Positive developmental updates on the investigational BTK inhibitor, zanubrutinib, as a treatment for Waldenström macroglobulinemia were recently released by BeiGene, Ltd at the 23rd Congress of the European Hematology Association (EHA). The updates included results from the phase 1 trial of zanubrutinib as a monotherapy in patients with different subtypes of B-cell malignancies and a
pooled analysis of the safety data from the zanubrutinib monotherapy trials.
, also known as BGB-3111, is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK). It is currently being investigated both as a monotherapy and in combination with other therapies to treat various lymphomas. According to the presented data
, as of November 3, 2017, the phase 1 trial being conducted in Australia, New Zealand, the United States, Italy, and South Korea enrolled 67 patients with Waldenström macroglobulinemia. Of these 67 patients, 51 were found to be evaluable for efficacy.
Patients with less than 12 weeks of follow-up (n = 13) and those with an IgM <5 g/L at baseline (n = 3) were excluded, leaving 12 patients who were treatment naïve and 39 patients who were relapsed or refractory to prior treatment.
The overall response rate (ORR) in the participants was 92% (47 out of 51 patients), and the major response rate was 80%. Forty-three percent patients achieved a very good partial remission (VGPR) defined as a >
90% reduction in baseline IgM levels and improvement of extramedullary disease by CT scan.
According to the recent press release, the 12-month progression-free survival (PFS) was estimated as 91%. (The median PFS has not yet been obtained.) The median time to response (partial response or higher) was 88 days (range, 77-279). The median IgM decreased from 32.5 g/L (range, 5.3-88.5) at baseline to 4.9 g/L (range, 0.1-57). Of the 22 patients with hemoglobin <10 g/dL at baseline, the median increased from 8.7 g/dL (range, 6.3-9.8) to 13.8 g/dL (range, 7.7-15.8).
Serious AEs (SAEs) which included febrile neutropenia, colitis, atrial fibrillation, hemothorax (spontaneous), and headache were observed in 22 patients (33%) with events in 5 patients (7%) considered to be possibly related to zanubrutinib treatment. Two patients experienced all Grade 1-2 major hemorrhage, and 4 patients (6%) experienced atrial fibrillation/flutter.
Four patients (6%) discontinued treatment because of SAEs that included fatal worsening bronchiectasis, prostate cancer, gastric adenocarcinoma, and acute myeloid leukemia. Two patients (3%) discontinued treatment because of disease progression, and 1 patient is currently remaining on treatment post disease progression.
Pooled analysis of the safety data from
4 ongoing zanubrutinib monotherapy studies was also reported.
Events of interest with BTK inhibitor therapy were recorded as infrequent, which included atrial fibrillation/flutter (2%), major hemorrhage (2%), and Grade 3 and above diarrhea (1%). Additionally, zanubrutinib-related AEs related to treatment discontinuation were uncommon.
One or more AE of any attribution, which primarily included Grades 1 or 2, was experienced by the majority of patients (94%). Neutropenia/neutrophil count decrease/febrile neutropenia (14%), anemia (7%), and thrombocytopenia/platelet count decrease (7%) included the most common Grade 3 or higher AEs of any attribution.
SAEs were reported in 116 patients (24%) and 38 patients (8%) experienced the most common SAEs, pneumonia/lung infection (6%), pleural effusion (1%), and febrile neutropenia (1%). Pneumonia/lung infection (2%) was the only treatment-related SAE reported in greater than 1% of patients. No instances of pneumocystis jiroveci pneumonia (PJP) or cytomegalovirus (CMV) reactivation were recorded.
Petechiae/purpura/contusion (26%) and hematuria (11%) was the most common bleeding events observed. Additionally, gastrointestinal hemorrhage/melena (n = 3), intraparenchymal CNS hemorrhage Grade 5, hematuria, purpura, hemorrhagic cystitis, renal hematoma, and hemothorax (1 each) included major hemorrhage (2%). The first major hemorrhage median time was 1.2 months.
Among those patients with emergent atrial fibrillation/flutter, the majority ( n= 8) had known risk factors, such as hypertension (n = 2), pre-existing cardiovascular disease (n = 2), and concurrent infection (n = 1).
At 6 months, the cumulative rates of Grade 3 or higher infections were 14%, followed by 19% at 12 months, and 21% at 18 months. A measure of 1.82 per 100 person-months stood the exposure-adjusted incidence rate. Basal cell carcinoma (3%) and squamous cell carcinoma of the skin (1%) included the most common second primary malignancies.
Commenting on the presented results, Constantine Tam, MD, Director of Haematology, St. Vincent’s Hospital and Consultant Haematologist, Peter MacCallum Cancer Center, in Australia, shared his optimism for the future of the zanubrutinib treatment. “We are hopeful that, if approved, patients with these hematologic malignancies could potentially lessen drug safety concerns, to focus on their lives rather than their disease.”
Looking forward, BeiGene, Ltd plans to submit its first new drug application (NDA) for zanubrutinib in patients with Waldenström macroglobulinemia in 2019.