Orelabrutinib: rapid and lasting responses
Second-generation BTK inhibitors such as orelabrutinib and tirabrutinib are currently being evaluated in the treatment of Waldenström’s macroglobulinemia (WM). Orelabrutinib is a BTK inhibitor with excellent target selectivity and almost 100 % BTK occupancy . At ASH 2021, Zhou et al. reported the results for 47 patients with relapsed/refractory WM who received orelabrutinib 150 mg/d in the single-arm, multicenter, open-label, phase II ICP-CL-00105 study . The major response rate (MRR; complete, partial, and very good partial responses) was defined as the primary endpoint.
Major responses were achieved quickly, after a median of 1.99 months. The MRR was 78.7 %, and the overall response rate amounted to 87.2 % (Table). Disease control resulted in 97.9 %. Remissions proved durable, which was mirrored by the 12-month rates: for major responses, this was 91.3 %, and for responses in general, 92.6 %. Subgroup analyses showed a consistent treatment effect across the prespecified groups. At 12 months, 93.6 % of participants were alive, and 89.3 % were progression-free. Durable improvement in hemoglobin level was found in 78.7 %, with a median maximal increase of 33 g/L. For serum IgM levels, the median reduction from baseline amounted to 79.7 %.
Orelabrutinib demonstrated a favorable safety profile, with relatively low rates of off-target toxicities. The most common adverse events (AEs) included thrombocytopenia (all grades, 27.7 %), hemorrhage (27.7 %), infections (21.3 %), and neutropenia (19.1 %), which were mostly mild to moderate. No treatment-emergent grade ≥ 3 events were reported for diarrhea, atrial fibrillation/flutter, hypertension, and hemorrhage. Treatment-related AEs prompted dose reduction and study drug discontinuation in 6.4 % and 2.1 %, respectively. Summarizing these findings, the authors noted that orelabrutinib has the potential to be the agent of choice for patients with relapsed/refractory WM.