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18-10-2018 | Melanoma | News | Article

Neoadjuvant checkpoint blockade investigated in high-risk melanoma

medwireNews: In patients with high-risk resectable melanoma, neoadjuvant treatment with the combination of nivolumab and ipilimumab is associated with high response rates but also considerable toxicity, while single-agent nivolumab has better tolerability but is less efficacious, trial results show.

Indeed, the phase II trial was terminated early by the Data Safety Monitoring Board due to concerns about the high rates of grade 3 treatment-related adverse events (TRAEs) with the combination, and the marked disease progression that prevented surgery in around a fifth of the participants receiving monotherapy.

The investigators nonetheless believe that the findings point to “the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.”

The noncomparative study included 23 patients with stage III or oligometastatic stage IV disease who were randomly assigned to receive either the PD-1 inhibitor nivolumab 1 mg/kg plus the CTLA-4 inhibitor ipilimumab 3 mg/kg every 3 weeks for up to three doses or nivolumab alone at a dose of 3 mg/kg every 2 weeks for up to four doses.

Over median follow-up periods of 15.6 and 15.0 months in the combination and monotherapy groups, respectively, the RECIST overall response rates were 73% and 25%, while the corresponding pathologic complete response rates were 45% and 25%.

Exploratory analyses showed that all measures of survival – including progression-free, relapse-free, and overall survival – were better with the combination than with monotherapy, but the results did not reach statistical significance, “likely owing to the small sample size due to early closure of the trial,” say the researchers.

They note that all 11 of the patients given combination therapy were alive after a median of 15.6 months, “which is a higher proportion surviving at this time point than expected compared with historical controls for this high-risk patient population.”

This efficacy came at a cost of toxicity, however, with 73% of patients in the nivolumab plus ipilimumab group experiencing grade 3 TRAEs, most commonly transaminitis (27%), colitis (18%), pneumonia (18%), and hyponatremia (18%).

By contrast, the rate of grade 3 TRAEs in the monotherapy arm was 8%, with tumor-related pain the only TRAE of this grade.

There were no TRAEs of grade 4 or 5 in either treatment arm, report Jennifer Wargo (The University of Texas MD Anderson Cancer Center, Houston, USA) and team in Nature Medicine.

In conclusion, they highlight the advances that have been made with regard to optimizing dosing regimens for these agents since this trial was designed, and suggest future directions for research.

“For example, shorter neoadjuvant treatment regimens have been explored incorporating anti-PD-1 monotherapy in melanoma and lung cancer with success,” write the authors.

Additionally, alternative dosing strategies for combined PD-1 and CTLA-4 blockade “are being explored to preserve efficacy while limiting toxicity,” as are “new agents with potentially lower toxicity than CTLA-4 blockade,” they conclude.

By Shreeya Nanda

medwireNews is an independent medical news service provided by Springer Healthcare. © 2018 Springer Healthcare part of the Springer Nature group

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