Expert Highlights Potential of Zanubrutinib in Waldenstrom Macroglobulinemia

Judith Trotman, MBChB, FRACP, FRCPA

Zanubrutinib (BGB-3111), an investigational small molecule inhibitor of BTK, showed promising activity in patients with Waldenström macroglobulinemia (WM), according to updated results presented at the 2018 European Hematology Association Congress.

First author Judith Trotman, MBChB, FRACP, FRCPA, clinical professor of Medicine, Concord Clinical School, director of Clinical Research Unit, Haematology Department, Concord Hospital in Sydney, Australia, presented results from a subgroup of 67 patients with WM who received zanubrutinib in a phase I trial. Among the 51 patients evaluable for efficacy, the overall response rate was 92%, with a major response rate of 80% and a very good partial response (VGPR) rate of 43.1%. The median time to response was 88 days (range, 77-279).

“Zanubrutinib is extremely well tolerated and extraordinarily effective in the treatment of symptomatic Waldenström macroglobulinemia,” she said.

Moreover, the 12-month progression-free survival (PFS) rate was estimated at 91%, and the median PFS has not been reached.

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) for all evaluable patients. At baseline, 22 patients had hemoglobin <10 g/dL. Of these, median hemoglobin increased from 8.7 g/dL (range, 6.3-9.8) to 13.8 g/dL (range, 7.7-15.8).

Researchers identified what appears to be an association between the presence of MYD88L265P and response and depth of response with zanubrutinib treatment. They also observed a strong response in patients who were MYD88 wild-type, with an ORR or 83%, a major response rate of 50%, and a VGPR of 17%.

The most frequent adverse events (AEs; ≥15%) included petechia/purpura/contusion (37%), upper respiratory tract infection (34%), constipation (18%), and diarrhea (18%). All but 1 of those events were grade 1/2.

Grade 3/4 AEs observed in ≥2 patients included anemia (7%), neutropenia (6%), basal cell carcinoma (3%), hypertension (3%), squamous cell carcinoma (3%), pyrexia (3%), pneumonia (3%), major hemorrhage (3%), and actinic keratosis (3%). Five patients experienced treatment-related serious AEs.

“We're quite happy with the safety profile of this agent,” Trotman said.

BeiGene, the manufacturer of zanubrutinib, announced in July 2018 that the FDA granted fast track designation to the BTK inhibitor for WM based on these phase I results. The company plans to submit a new drug application seeking accelerated approval in early 2019.

The phase III BGB-311-302 trial (NCT03053440) comparing zanubrutinib with ibrutinib (Imbruvica) for patients with MYD88^MUT WM completed enrollment in 2018. BeiGene is also exploring zanubrutinib versus bendamustine/rituximab for patients with chronic lymphocytic leukemia (CLL) in a global phase III trial (NCT03336333). The company plans to evaluate zanubrutinib versus ibrutinib for patients with relapsed/refractory CLL/small lymphocytic lymphoma in a phase III trial.

OncLive: Please explain the rationale behind this study.

In an interview with OncLive, Trotman discussed zanubrutinib’s effect on patient quality of life and how the BTK inhibitor can be used to extend survival for younger patients with WM.Trotman: This is a phase I study of zanubrutinib, a next-generation BTK inhibitor with, we believe, greater specificity, less off-target effects, and fewer side effects than the first-generation BTK inhibitors. This is a study primarily to address safety, but as there are more than 300 patients, we're acquiring quite a lot of efficacy data as well.

There are roughly 67 patients with WM participating in this study, 59 of whom have been on study for at least 1 year. Fifty-one patients have evaluable disease. Within that 51, we had a greater than 90% response rate, with a major response rate about 80% and 43% of patients achieving a VGPR. We also observed quite a dramatic reduction in IgM levels, which occurred quite rapidly but also improved with time.

In the main study, the bulk of patients had CLL, mantle cell lymphoma, or WM. There were a few patients with marginal zone lymphoma, almost a dozen with hairy cell leukemia, and a few with follicular lymphoma. The main study aimed to analyze the safety, safe deliverability, and dose findings to identify the optimal dosing. We identified that, with 160 mg twice a day, we had complete occupation of the BTK receptors and lymphocytes—both in circulating nuclear cells and also in tissue lymphocytes—so that's been the dose carried forward.

This dose is extremely well tolerated. It's actually hard to identify in this patient population, mainly relapsed/refractory indolent lymphomas, which side effects are caused by zanubrutinib and which are the general risk of infections these patients are generally exposed to.

What challenges in treating these patients do you hope zanubrutinib will address?

There's a lower rate of bleeding. We see some minor petechia, bruising, and contusions, but a very low rate of serious bleeding. In the WM cohort, we only had 2 serious hemorrhages.Zanubrutinib and, indeed, the BTK inhibitors in general, are providing a fantastic solution for most patients with WM at the moment. There's no doubt it has quite profound effects, not just on bringing patients' hemoglobin up as their IgM levels decline, but also their general sense of well-being. In the patient-reported outcomes (PROs) in the trials that have collected PROs and in my own experience with BTK inhibitors, patients feel great on these agents. If patients have a sustained response for many years, then that does provide a solution for most of our older patients with WM.

However, for our younger patients, and there is a significant cohort of younger patients and even not-so-young patients who have very prolonged expectations for their life expectancy, we need to be thinking about how we combine these BTK inhibitors with other agents to get patients into a complete remission and off study drug.

Trotman J, Tam CS, Marlton P, et al. Improved depth of response with increased follow-up for patients (PTS) with Waldenström macroglobulinemia (WM) treated with Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib. In: Proceedings from the 2018 European Hematology Association Congress; June 14-17, 2018; Stockholm, Sweden. Abstract PS1186.