible to receive that treatment and if they don’t, the drug won’t be able to recognize the antigen that’s being expressed.

Patients with metastatic uveal melanomagenerally don’t do as [well as] patients with cutaneous or even mucosal melanomas with the standard immune checkpoint inhibitors. [In this trial, however,] patients had substantial benefit, specifically an improvement in overall survival, which was a prima-ry end point compared with investigator’s choice. That’s huge to have a potentially new therapy. It’s challenging to deliver because [patients] have to receive a weekly infusion. [Tebentafusp should] get approved at some point in the coming months, so it is changing the way we think about treating uveal melanoma (Table 2^2-4).

References

1. Tecentriq. Prescribing information. Genentech, Inc; 2020. Accessed October 29, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/la-bel/2020/761034s028lbl.pdf
2. Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo after com-plete resection of high-risk stage II melanoma: efficacy and safety results from the KEY-NOTE-716 double-blind phase III trial. Ann Oncol. 2021;32(suppl 5):S1314-S1315. doi:10.1016/j.annonc.2021.08.2116
3. Lipson EJ, Tawbi HAB, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol. 2021;39(suppl 15):9503. doi:10.1200/JCO.2021.39.15_suppl.9503
4. Nathan P, Hassel JC, Rutkowski P, et al; IMCgp100-202 Investigators. Overallsurvival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385(13):1196-1206. doi:10.1056/NEJMoa2103485