New BTK Inhibitor Expands Treatment Options for Patients With MCL

Javier Munoz, MD, MS, FACP

Therapeutic options for patients with mantle cell lymphoma (MCL) now include the novel Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa). On November 14, 2019, the FDA granted accelerated approval to zanubrutinib for adult patients with MCL who have received ≥1 prior treatment. The approval for the rare and aggressive subtype of B-cell non-Hodgkin lymphoma was handed down 3 months ahead of the planned action date based on the overall response rates (ORRs) observed in 2 single-arm trials.

The third BTK inhibitor to gain FDA approval, zanubrutinib joins ibrutinib (Imbruvica) and acalabrutinib (Calquence), which are both indicated for adults with MCL who have received ≥1 prior therapy. “The introduction of BTK inhibitors to the clinic has been transformative for the treatment landscape of B-cell malignancies,” Javier Munoz, MD, MS, FACP, a leading investigator of the drug, said in an interview with OncLive.

Munoz, a hematologist/oncologist and director of the Cancer Immunotherapy Program at Banner MD Anderson Cancer Center in Gilbert, Arizona, discussed zanubrutinib’s path to approval and its future potential.

OncLive: Could you please provide an overview of the trials?

Munoz: Efficacy was assessed in BGB-3111-206 (NCT03206970), a phase II openlabel, multicenter, single-arm trial of 86 patients with MCL who had received at least 1 prior treatment. Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity. Efficacy was also addressed in BGB-3111-AU-003 (NCT02343120), a phase I/II, open-label, dose-escalation, global, multicenter, single-arm trial of B-cell malignancies, including 32 patients with MCL previously treated with zanubrutinib administered orally at 160 mg twice daily or 320 mg once daily.

Zanubrutinib is currently under evaluation for the treatment of other B-cell malignancies in clinical trials.

Could you discuss the pivotal efficacy data?

The primary efficacy variable in both trials was overall response rate, as determined by an independent review committee. In the trial BGB-3111-206, FDG-PET [fluorodeoxyglucose-PET] scans were required, and the overall response rate was 84%, with a complete response rate of 59% and a median response duration to zanubrutinib of 19.5 months.

In the trial BGB-3111-AU-003, FDG-PET scans were not required, and the overall response rate was 84%, with a complete response rate of 22% and a median response duration to zanubrutinib of 18.5 months.

It is possible that variances in trial design may explain the differences when it comes to complete and partial responses. Nevertheless, it is reassuring that the overall response rate and median response duration were similar across studies.

Could you describe the mechanism of action?

Zanubrutinib is a Bruton tyrosine kinase inhibitor. BTK plays a critical role in the B-cell receptor pathway, which is pivotal for survival and proliferation of B-cell malignancies. BTK inhibitors have provided novel treatment options for patients with MCL and other hematologic malignancies.

What about the agent’s tolerability?

The BGB-3111-206 and BGB-3111-AU-003 trials showed adverse events that have previously been described in other trials from the BTK inhibitor family without new toxicity signals.

Regarding zanubrutinib, the most common adverse events included neutropenia, thrombocytopenia, upper respiratory tract infection, leukopenia, anemia, rash, easy bruising, diarrhea, and cough. The most common serious adverse events were pneumonia in 11% and hemorrhage in 5% of patients. Tolerability and ease of administration are critical when making therapeutic decisions with our patients.

How does zanubrutinib fit into the current treatment paradigm?

MCL is a rare disease that does not have strong consensus when it comes to the current treatment paradigm. The National Comprehensive Cancer Network mentions multiple therapeutic options both for patients with newly diagnosed and relapsed MCL. We are fortunate to have several nonchemotherapy options in the relapsed/refractory setting, including the BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib. There are multiple variables that can help us make treatment decisions, including age, comorbidities, performance status, dosing, and concomitant medications.

Zanubrutinib is an attractive medication due to the flexibility in dosing and the fact that absorption does not seem to be impaired by proton pump inhibitors. Of note, at this point, zanubrutinib is only FDA approved for adult patients with MCL who have received at least 1 prior treatment, and the recommended zanubrutinib dose is 160 mg orally twice daily or 320 mg orally once daily.

Finally, we will need to wait for head-to-head comparison data to guide us on how to best incorporate novel therapies into optimal management paradigms for our individual patients with MCL.

What are the next steps for zanubrutinib?

Second-generation BTK inhibitors were developed hoping to find an appropriate balance between efficacy and toxicity. Zanubrutinib is currently being studied in clinical trials for several B-cell malignancies either as a single agent or in combination therapy. Randomized clinical trials comparing zanubrutinib versus other therapies including other BTK inhibitors are under way, and we are eagerly waiting for results so we can clarify the role of zanubrutinib in the current therapeutic landscape.

Is there anything else you’d like to highlight?

The introduction of BTK inhibitors to the clinic has been transformative for the treatment landscape of B-cell malignancies. I have been honored to be part of some clinical trials with BTK inhibitors including zanubrutinib. We are fortunate to have seen a paradigm shift away from chemotherapy; thus, BTK inhibitors are currently my preferred second-line therapy for relapsed refractory MCL. It is an exciting time for our patients with MCL and we wholeheartedly welcome additional therapies.

Disclosures: Dr Munoz reports relationships with Pharmacyclics/Janssen, AstraZeneca, and BeiGene.