Constantine Tam, MD, Professor, Consultant Hematologist at Peter MacCallum Cancer Centre and University of Melbourne, Australia, overviews results from the phase 3 SEQUOIA study on zanubrutinib versus bendamustine-rituximab in patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL). These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript:

Dr Tam: Hi, I'm Professor Con Tam from Peter MacCallum Cancer Center and University of Melbourne in Melbourne, Australia. I am a hematologist with a special interest in CLL.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr Tam: Recently, the new class of drugs, the BTK inhibitors, especially ibrutinib, has been shown to be very active in CLL, and it's becoming used earlier and earlier in the line of therapy.

Ibrutinib has been compared against multiple forms of chemotherapy. It showed a superior progression-free survival (PFS), and therefore, it's regarded as the standard of care as first-line treatment of CLL.

However, ibrutinib does have some side effects, including atrial fibrillation and hypertension. There are now second-generation drugs such as acalabrutinib or zanubrutinib, which is a drug understudy in the SEQUOIA Study, which had been demonstrated in head-to-head comparisons with ibrutinib to be less toxic.

We're taking zanubrutinib, and we're going to use it in the front-line in this study to see if we can achieve the same results as ibrutinib i.e a superior outcome compared to chemotherapy but with a reduced incidence of BTK related side effects.

OLN: Please briefly describe your study and its findings.

Dr Tam: This study is a front-line study in CLL with patients with comorbidities, randomly assigned 1 to 1 to either zanubrutinib as a single agent or bendamustine-rituximab chemotherapy, which is the comparator.

Bendamustine-rituximab is regarded in the US and in Europe and also in Australia as a standard of care for patients with CLL and comorbidities.

There are other arms in this study, but those other arms are designed to handle those patients who are identified to have 17p deletion at diagnosis at the time of enrollment because it is unethical to randomize patients with 17p deletion to bendamustine-rituximab.

The main bulk of this study is patients without 17p deletion, randomized 1 to 1 to zanubrutinib or bendamustine-rituximab.

In this randomized comparison, what was shown was that in a total of 479 patients that zanubrutinib was superior in terms of PFS with a 2-year PFS of 85.5% for zanubrutinib versus 69.5% for bendamustine-rituximab.

In terms of side effects, zanubrutinib demonstrated the expected side effects of BTK inhibitor with an increased risk of bleeding. This is a well-known class effect, but had a reduced risk of nausea, cytopenias, and all the other side effects that one would normally associate with chemotherapy. That's not a surprising finding.

What is a gratifying finding in this study was that the risk of atrial fibrillation was not different between the zanubrutinib arm and bendamustine-rituximab. I highlight this result because zanubrutinib has been designed to have a lower side effect profile compared to ibrutinib. In previous comparisons of Ibrutinib versus chemotherapy, in every comparison every made, ibrutinib has been associated with an increased risk of atrial fibrillation.

This is one of the first studies—to my awareness—where a BTK inhibitor was compared head-to-head against chemotherapy without an increase in the risk of atrial fibrillation, which I think underscores the safety of zanubrutinib as a drug.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Tam: I think that first, this study has another layer of studies to confirm that BTK inhibitors is a standard of care for front-line patients. There are now multiple studies with ibrutinib, zanubrutinib, and acalabrutinib, that these drugs are superior to chemoimmunotherapy every time it's been compared in CLL. One more study to confirm BTK as the preferred front-line class of drug to use in CLL.

The second indication in this study is that we believe that this provides a platform for zanubrutinib to apply for registration in front-line CLL because it now has been compared against the standard of care, which is bendamustine-rituximab, and shown to be superior.

If zanubrutinib should become available in the front-line across multiple markets, then it provides a good option for patients needing frontline therapy, because zanubrutinib appears to be less toxic than Ibrutinib, and indeed has been proven to be less toxic than Ibrutinib in multiple phase 3 studies.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what are/will be your next steps?

Dr Tam: At the moment, this is the registration study for zanubrutinib, so we will want a prolonged follow-up to see if there's differences in overall survival (OS) and to see that the PFS advantage is maintained over time.

How the SEQUOIA study as I mentioned before, also, we have patients who identify that 17p deletion diagnosis where those patients (are) actually assigned to zanubrutinib monotherapy because it's unethical to treat these patients with bendamustine-rituximab. That is the arm C, and that's shown in 17p deletion that zanu is very effective, but of course, the whole world is moving towards combinations.

When that arm finishes, we've now opened a new arm called arm D, which is the combination of zanubrutinib plus venetoclax in patients with 17p deletions. That will be a really good platform for exploring the safety and tolerability of zanubrutinib-venetoclax combination, which if proven to be safe and effective in this arm, we tend to take to further randomized studies.