1. The event-free survival at 12 months was 83.7% in the neoadjuvant group vs 57.2% in the adjuvant group.

2. Systemic treatment-related adverse events grade 3 or higher occurred in 29.7% in the neoadjuvant group vs 14.7% in the adjuvant group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Surgery remains the primary treatment for resectable stage III melanoma, often followed by adjuvant systemic therapy. Recent trials suggest that neoadjuvant immune checkpoint inhibitors (ICIs) may offer superior efficacy compared to adjuvant therapy. This study investigates the efficacy of neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma in a pathological response-adapted approach where patients with a major pathological response or greater would de-escalate to no adjuvant treatment otherwise they would proceed to adjuvant targeted treatment or immunotherapy. The primary endpoint was event-free survival (EFS), and secondary endpoints included overall survival (OS), recurrence-free survival (RFS), pathological response, safety, and quality of life (QoL). The overall EFS at 12 months was 83.7% in the neoadjuvant group vs 57.2% in the adjuvant group. When comparing BRAF mutation status, the EFS at 12 months with a BRAF mutation was 83.5% in the neoadjuvant group vs 52.2% in the adjuvant group (HR 0.29 [significant]), and the EFS at 12 months with BRAF wild-type was 83.9% in the neoadjuvant group vs 62.4% in the adjuvant group (HR 0.35 [non-significant]). In the neoadjuvant group, 59.0% had a major pathological response (47.2% had a pathological complete response, 11.8% had a pathological near-complete response), 8.0% had a pathological partial response, and 26.4% had a pathological nonresponse. The RFS at 12 months was 95.1% for those with a major pathological response, 76.1% for those with a pathological partial response, and 57.0% for those with a pathological nonresponse. With regards to safety, adverse events grade 3 or higher related to systemic treatment occurred in 29.7% in the neoadjuvant group vs 14.7% in the adjuvant group, with the most frequent events being hypothyroidism and adrenal insufficiency. The strengths of this study included its methodology and the number of patients, and the limitations included short follow-up time which led to some non-reported endpoints. The trial is one of the first to use a pathological response-adapted approach to de-escalate treatment. Overall, this study found that neoadjuvant ICIs had favourable outcome measures when compared to adjuvant ICIs in patients with resectable stage III melanoma.

Click to read the study in NEJM

Relevant Reading: Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma

In-Depth [ randomized controlled trial]: This international, multicenter, phase 3 trial enrolled adults with resectable stage III melanoma and randomized them (1:1) to neoadjuvant (n=212) or adjuvant (211) nivolumab and ipilimumab. The neoadjuvant group received 2 cycles of ICIs followed by a lymph node resection and received further ICI if there was a pathological partial response or nonresponse. Surgery was performed on time in 81.8% in the neoadjuvant group vs 98.6% in the adjuvant group. The median duration of follow-up was 10.6 months in the neoadjuvant group and 9.9 months in the adjuvant group. The overall EFS at 12 months was 83.7% (99.9%CI, 73.8-94.8) in the neoadjuvant group vs 57.2% (99.9%CI, 45.1-72.7) in the adjuvant group. When comparing BRAF mutation status, the EFS at 12 months with a BRAF mutation was 83.5% (99.9%CI, 70.3-99.2) in the neoadjuvant group vs 52.2% (99.9%CI, 35.9-75.8) in the adjuvant group (HR 0.29 [99.9%CI, 0.11-0.79]), and the EFS at 12 months with BRAF wild-type was 83.9% (99.9%CI, 70.1-99.9) in the neoadjuvant group vs 62.4% (99.9%CI, 46.0-84.7) in the adjuvant group (HR 0.35 [99.9%CI, 0.12-1.03]). In the neoadjuvant group, 59.0% had a major pathological response (47.2% had a pathological complete response, 11.8% had a pathological near-complete response), 8.0% had a pathological partial response, and 26.4% had a pathological nonresponse. The RFS at 12 months was 95.1% (99.9%CI, 87.4-99.9) for those with a major pathological response, 76.1% (99.9%CI, 44.4-99.9) for those with a pathological partial response, and 57.0% (99.9%CI, 33.3-97.6) for those with a pathological nonresponse. With regards to safety, adverse events grade 3 or higher related to systemic treatment occurred in 29.7% in the neoadjuvant group vs 14.7% in the adjuvant group, with the most frequent events being hypothyroidism and adrenal insufficiency. Overall, this study found that neoadjuvant ICIs had favorable outcome measures when compared to adjuvant ICIs in patients with resectable stage III melanoma.

Image: PD

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