Dr Sznol on Optimal Treatment Sequencing in Melanoma

“The other [challenge with] treating [patients in the] adjuvant [setting] is that it’s not even clear that treating patients…at that point in time is better than waiting until they progress….There’s no evidence [to suggest that improving] progression-free survival in the adjuvant setting…[leads to] an improvement in overall survival. So, it’s a very difficult discussion to have with patients…in that setting.”

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 management of melanoma in the adjuvant setting.

BRAF/MEK inhibitor combinations continue to provide meaningful clinical benefit for patients with BRAF-mutant melanoma, and KIT inhibitors may offer responses in patients with KIT-mutated disease, Sznol said. However, he noted that these mutation-defined populations represent only a minority of patients with melanoma, limiting the broader impact of targeted therapy in routine clinical practice. In contrast, immune checkpoint inhibition has consistently demonstrated the potential for durable responses and remains the backbone of treatment across disease settings.

When it comes to adjuvant therapy for patients with resected melanoma and positive sentinel lymph nodes, who are considered at high risk for recurrence, anti–PD-1 monotherapy remains the standard adjuvant approach in the absence of a BRAF mutation, Sznol explained. He added that attempts to improve upon outcomes seen with single-agent PD-1 blockade have not shown superiority. Trials evaluating the addition of anti–CTLA-4 therapy to PD-1 inhibition failed to improve outcomes compared with anti–PD-1 therapy alone, Sznol said. Similarly, the phase 3 RELATIVITY-098 trial (NCT05002569), which evaluated the combination of nivolumab and relatlimab-rmbw (Opdualag) in the adjuvant setting did not show improved efficacy vs nivolumab (Opdivo) alone.

Despite improvements in recurrence-free or progression-free survival, no adjuvant immunotherapy strategy has demonstrated a clear overall survival advantage, Sznol underscored, creating a nuanced and often difficult discussion between physicians and patients regarding the timing of treatment initiation. As such, Sznol recommended balancing the potential reduction in recurrence risk against the possibility of significant immune-related toxicities. This includes severe adverse effects, which occur in approximately 10% of patients receiving checkpoint inhibitors.

For patients with BRAF-mutant disease, adjuvant BRAF/MEK inhibition remains an important alternative treatment option. Cross-trial comparisons suggest that outcomes with these agents may be comparable to those achieved with anti–PD-1 therapy, Sznol said. Although targeted therapy may be less well tolerated in the short term, Sznol noted that these regimens are generally not associated with the same risk of long-term immune-related toxicities seen with checkpoint blockade. Ultimately, treatment selection in this setting requires individualized discussion based on patient preferences, risk tolerance, and anticipated toxicity profiles.

Sznol concluded by highlighting emerging data surrounding vaccine-based approaches, noting a randomized phase 2 study evaluating a neoadjuvant vaccine strategy in combination with pembrolizumab (Keytruda). Findings from the study suggested potential enhancement of antitumor activity in the adjuvant setting. However, these preliminary results require confirmation in larger phase 3 studies before altering current standards of care.