Multinational phase 3 trial of adding pirtobrutinib to fixed-duration venetoclax-rituximab for previously treated CLL/SLL

The phase 3 BRUIN CLL-322 trial, at 152 centers across 22 countries, evaluated addition of the non-covalent BTK inhibitor pirtobrutinib to venetoclax-rituximab (VR) as a fixed-duration regimen in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). Adult patients who had previously been treated with at least on line of therapy, but not a non-covalent BTK inhibitor, venetoclax or another BCL2 inhibitor, were randomized 1:1 to receive either pirtobrutinib plus VR (PVR group; n=321) or VR (n=318). Oral pirtobrutinib was given for 28 cycles, oral venetoclax for 25 cycles, and intravenous rituximab for six cycles. The primary endpoint for the now published prespecified interim analysis was progression-free survival assessed by a masked independent review committee (IRC PFS). PVR showed a significant improvement in IRC PFS compared with VR (HR 0.547; p=0.0001) with a 24-month PFS rate 87% versus 72%, and median PFS not reached versus 39.7 months. This benefit was consistent across prespecified subgroups. The frequency of treatment-emergent adverse events of grade ≥ 3 was similar in both groups, whereas the rate of tumor lysis syndrome was lower in the PVR group than in the VR group (1% versus 4%), as were rates of treatment discontinuation owing to treatment-emergent adverse events (5% versus 5%). There was one treatment-related death in the PVR group and four in the VR group. The authors conclude that in patients with previously treated CLL/SLL, addition of P to VR was associated with significant improvement in PFS, with no new safety signals.