The landscape of treatment for resectable stage III melanoma is evolving, with neoadjuvant immunotherapy emerging as a superior approach compared to resection followed by adjuvant therapy. Recent updates from pivotal neoadjuvant studies, including the NADINA trial and pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC), presented at the European Society for Medical Oncology (ESMO) Congress 2024, reinforce this paradigm shift and highlight the importance of pathologic complete response as a key predictor of outcomes.
NADINA Trial: Ipilimumab Plus Nivolumab
The NADINA trial, involving 423 patients, compared neoadjuvant ipilimumab plus nivolumab followed by response-adapted adjuvant therapy to standard adjuvant nivolumab after resection. Minke Lucas, MD, of the Netherlands Cancer Institute, presented the updated findings at ESMO, stating that "Neoadjuvant ipilimumab plus nivolumab is superior to adjuvant nivolumab and should be considered as a new standard of care." At a median follow-up of 15.4 months, the event-free survival benefit with neoadjuvant ipilimumab plus nivolumab remained consistent, with improved distant metastasis-free survival compared to adjuvant PD-1 blockade.
The 18-month event-free survival was 80.8% in the neoadjuvant arm versus 53.9% in the control arm (HR = 0.32; P < .001), and distant metastasis-free survival was 85.7% and 62.4%, respectively (HR = 0.37; P < .001). Notably, 68.8% of patients in the neoadjuvant arm had a pathologic response, with 49.1% achieving a complete pathologic response. Georgina V. Long, PhD, MBBS, emphasized that the magnitude of pathologic response correlated strongly with outcomes at 18 months.
Updated Pooled Analysis from INMC
Georgina V. Long also presented an updated pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC), which included 818 patients from 18 melanoma centers across eight countries. The analysis revealed that the highest rates of major pathologic complete response, recurrence-free survival, and event-free survival were achieved with combination checkpoint inhibition. Specifically, major pathologic response rates ranged from 58% to 67%, with a 3-year event-free survival of 78% overall, regardless of pathologic response.
The analysis also indicated that adding a BRAF/MEK inhibitor to checkpoint inhibitors did not provide substantial benefit, and neoadjuvant BRAF/MEK inhibition was not as effective as checkpoint inhibition. The best outcomes were observed with anti-PD-1 therapy, with 3-year event-free survival rates of 95% with anti-PD-1 therapy plus any other immunotherapy, 81% with anti-PD-1 therapy plus anti-LAG-3 therapy, and 77% with anti-PD-1 therapy plus anti-CTLA-4 therapy.
Impact of Pathologic Response
The INMC analysis underscored the importance of pathologic response as a predictor of recurrence-free survival. Patients with major pathologic responses had significantly better outcomes, with 3-year recurrence-free survival approaching 90% for pathologic complete or near-complete responders, compared to 68% for partial responders and 40% for non-responders. Notably, patients with a major pathologic response who received neoadjuvant immune checkpoint inhibitors alone had the highest 3-year recurrence-free survival (> 93%).
Expert Commentary
Iván Márquez-Rodas, MD, PhD, highlighted the excitement surrounding neoadjuvant therapy following the initial NADINA results but cautioned against relying solely on surrogate endpoints. He emphasized the need for pretreatment biomarkers to tailor treatment and raised the question of the relative superiority of ipilimumab plus nivolumab over single-agent pembrolizumab, suggesting a head-to-head trial would be ideal.
Dr. Márquez-Rodas summarized key points:
- Checkpoint inhibition as neoadjuvant therapy yields high major pathologic response rates and prolonged event-free survival.
- Targeted therapy does not appear to add value in the neoadjuvant setting.
- Major pathologic response is a strong prognostic marker.
- Surgery remains important, as predictors for patients who fare well without it are lacking.
- Adjuvant therapy is still preferred for patients with clinically undetectable stage III melanoma.
- Overall survival data will be crucial for widespread adoption of neoadjuvant strategies.
- A formal comparison of ipilimumab/nivolumab and single-agent pembrolizumab is warranted.
Implications for Clinical Practice
The accumulating evidence from trials like NADINA and the INMC analysis solidifies the role of neoadjuvant immunotherapy as the new standard of care for resectable stage III melanoma. These findings emphasize the importance of achieving a major pathologic response and suggest that patients who do not achieve such a response may require alternative treatment strategies. Further research is needed to identify predictive biomarkers and optimize neoadjuvant regimens for individual patients.
