B cell depletion improves therapeutic index of combination checkpoint blockade in patients with advanced melanoma.
Kavita M Dhodapkar, Antonio Matera, Alyssa M Duffy et al.
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In 30 seconds
This randomized controlled trial evaluated whether B-cell depletion with one cycle of rituximab could reduce immune-related adverse events (irAEs) from ipilimumab plus nivolumab in patients with advanced melanoma. Fourteen patients were assigned to checkpoint blockade alone or with rituximab. Grade 3 or higher irAEs occurred in 14% with rituximab versus 57% with checkpoint blockade alone; 2-year grade 3-irAE-free survival was 86% versus 29% (P = 0.01). Tumor regression and survival were not adversely affected, but grade 3 rituximab hypersensitivity reactions occurred in 43% of the combination group, prompting trial closure.
Key findings
- Grade 3 or higher irAEs occurred in 14% with rituximab plus checkpoint blockade versus 57% with checkpoint blockade alone.
- Two-year grade 3-irAE-free survival was 86% versus 29% (P = 0.01), favoring rituximab.
- Grade 3 hypersensitivity reactions to rituximab occurred in 43% of recipients and prompted trial closure.
- Rituximab did not adversely affect tumor regression or survival in this trial.
Why it matters
The findings suggest that B-cell depletion may alter immune activation in a way that reduces severe toxicity from combined PD-1 and CTLA-4 blockade, without an observed loss of antitumor activity. However, the substantial rate of severe rituximab hypersensitivity reactions highlights that toxicity prevention strategies can introduce important harms and require careful evaluation.
What to keep in mind
The trial included only 14 patients and was closed after grade 3 rituximab hypersensitivity reactions, limiting the precision and generalizability of the findings.