Emerging BTK Inhibitor Tested in B-Cell Malignancies
BGB-3111, a second-generation BTK inhibitor, is being tested in patients with refractory B-cell lymphoid malignancies in an effort to determine whether the novel oral small molecule is a viable therapeutic option and to better understand its pharmacologic properties.
Constantine S. Tam, MBBS
BGB-3111, a second-generation Bruton tyrosine kinase (BTK) inhibitor, is being tested in patients with refractory B-cell lymphoid malignancies in an effort to determine whether the novel oral small molecule is a viable therapeutic option and to better understand its pharmacologic properties. Investigators also are seeking to differentiate BGB-3111 from ibrutinib (Imbruvica), the first and thus far only FDA-approved BTK inhibitor.
BGB-3111 is a potent, irreversible, and highly selective BTK inhibitor that blocks the signaling that leads to growth inhibition and cell death in malignant B cells. “The mechanism is the same as ibrutinib, but with less off-target kinase activity,” said Constantine S. Tam, MBBS, MD, a hematologist at the Peter MacCallum Cancer Centre in Melbourne, Australia, in an e-mail interview. Tam is the principal investigator for the trial.
Tam said that investigators are targeting “the diseases known to be sensitive to ibrutinib, such as chronic lymphocytic leukemia [CLL], follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, and activated B-cell like—diffuse large B-cell lymphoma.”
Early Indications of Efficacy
If successful, BGB-3111 could fulfill a need for a more concentrated therapy to treat patients with chemotherapy-refractory B-cell malignancies and patients in frontline settings who are not good candidates for chemotherapy, according to Tam.Results from preclinical biochemical and cellular assays show that BGB-3111 has similar potency for BTK inhibition compared with ibrutinib while being less active than ibrutinib against other kinase targets including EGFR, ITK, JAK3, HER2, and TEC.1 This is reflected in the higher BGB-3111 dose required to inhibit half of the off-target enzymatic activity compared with ibrutinib; a 2- to 70-fold higher concentration of BGB-3111 versus ibrutinib is needed to achieve similar levels of inhibition in other targets. Therefore, BGB-3111 appears to be associated with less toxicity.1
In early findings from a safety analysis of the ongoing phase I trial reported at the 2016 American Society of Hematology Annual Meeting, the objective response rate (ORR) with BGB-3111 therapy was 96% among patients with CLL and small lymphocytic leukemia (SLL).2 The cutoff date for this analysis was October 3, 2016.
The ORR with BGB-3111 consisted of partial responses (PRs; 67%) and PRs with lymphocytosis (28%). In those with high-risk molecular characteristics (del17p and/or del11q; n = 17), the ORR was 100%.
At the time of reporting, 66 patients with CLL or SLL had received BGB-3111 at escalating doses starting at 40 to 160 mg twice daily. The analysis included 46 patients with at least 12 weeks of follow-up; the median duration of follow-up was 8.6 months.
Tam and colleagues reported that none of the patients treated experienced progressive disease or Richter transformation. The most common all-grade adverse events (AEs) were contusion/petechiae/purpura (48%), upper respiratory tract infection (33%), fatigue (28%), cough (20%), diarrhea (20%), headache (20%), muscle spasms (17%), nausea (15%), arthralgia (13%), dizziness (11%), constipation (11%), neutropenia (11%), and rash (11%).2
Tam said that the AEs with BGB-3111, including arthralgia, easy bruising, and delayed wound healing, are similar to those seen with ibrutinib but at a low frequency.
Most patients have no significant AEs,” Tam said. “We are happy with the very high drug exposures reached in this study, approximately 8 to 10 times higher than ibrutinib, and the favorable AE profile despite these very high drug doses, due to the specificity of the drug. We will be interested to know if this high drug level translates to better clinical efficacy than ibrutinib in head-to-head studies.”
Next steps for this research include phase III studies comparing the efficacy of BGB-3111 with ibrutinib. One study currently underway is randomizing participants with MYD88 mutation—positive Waldenström macroglobulinemia to BGB-3111 versus ibrutinib; a third arm will administer BGB-3111 monotherapy to patients with wild-type disease (NCT03053440).
BGB-3111 is also being combined with obinutuzumab (Gazyva) (NCT02569476), and BGB-A317, an investigational PD-1 inhibitor (NCT02795182), in phase I trials for patients with B-cell lymphoid malignancies.
The trials are being sponsored by BeiGene, a biopharmaceutical company with a clinical headquarters in Fort Lee, New Jersey, and a research and development center in Beijing, China.
References
- BGB-3111: Small molecule BTK inhibitor to treat B-cell malignancies. BeiGene website. http://www.beigene.com/pipeline/clinical-candidates/bgb-3111/. Updated 2017. Accessed April 5, 2017.
- Tam CS, Opat S, Cull G, et al. Twice daily dosing with the highly specific BTK Inhibitor, Bgb-3111, achieves complete and continuous BTK occupancy in lymph nodes, and is associated with durable responses in patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Presented at: 2016 American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 642. http://ash.confex.com/ash/2016/web- program/Paper96122.html.
The phase I study (NCT02343120) features a dose escalation component followed by an expansion stage in which patients will be assigned to different cohorts based on the histology of their cancer. The trial, which seeks to recruit 235 participants, is open to patients with most B-cell lymphoid malignancies. The study is enrolling patients at The University of Texas MD Anderson Cancer Center in Houston and at centers in Australia, New Zealand, and South Korea.
