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Study of Combination Immune Checkpoint Blockade in Stage III Melanoma Halted

By: Sarah Campen, PharmD
Posted: Wednesday, January 9, 2019

Recent advances in the treatment of patients with high-risk resectable stage III melanoma with adjuvant immune checkpoint blockade have enhanced survival. A new phase II study published in Nature Medicine found that treatment with a combination of two immune checkpoint inhibitors, nivolumab and ipilimumab, yielded a higher overall response rate than nivolumab alone (73% vs. 25%). However, the combination therapy was also associated with substantially higher rates of toxicity.

Based on the increased rate of grade 3 treatment-related adverse events observed with the neoadjuvant combination treatment, the data safety monitoring board halted the trial early, “especially in light of more recent trial designs that studied alternative dosing regimens of combined ipilimumab with nivolumab that were better tolerated,” stated Rodabe N. Amaria, MD, of the MD Anderson Cancer Center, Houston, and colleagues.

In total, 23 patients with resectable clinical stage III or oligometastatic stage IV melanoma were randomly assigned to receive either nivolumab monotherapy (n = 12) or combined therapy with ipilimumab and nivolumab (n = 11). Pathologic complete response rates were 25% and 45%, respectively. Dose delays were required in 64% of patients receiving the combination therapy due to grade 3 treatment-related adverse events, which included transaminitis (27%), colitis (18%), pneumonia (18%), and hyponatremia (18%). No patients in the monotherapy arm required dose delays, and just 8% of patients in this group reported grade 3 treatment-related adverse events.

The researchers noted that responders to both therapies demonstrated higher lymphoid infiltrates, and a response to nivolumab monotherapy correlated with more clonal and diverse T-cell infiltrates. They concluded that these findings “emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.”

Disclosure: The study authors’ disclosure information may be found at

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