Mario Sznol, MD, discusses how the field is balancing dual checkpoint blockade and novel combinations in melanoma, plus unmet needs and emerging strategies.
Although nivolumab (Opdivo) plus ipilimumab (Yervoy) and nivolumab plus relatlimab-rmbw (Opdualag) remain established standards of care in the United States for patients with newly diagnosed metastatic melanoma, Mario Sznol, MD, is hopeful that investigational approaches such as engineered cytokines, T-cell engagers, and next-generation cell therapy platforms will extend the long-term responses associated with dual checkpoint inhibition.
“There are some very interesting approaches out there that the field is developing, so I’m optimistic. I’m not sure we’re going to cure 100% of patients in the next 2 to 3 years, but even if we move the survival curve by 10%, 15%, or 20%, that’s a huge reduction in the number of [individuals who] would ultimately die from this disease,” Sznol said in an interview with OncLive®.
In the interview, Sznol, professor emeritus at Yale School of Medicine in New Haven, Connecticut, and recently appointed faculty at the University of Miami in Florida, discussed the role of dual checkpoint blockade in frontline metastatic melanoma treatment, challenges in managing primary and acquired resistance, and the limited predictive power of biomarkers such as tumor mutational burden (TMB) and PD-L1. Sznol also covered investigational therapeutic approaches and how improvements in radiation techniques such as gamma knife have reshaped treatment expectations for patients with brain metastases.
Sznol: In the US, doublet immune therapy, which is either ipilimumab and nivolumab, or nivolumab and relatlimab, is the standard of care [SOC]. They both improve progression-free survival compared with anti–PD-1 [therapy] alone, and there’s a trend toward improved survival for both of those doublets compared with the single-[agent] arms.1,2 [Both regimens] remain a SOC for first-line systemic therapy of advanced disease. Phase 3 trials are ongoing, but nothing has been proven better than those two combinations.
In melanoma, of the 50% of long-term survivors with advanced metastatic disease, up to 30% don’t have long-term [responses]. In other words, 30% don’t achieve complete responses that last forever. There’s a group that have either discordant, progressing lesions or residual lesions that need to be treated with surgery or radiation, and there’s a subset of patients that need reinduction with the same drugs to achieve that long-term survival. But once [patients reach] the 5-year point, the chances that they’ll die from melanoma is exceedingly low beyond that point.
The challenge is, after patients progress after frontline therapy, how do we distinguish the ones who will never benefit from surgery, radiation, or additional reinduction with DNA checkpoints from those who won’t benefit from those therapies? And then what’s available for that other 50% of patients? We can treat some patients with BRAF/MEK inhibitors, [because] up to 50% have BRAF mutations. Data from Yale found that 10% of those patients who are treated with BRAF/MEK inhibitors will have long-term, durable responses [that enable us to] take them off therapy. [Approximately] 20% of those patients live 4 years or longer, so they do very well with targeted therapy, but of course, most don’t.
Tumor-infiltrating lymphocyte [TIL] therapy is approved for melanoma, and a small subset of patients benefit from that therapy. The problem with interpreting the TIL data is that the more heavily pretreated patients are, in other words, the more you go back to immune checkpoint inhibitors and other drugs, the less likely they are to respond to cell therapies.
Then there are experimental therapies, and the sorts of experimental therapies that are being explored now are things like the intratumoral oncolytic viruses like vusolimogene oderparepvec [RP1], which, in combination with anti–PD-1 therapy, has shown a respectable response rate. The real question is, are those patients who are responding among the 50% who would never really benefit from immune therapy, or are they the ones in that 15% who, if you had continued to give them ipilimumab/nivolumab, nivolumab/relatlimab, or another immune therapy because they have secondary resistance, would have benefited from those therapies? A few patients in that group who were going to [have bad outcomes] probably do benefit from those therapies, but it’s a very small number. Then the question is, what do we do next for those patients? That still is an enormous challenge.
