Building on BTK Inhibition in CLL

Anthony R. Mato, MD, MSCE, director of the CLL Program at Memorial Sloan Kettering Cancer Center

Anthony R. Mato, MD, MSCE

BTK inhibitors have established a foothold in the treatment of patients with chronic lymphocytic leukemia (CLL) in both the newly diagnosed and relapsed/refractory settings, said Anthony R. Mato, MD, MSCE. They have also provided a foundation upon which to evaluate combination strategies with BCL-2 inhibitors and CD20-directed antibodies, he added.

“The field continues to evolve,” said Mato. “We're learning how to address resistance mechanisms and intolerance by figuring out how to combine these agents and who to combine them in, so we can deepen responses and potentially cure our patients.”

In addition to ibrutinib, the second-generation BTK inhibitor acalabrutinib (Calquence) has shown profound benefit both as monotherapy and when used in combination with obinutuzumab (Gazyva). In November 2019, the FDA approved acalabrutinib for use in patients with CLL or small lymphocytic lymphoma, based on data from the phase III ELEVATE-TN and ASCEND trials.

At the 2019 ASH Annual Meeting, updated findings from the ELEVATE-TN trial showed sustained benefit with acalabrutinib in previously untreated patients with CLL, either as a single-agent (HR, 0.20; P <.0001), or in combination with obinutuzumab (HR, 0.10; P <.0001), compared with obinutuzumab and chlorambucil.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Mato, a hematologic oncologist and director of the Chronic Lymphocytic Leukemia Program at Memorial Sloan Kettering Cancer Center, discussed recent treatment advances that have been made in the frontline and relapsed/refractory settings of CLL.

OncLive: Could you discuss some of the data that have emerged with ibrutinib?

Mato: Ibrutinib has become a standard of care in the frontline and relapsed/refractory settings. In the frontline setting, it's approved for use as continuous monotherapy or in combination with the anti-CD20 antibody, obinutuzumab. In the relapsed/refractory setting, it's approved as monotherapy. The agent is quite active and has been shown to prolong survival in several studies.

Should ibrutinib be evaluated in combination with other agents?

It’s an interesting question but it’s also difficult to answer based on current data. Data from 2 recent clinical trials [gave us pause] with regard to the way we’re evaluating combinations. The first was the phase III ALLIANCE A041202 trial, which was presented by Jennifer Woyach, MD, of The Ohio State University Comprehensive Cancer Center—James, at the 2018 ASH Annual Meeting. Investigators evaluated ibrutinib alone and in combination with rituximab (Rituxan) compared with bendamustine and rituximab (BR). The trial was positive, in that ibrutinib-based therapy was found to be better than bendamustine-based therapy. However, the addition of rituximab did not appear [to result in] a progression-free survival or overall survival benefit.

A similar study was presented by Jan A. Burger, MD, PhD, of The University of Texas MD Anderson Cancer Center. In this trial, investigators evaluated ibrutinib alone or in combination with rituximab in the relapsed/refractory setting. No obvious clinical benefit was observed [with the addition of rituximab]. In a randomized setting, the ibrutinib-based combinations have not shown a benefit versus ibrutinib alone. Several studies looking at ibrutinib plus something—be it venetoclax, an anti-CD20 antibody&mdash;or a PI3K inhibitor, are being planned or are already underway. Phase I/II trials have demonstrated safety and marked activity leading to undetectable minimal residual disease.

The question is whether these combinations will be better than giving ibrutinib followed by venetoclax. That sort of sequential approach is untested, and there aren't accruing clinical trials that are testing sequential monotherapy versus combination therapy. For right now, ibrutinib should be used as monotherapy in the frontline and relapsed/refractory settings.

What are some of the differences between ibrutinib and acalabrutinib?

Ibrutinib is a first-in-class BTK inhibitor that is approved in many indications including CLL, Waldenström macroglobulinemia, marginal zone lymphoma, mantle cell lymphoma (MCL), and graft-versus-host disease. The agent has been available for more than 5 years in clinical practice and much longer in the context of clinical trials. Acalabrutinib is a next-generation BTK inhibitor that is perhaps more specific to BTK with less off-target effects. Acalabrutinib is approved for use in the relapsed/refractory setting in MCL and is being used in the same setting in CLL.

It’s difficult to compare the 2 drugs. We have longer follow-up data with ibrutinib, whereas we have almost no real-world experience that has been reported with acalabrutinib. I hesitate to make direct comparisons between these agents; they’re both effective. Next-generation BTK inhibitors have been touted to have less adverse events, but we don't have a direct comparison [with ibrutinib] in a similar patient population to say that definitively. A randomized trial of acalabrutinib versus ibrutinib is ongoing in the relapsed/refractory setting, specifically for patients with deletion 17p or 11q deletion. Hopefully, those data will read out within the next 1 to 2 years and provide insight into the efficacy and toxicity differences among these drugs.

Could you shed light on data from the CLL14 trial?

The CLL14 trial was presented by Kirsten Fischer, MD, from the German CLL Study Group, at the 2019 ASCO Annual Meeting. Investigators randomized patients to receive the combination of venetoclax and obinutuzumab versus obinutuzumab and chlorambucil; this was largely an older, unfit patient population. The primary endpoint of the trial was PFS. The study was conducted in Europe. The primary endpoint was met. Venetoclax and obinutuzumab resulted in a superior PFS versus obinutuzumab and chlorambucil. However, we haven’t seen a clear benefit in OS yet. These data show, for the first time, that we can give a fixed-duration venetoclax-based combination in the frontline setting that results in deep and durable remissions. The combination was approved and has since become a standard of care in the frontline setting for patients with CLL.

Editor’s note: This interview took place prior to the November 2019 FDA approval of acalabrutinib in CLL.

Sharman P, Banerji V, Fogliatto L, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):31. doi: 10.1182/blood-2019-128404.