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 several very interesting approaches in development, so I remain optimistic that we can improve outcomes beyond the current standard of care. Even if we move the survival curve up by 10, 15, or 20 percentage points, 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 with 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 of other combinations with anti-PD-1 are ongoing, but nothing has been proven better than those two combinations. A phase 2 trial of nivolumab-relatlimab plus ipilimumab produced promising results in a phase 2 trial, but a large phase 3 has not been initiated. Adding agents to already approved doublets can be challenging, from a toxicity perspective and the challenge of detecting a clinical signal above the already relatively high response rates and high short term overall survival rates.
In melanoma, of the 50% of long-term survivors with advanced metastatic disease who were treated with front-line doublets of ipilimumab-nivolumab or nivolumab-relatlimab, up to 30% of those 50% do not achieve that long period of disease-free survival with just the immunotherapy doublets alone. For this latter subset of patients, surgery or radiation may be required to treat a limited number of discordant, progressing lesions or residual lesions to achieve a durable disease-free state. Another subset could have an initial response to doublet therapy and progress during maintenance or after stopping treatment but can respond again when retreated with the same induction immunotherapy and will achieve long-term survival. For most patients that remain progression-free or have no active disease at the 5-year point, the chances of dying from melanoma with extended follow-up is very low.
The biggest challenge is to identify effective therapies for the 50% of patients who will not achieve long-term benefit from doublet immunotherapy alone, with or without subsequent local therapies or re-treatment. We can offer BRAF/MEK inhibitors for the 40-50% who have BRAF V600 mutations. Retrospective 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. Another 10% of those patients remain on drug and live 4 years or longer, but most patients have more limited benefit from targeted therapy.
Tumor-infiltrating lymphocyte [TIL] therapy is now approved for metastatic melanoma that progressed on immune therapy plus or minus targeted therapy.It is an intense regimen, and while objective response rates are in the range of 30%, only a subset of the responders have prolonged progression-free survival, and perhaps we are providing long-term benefit to only 15-20% of the patients who receive the therapy. There is certainly a need for new and more effective therapies. There are multiple mechanisms of resistance to immune therapy and to targeted therapies. New therapies address only a few or perhaps only one mechanism of resistance, and identifying patients by mechanism of resistance is very difficult, which creates major challenges for developing new agents in the disease.
Several experimental therapies are in late-stage development. One example is the intratumoral oncolytic virus vusolimogene oderparepvec [RP1], which in combination with anti–PD-1 therapy, has shown a respectable response rate in patients whose disease is progressing on standard immunotherapy. We don’t know how many of those responders were in the group destined to do well, for example that subset who progresses on doublet immune therapy but can be ‘salvaged’ with local therapies or re-treatment, and how many were among the overall 50% who would not have survived to the 5 year mark. Other investigational therapies for patients progressing after doublet immune therapies plus or minus targeted therapies, such as vaccines, modified TIL therapies, TCR-T cell therapies, T cell engagers, engineered cytokines, and multiple other immune modulators and targeted therapies, address various potential mechanisms of resistance to current standard of care. These therapies also face similar challenges of identifying patients likely to respond to the investigational agent and interpretation of outcomes among heterogeneous patient populations.
At the moment, it is very difficult to distinguish who will receive long-term benefit from any therapy in melanoma. TMB and PD-L1 are not very useful in melanoma. Perhaps we can enrich for responders with various investigational predictive biomarkers, but most do not identify all patients who would benefit from treatment, and we still don’t know how to put together all these potential biomarkers into something that we can use clinically. The list of investigational biomarkers includes certain bacterial species in the microbiome, tumor gene signatures, host HLA genetics, tumor metabolism, serum proteomics, and characteristics of the tumor T cell infiltrate. Investigators have also been trying to distinguish who would do well with anti–PD-1 therapy alone vs those who might need the combination, because single agent anti-PD-1 would be associated with less toxicity. The latter is now less clinically relevant given that nivolumab-relatlimab is only modestly more toxic than nivolumab alone.
We just don’t have great biomarkers for patients with advanced metastatic disease, and promising biomarkers may be too complex to use in a clinical setting. Outcomes from treatment in the clinic often vary from our expectations based on disease burden or sites of disease or performance status.
Immune therapies work in metastatic disease to the brain and even rarely in the ominous leptomeningeal disease. Outcomes in patients who have brain metastases (excluding leptomeningeal disease) appear to be just as good as those in patients who have metastases to other organs. In my experience, the brain is not the most dire site of disease anymore. The gamma knife radiation techniques have also substantially improved the care of these patients. Although a subset of patients with brain metastases can be treated with just systemic therapy, most patients require multi-disciplinary management with Neurosurgery and Radiation Oncology. A promising systemic approach was pioneered by Harriet Kluger, MD, of Yale Cancer Center, with the combination of anti-VEGF and anti–PD-1 in melanoma brain metastases. She observed promising activity of the combination although additional studies will be necessary.
One important concern for brain metastases is neurologic dysfunction. Even with effective therapy, CNS lesions can bleed and cause substantial morbidity, and the lesion itself may have damaged a critical part of the brain before effective treatment. This a major reason to prevent brain metastasis perhaps by treating earlier in the disease course. A major complication of the stereotactic radiation is radiation necrosis which can develop months to years after initial radiation. The edema and complications from the radiation necrosis can be as bad as having an active tumor in that site. Management for Radiation necrosis is improving but remains a major problem for a subset of patients.
Myself and my former colleagues at Yale have been very interested in engineered cytokine therapies. I believe there will be a role for these engineered cytokines, either alone or in combination with other approaches. Combinations of cytokines can produce profound and distinct effects on T cell populations in vitro and in animal models, which could lead to improved anti-tumor effects. I’m anxious to see this attempted in the clinic.
T-cell engagers are also very interesting, and we haven’t even begun to scratch the surface of combining T-cell engagers with other agents that could enhance their activity. For example, combining cytokines with T-cell engagers makes a lot of sense – cytokines expand the T cells that are then ‘engaged’ by the T cell engagers to kill tumor cells. Those combinations are just now being evaluated in early phase trials. There is an approved T-cell engager for uveal melanoma and another in trials targeted to PRAME that could be more broadly applicable to melanoma subtypes.
The cell therapy approaches are also advancing. One TIL therapy is engineered to make its own inducible IL-15, which can result in a huge expansion of T cells following administration to patients. This type of cytokine support could increase cell persistence and function and perhaps produce improved anti-tumor activity.
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.
