Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)

PHOENIX is the most instructive negative trial in diffuse large B-cell lymphoma, because the reason it failed is legible. 838 patients with non-germinal-centre disease, 75.9 per cent of them of the activated B-cell subtype, were randomised to ibrutinib 560 mg daily or placebo with R-CHOP. Median age was 62.

The trial missed its primary endpoint in both the intention-to-treat population (event-free survival hazard ratio 0.934) and the activated B-cell subgroup (0.949). A preplanned analysis found a significant interaction between treatment and age. In patients under 60, ibrutinib improved event-free survival (hazard ratio 0.579), progression-free survival (0.556) and overall survival (0.330), with serious adverse events rising from 28.6 to 35.7 per cent and the proportion receiving at least six cycles of R-CHOP unchanged at 92.9 against 93.0 per cent. In patients aged 60 or over, ibrutinib worsened all three endpoints, raised serious adverse events from 38.2 to 63.4 per cent, and cut the proportion completing six cycles of R-CHOP from 88.8 to 73.7 per cent.

The mechanism of the failure is therefore not biological but practical: the added drug stopped older patients from receiving the chemotherapy that cures the disease. That is the finding behind every subsequent attempt to use a better-tolerated Bruton tyrosine kinase inhibitor in this setting, including the ARCHED trial.