Phase Ib results presented at the 2017 ASH Annual Meeting demonstrated that zanubrutinib (BGB-3111), an investigational BTK inhibitor, had encouraging rates of clinical activity in patients with non-Hodgkin lymphoma, including an overall response rate of 78% among patients with marginal zone lymphoma.
Constantine Tam, MD
Phase Ib results presented at the 2017 ASH Annual Meeting demonstrated that zanubrutinib (BGB-3111), an investigational BTK inhibitor, had encouraging rates of clinical activity in patients with non-Hodgkin lymphoma, including an overall response rate (ORR) of 78% among patients with marginal zone lymphoma (MZL).
Among patients with follicular lymphoma (FL), zanubrutinib induced an ORR of 41%. The ORRs were 31% and 88% in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), respectively.
“Durable responses were observed across a variety of histologies,” lead author Constantine Tam, MD, Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at Peter MacCallum Cancer Centre, Director of Haematology at St. Vincent’s Hospital, Australia, said when presenting the data at ASH.
The open-label phase Ib trial accrued patients with B-cell malignancies in Australia, New Zealand, South Korea, the United States, and Europe. In the completed dose-escalation component of the study, patients received once daily zanubrutinib at 40 mg, 80 mg, 160 mg, or 320 mg, or a 160-mg twice daily dose. In the ongoing dose-expansion cohort, patients are receiving zanubrutinib at either 320 mg once daily or 160 mg twice daily.
Ninety-nine patients with NHL subtypes other than Waldenstrom macroglobulinemia (WM) or chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) were enrolled at the data cutoff of September 15, 2017.
There were 65 patients with aggressive lymphoma, comprising 38 patients with MCL and 27 patients with DLBCL. The median age for patients with aggressive lymphoma was 70 (range, 20-86). The ECOG performance status (PS) was 0 for 43% of patients, 1 for 45% of patients, and 2 for 12% of patients. Three percent of patients were treatment-naive. Among the 97% of patients who were relapsed/refractory, the median number of prior therapies was 2 (range, 1-10). Five percent of patients had bulky disease and 86% of patients had stage III/IV disease at study entry.
The other 34 patients in the analysis presented at ASH had indolent lymphoma, including 10 with MZL and 24 with FL. The median age in these patients was 65 (range, 41-79), 47% had ECOG PS 0, 44% had PS 1, and 9% had PS 2. Eighty-six percent of patients had stage III/IV disease.
The median follow-up was 5.1 months (range, 0.1-31.9) for patients with aggressive lymphoma and 5.6 months (range, 0.3-22.3) for patients with indolent lymphoma.
Seventeen patients with FL and 26 patients with MZL were evaluable for efficacy. The responses in patients with FL included an 18% complete response (CR) rate and 24% partial response (PR) rate, with stable disease (SD) in 41% of patients and progressive disease in 1 patient. In MZL patients, there were no CRs, the PR rate was 78%, 22% of patients had stable disease, and no PD was reported.
In the aggressive lymphoma group, 58 patients were evaluable for efficacy, including 26 patients with DLBCL and 32 patients with MCL. The CR rate in DLBCL patients was 15%, the PR rate was 15%, 15% of patients had SD, and 50% had PD. Among patients with MCL, the CR and PR rates were 25% and 63%, respectively, and 1 patient each had SD and PD.
Among 34 evaluable patients in the indolent lymphoma cohort, all-grade adverse events (AEs) occurring in at least 15% of patients included petechiae/purpura/contusion (24%), upper respiratory tract infection (URTI; 21%), nausea (18%), and pyrexia (15%). Grade ≥3 AEs occurring in at least 5% of patients included anemia (9%), neutropenia (9%), urinary tract infection (6%), and abdominal pain (6%).
Eleven patients (32%) had serious AEs. There were 4 serious AEs potentially related to zanubrutinib: nausea, urinary tract infection, diarrhea, and creatinine increase.
The safety evaluation for the aggressive lymphoma cohort included all 65 patients. All-grade AEs occurring in ≥15% of patients included petechiae/purpura/contusion (25%), diarrhea (23%), constipation (22%), fatigue (18%), URTI (18%), anemia (17%), cough (15%), pyrexia (15%), and thrombocytopenia (15%). Grade ≥3 AEs occurring in ≥5% of patients included anemia (11%), neutropenia (9%), thrombocytopenia (9%), and pneumonia (6%).
Twenty-six patients (40%) had serious AEs. Three patients had serious AEs that were potentially related to zanubrutinib: peripheral edema and joint effusion (same patient), pneumonia, and pneumonitis.
Previously presented results from this study showed the efficacy of zanubrutinib in other types of NHL. In data presented at the 2016 ASH Annual Meeting zanubrutinib had an ORR of 96% for patients with CLL/SLL. Results presented at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland, showed an ORR of 90% in patients with WM.
Ongoing studies of zanubrutinib include single-agent registrational trials in WM and CLL and a registration trial exploring the combination of zanubrutinib and obinutuzumab (Gazyva) in FL. Additional phase III trials are also being planned.
Tam CS, Simpson D, Opat S et al. Safety and Activity of the Highly Specific BTK Inhibitor BGB-3111 in Patients with Indolent and Aggressive Non Hodgkin’s Lymphoma. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 152.