At the moment, it is very difficult to distinguish who’s going to get the long-term benefit. TMB is not a great biomarker in melanoma. PD-L1 is also not a great biomarker in melanoma, so it’s very hard to tell upfront who’s going to respond and who’s not to these immune therapies. Perhaps we can enrich a little bit for responders, but there’s no clinically actionable biomarker upfront, and we still don’t know how to put together all these potential biomarkers into something that we can use clinically. We don’t know how to put together microbiome heterogeneity, HLA class I expression, and metabolics of the tumor microenvironment into a biomarker that’s useful in the clinic. [Investigators] have been working on trying to distinguish who would do well with anti–PD-1 therapy alone vs those who might need the combination. That would be very useful, because if you only have to give anti–PD-1 therapy alone, you reduce the amount of severe toxicity. But [it’s also worth noting that] the combination of nivolumab is only a little bit more toxic than nivolumab alone.
The long answer is, we don’t have great biomarkers for patients with advanced metastatic disease. When I’m treating patients in the clinic, I sometimes think that this patient is going to respond [to therapy], and they don’t respond. Other times, I think this patient is going to have great long-term benefit, and they don’t. Other times, patients come in with such advanced disease with tons of liver metastases and 10 brain metastases [for which] we treat with gamma knife because it’s such an aggressive disease, and those are the patients who have great long-term responses. It’s hard to [tell what kind of response a patient will have when they] come in. There are investigational [approaches], but nothing that we can [use in] practice.
The beautiful thing about the immune therapies is that they work in metastatic disease to the brain, and outcomes in patients who have brain metastasis are just as good as those in patients who have metastases to other organs. In our experience, the brain is not the most dire sight anymore. The gamma knife radiation techniques have really improved the care of these patients substantially. Gamma knife is very effective if you need to use it. Systemic therapies are [also] being looked at. Harriet Kluger, MD, of Yale Cancer Center, looked at the combination of anti-VEGF and anti–PD-1 therapy and saw very interesting results in patients with brain metastases. Other [techniques] are [considering] systemic approaches for brain metastasis, but at the moment, we do pretty well. I’d much rather treat somebody who has 2 or 3 brain metastases than 5 or 6 huge liver metastases, for example.
The problem with brain metastases is that once you have a brain metastasis, you can have neurologic consequences. There are certain patients [for whom you’re able to] treat the lesion successfully and then bleed into those lesions. That creates a substantial amount of morbidity, which is another reason why [we’d like to] keep them from developing brain metastasis in the first place. There are patients whom you treat successfully, and then a year or two later come back with radiation necrosis. The edema and complications from the radiation necrosis can be as bad as having an active tumor in that site. We have ways to manage it, but it can also create complications.
We do a lot better than we used to say 25 years ago when [outcomes were] the worst [in that population]. But there are still a lot of reasons to try and keep that from happening, if possible.
I retired from Yale and am going to be working at the University of Miami, but my former colleagues at Yale have been very interested in cytokine therapies. I believe that there’s a role for these engineered cytokines, either alone or in combination [with other approaches]. At some point, combinations of γ chain cytokines could be very interesting. That’s the direction my former group is headed in.
T-cell engagers are also very interesting, and we haven’t even begun to scratch the surface of combining T-cell engagers with other rational targets. For example, combining cytokines with T-cell engagers makes a lot of sense because you need to expand T cells in the tumor microenvironment. Those are the T cells that the T-cell engager is going to engage to kill the tumor. Those kinds of combinations are just now starting [to be evaluated]. We do have a couple of interesting T-cell engagers in melanoma, so that could be very interesting to [investigate] in the future.
The cell therapies are also advancing. There are these T-cell TIL therapies that can make their own IL-15, and you can induce the cytokines and get huge expansion of T cells in vivo. That could make a difference in the long run.
Disclosures: Sznol has stock and stock options with Actym (stock options only), Asher Bio, Evolveimmune, GSK (stock), Intensity (stock options only), Johnson & Johnson (stock), Nextcure, Normunity, Oncohost, and Thetis; and has received consulting fees from Asher Bio, BioInvent, Biond (DSMC), BioNTech (DSMC), Bristol Myers Squibb, Cullinan Therapeutics, DynamiCure, EvolveImmune, GI Innovation, IDEAYA (DSMC), Immatics, ImmunoGenesis, Innate Pharma, IO Biotech, Lyvgen, Nimbus, NextCure, Pathios, Pfizer, Pliant Therapeutics, Regeneron, Sanofi (DSMC), Simcha Therapeutics, Teva, Turnstone Biologics, and Xilio Therapeutics.
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