Dr Sznol on Overcoming Primary and Acquired Resistance in Metastatic Melanoma

“The problem is how to distinguish when [individuals] progress after frontline therapy. How [do we] distinguish the [patients] that will never benefit from surgery, radiation, or additional reinduction with immune checkpoint [inhibitors] from those who won’t benefit from those therapies? And then, what’s available for that other 50%, and for the other 50% it’s still problematic.”

Mario Sznol, MD, professor of clinical medical oncology at the Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Health System, discussed the evolving landscape of long-term outcomes for patients with advanced melanoma.

Approximately 50% of these patients now achieve long-term survival, Sznol said. However, up to 30% of those long-term survivors do not experience complete, durable remission. Instead, they may face residual or discordant disease that requires additional intervention, such as surgery, radiation, or even reinduction with previously used systemic therapies.

Patients who remain progression-free at 3 years—and especially at 5 years—have an exceedingly low likelihood of dying from melanoma thereafter, Sznol said. Still, the central dilemma lies in determining which patients who progress after frontline therapy will benefit from further intervention vs those unlikely to respond. For the remaining 50% of patients who do not achieve long-term survival, treatment options are still imperfect. Targeted therapy with BRAF and MEK inhibitors offers meaningful benefit for the 40% to 50% of patients with BRAF-mutant disease, Sznol explained. Institutional data suggest that approximately 10% of these patients experience durable, long-term responses, and approximately 20% may live beyond 4 years. Yet, most patients ultimately experience disease progression.

Cellular therapies, including tumor-infiltrating lymphocyte therapy, have shown promise in a subset of patients. However, efficacy appears to diminish in heavily pretreated populations, raising questions about optimal sequencing and patient selection. Meanwhile, experimental approaches—such as intratumoral oncolytic viruses combined with checkpoint inhibitors—are generating interest, though it remains unclear whether these therapies benefit truly resistant patients or those who might have responded to continued immunotherapy, Sznol added.

Ultimately, the field continues to grapple with a critical unmet need: identifying effective strategies for patients who do not respond to current standards. Despite meaningful advances, improving outcomes for this population remains an ongoing and formidable challenge.