Dr Sznol on the Nuances of Recommending Neoadjuvant Therapy in Metastatic Melanoma

“In the neoadjuvant setting, it [likely] turns out that the combination of ipilimumab and nivolumab is better than anti–PD-1 [therapy] alone and probably better than targeted therapies [but] based on…not completely randomized trials.”

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 use of neoadjuvant therapy in the treatment of patients with metastatic melanoma.

Patients who present with active nodal disease, whether identified through imaging such as PET scans or through physical examination, are now considered strong candidates for neoadjuvant therapy prior to surgery, Sznol said. In this setting, emerging evidence suggests that combination immunotherapy with ipilimumab (Yervoy) plus nivolumab (Opdivo) may offer superior outcomes compared with anti–PD-1 monotherapy and potentially even targeted therapy approaches, although not all supporting trials have been fully randomized.

Sznol raised the phase 2 SWOG S1801 trial (NCT03698019), a large investigator-led study that compared neoadjuvant immunotherapy followed by surgery with the more traditional strategy of surgery first followed by adjuvant anti–PD-1 therapy. Data from SWOG S1801 demonstrated a significant improvement in event-free survival for patients treated with neoadjuvant therapy. Although overall survival data remain immature, the magnitude of benefit observed has already influenced clinical practice patterns. As a result, neoadjuvant treatment is favored in eligible patients because the differences in outcomes were “quite dramatic,” Sznol stated. Specifically, the preferred regimen at this time is the so-called “flip-dose” combination of ipilimumab and nivolumab administered for 2 cycles before surgery.

Importantly, pathologic response after neoadjuvant therapy is emerging as a critical prognostic marker, Sznol added. Patients who achieve a complete or near-complete pathologic response after those initial 2 cycles of treatment may not require additional systemic therapy following surgery. These patients often experience prolonged progression-free survival, raising the possibility of treatment de-escalation for select individuals.

Also at play is the evolving role of surgery, Sznol explained. In some cases, surgeons may only remove the involved lymph node rather than performing more extensive dissections. If pathology demonstrates a major response, patients can be reassured that their risk of recurrence is very low and transition them to surveillance with periodic imaging.

For patients who do not achieve a major pathologic response, however, questions remain regarding the optimal next step, Sznol said. Additional postoperative therapy, including BRAF/MEK targeted therapy in patients with actionable mutations, may represent a future strategy, although definitive evidence is still lacking.

Ongoing research in the post-neoadjuvant setting will be critical, Sznol added. Future clinical trials may focus on risk-adapted strategies for patients with residual disease after surgery. Therapeutic cancer vaccines represent an area of growing interest in this regard. The hope is that vaccines or other novel therapies could further reduce recurrence risk in patients who do not experience a pathologic complete response, though supporting data are not yet available, Sznol concluded.