Neoadjuvant ipilimumab plus nivolumab improves event-free survival in stage III melanoma

1. In this randomized controlled trial, two cycles of neoadjuvant ipilimumab plus nivolumab resulted in longer event-free survival than adjuvant therapy with nivolumab in patients with resectable, macroscopic stage III melanoma.

2. In this trial, neoadjuvant therapy had higher rates of adverse effects and toxicity than adjuvant therapy.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Currently, the standard treatment for resectable, macroscopic stage III melanoma is surgery which can be followed by adjuvant systemic therapy. Adjuvant therapy with programmed death 1 (PD-1) inhibitors, nivolumab, and pembrolizumab, has been shown to prolong recurrence-free survival compared to cytotoxic T lymphocyte antigen 4 (CTLA-4) ipilimumab. Despite these systemic treatments, many patients have disease recurrence within the first few years after surgery. Additionally, none of the approved adjuvant immunotherapies have shown significant improvements in overall survival. Based on preclinical and phase one and two data, neoadjuvant therapy with immune checkpoint inhibitors has been hypothesized to be superior to adjuvant therapy. Previous trials have shown that neoadjuvant combination therapy with ipilimumab plus nivolumab resulted in event-free survival and higher efficacy than neoadjuvant anti-PD-1 monotherapy. This provided the rationale for this study that evaluated neoadjuvant ipilimumab plus nivolumab against the current standard of care of adjuvant anti-PD-1 in resectable, macroscopic stage III melanoma. In this phase three clinical trial, patients who met inclusion criteria were randomly assigned to receive neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. The primary endpoint for this study was event-free survival. Results from this study found that neoadjuvant therapy followed by surgery resulted in longer disease-free survival than surgery followed by adjuvant therapy in patients with resectable, macroscopic stage III melanoma. Results also found that neoadjuvant therapy had higher rates of adverse effects and toxicity.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This phase three clinical trial assessed and compared the safety and efficacy of neoadjuvant therapy with ipilimumab plus nivolumab with the current standard of care of adjuvant therapy with nivolumab in patients with resectable, macroscopic stage III melanoma. Patients who were at least 16 years of age and had resectable, macroscopic stage III melanoma of unknown primary origin with at least one pathologically proven lymph metastasis and a maximum of three additional in-transit metastases were eligible for participation. A total of 423 patients were randomly assigned to receive either two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Patients in the neoadjuvant group who had a partial response or nonresponse also received adjuvant therapy. At the median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% Confidence Interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99% CI, 45.1 to 72.7) in the adjuvant group. In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse, and 2.4% had progression. In the neoadjuvant group, the estimated 12-month recurrence-free survival was 95.1% in patients who had a major pathological response, 76.1% in those with a partial response, and 57.0% among patients with a nonresponse. Adverse events of grade three or higher associated with the systemic treatment occurred in 29.7% of patients in the neoadjuvant group, compared to 14.7% in the adjuvant group. Overall, the results from this phase three clinical trial showed that neoadjuvant therapy with ipilimumab plus nivolumab followed by surgery resulted in longer event-free survival than surgery followed by adjuvant therapy with nivolumab in patients with resectable, macroscopic stage III melanoma.

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