Phase II data on novel BTK inhibitors for patients with Waldenström’s macroglobulinemia

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 [1]. 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 [2]. 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.


Two-year update for tirabrutinib

Tirabrutinib, a BTK inhibitor with kinase selectivity comparable to or greater than other BTK inhibitors, has already been approved in Japan for use in treatment-naïve or relapsed/refractory WM based on the results of a phase II study [3, 4]. Cohort A of this trial included 18 treatment-naïve patients, while Cohort B consisted of 9 patients with relapsed/refractory WM. Tirabrutinib was administered orally under fasting conditions at a daily dose of 480 mg. The MRR constituted the primary endpoint. According to the primary analysis, the trial met the primary endpoint despite the relatively short follow-up [4]. In Cohort A, MRR and overall response rate were 88.9 % and 94.4 %, respectively. In Cohort B, these amounted to 88.9 % and 100 %, respectively.

The updated results after a 2-year follow-up presented at ASH 2021 showed that responses deepened over time [5]. At data cutoff, 83 % and 78 % of patients in Cohorts A and B, respectively, were still on treatment. All patients were alive at 24 months, and freedom from progression was present in 94.4 % and 88.9 %, respectively. The MRR was 94.4 % and 88.9 %, respectively. Overall, 94.4 % and 100 % of patients responded. Median duration of response had not been reached yet in either cohort. Patients who remained on treatment demon­strated continued reductions in tumor size and serum IgM levels.

The most common AEs of special interest were skin-related disorders. Rash occurred in 44.4 % in the total population (61.1 % and 11.1 % in Cohorts A and B, respectively) but was restricted to grade 1 and 2. In 57 % of cases, the patients developed skin-related AEs within the first month of treatment; no onset was observed after 7 months. Neutropenia ranged second among the AEs, with 16.7 % and 66.7 % in treatment-naïve and pretreated patients, respectively. During the extended follow-up period, no new grade ≥ 3 treat­ment-related AEs were noted except for hypertriglyceridemia (3.7 %). The authors concluded that tirabrutinib is a useful treatment option for patients with Waldenström’s macrogobulinemia.


  2. Zhou D et al., Efficacy and safety of orelabrutinib in relapsed/refractory Waldenström’s macroglobulinemia patients: a multicenter, open-label, phase II study. ASH 2021, abstract 46
  3. Kaptein A et al., Potency and selectivity of BTK inhibitors in clinical development for B-cell malignancies. Blood 2018; 132 (Suppl 1): 1871
  4. Sekiguchi N et al., A multicenter, open-label, phase II study of tirabrutinib (ONO/GS-4059) in patients with Waldenström’s macroglobulinemia. Cancer Sci 2020; 111(9): 3327-3337
  5. Suzuki K et al., Two-year follow-up data of phase II study of tirabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, in patients with treatment-naïve or relapsed/refractory Waldenström’s macroglobulinemia. ASH 2021, abstract 1352

© 2022 Springer-Verlag GmbH, Impressum

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