Expert Point of View: Jacqueline C. Barrientos, MD, MS

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The ASCO Post invited Jacqueline C. Barrientos, MD, MS, Associate Professor of Medicine, CLL Research and Treatment Program, Zucker School of Medicine at Hofstra/Northwell, Lake Success, New York, to comment on the ALPINE findings presented at the European Hematology Association (EHA) Virtual Congress.1 Dr. Barrientos concluded that zanubrutinib may be a safer drug than ibrutinib and may be more effective in certain high-risk subsets, but conclusions cannot be drawn from interim data.

The treatment of chronic lymphocytic leukemia (CLL) “profoundly” changed with the approval of the Bruton’s tyrosine kinase (BTK) inhibitors, particularly ibrutinib and acalabrutinib, as front-line therapy. Despite their efficacy, however, the use of these agents can be limited by toxicity that often leads to treatment discontinuations contributing to early relapse, she said. In addition, as single agents, BTK inhibitors rarely achieve complete remissions. Most responses are partial remissions or partial remissions with lymphocytosis, “and as such, therapy is to be administered continuously until progression of disease or intolerable toxicity,” she said.

Safety, therefore, is an important consideration. The planned interim analysis of the phase III ALPINE trial compared two covalently bound BTK inhibitors—the first-in-class drug ibrutinib and zanubrutinib, a next-generation, more selective, irreversible BTK inhibitor. The initial “very promising” results suggest that zanubrutinib may be safer while at the same time achieving “a better response rate, albeit these data are too early to draw meaningful conclusions,” she concluded.

Jacqueline C. Barrientos, MD, MS

Jacqueline C. Barrientos, MD, MS

Response Rate as Primary Endpoint

The choice of investigator-determined objective response rate as the primary endpoint, however, makes it difficult to determine superiority, Dr. Barrientos pointed out. The more common endpoints are progression-free survival and event-free survival, which are selected as potential surrogates for overall survival.

“Choosing overall response rate in an indolent disease such as CLL is uncommon. We know that BTK inhibitors need time to achieve the maximal response, available salvage therapies may affect survival outcomes, and side effects may appear late,” she said. “Importantly, any novel agent could achieve a significantly better response rate and still demonstrate a shorter time in remission or lead to intolerable toxicity.” For example, idelalisib improved response rates in front-line trials, but high rates of adverse events led to treatment discontinuations and diminished progression-free survival, she noted.

Regulators may have selected this early efficacy endpoint as a means of determining safety sooner (vs longer-term endpoints) and therefore hasten the availability of the drug for patients, she suggested. But she noted again that continuous exposure to BTK inhibitors over a longer period than the 12-month data cutoff will be necessary to ensure safety, reminding clinicians “it took years” and randomized trials to fully understand the toxicities associated with ibrutinib. “More mature data are needed to draw conclusions that can affect our treatment selection,” she said.

“It is for this reason that in a trial where the goal is to ascertain whether a drug is safer than the comparator, the open-label design may introduce bias both from the patients’ and the investigators’ perspective,” she commented. “Patients may anticipate and report more toxicities when randomly assigned to the standard of care, and investigators may discontinue the drug earlier, especially if another drug is commercially available…. Ideally, a blinded study would have minimized this potential bias and the speed of drug discontinuation.”

Early Efficacy Findings

With regard to efficacy,Dr. Barrientos called attention to the “important early finding” of high response rates to zanubrutinib in patients with 17p deletion, who typically have a more aggressive course: 83% vs 54% with ibrutinib at the time of the interim analysis. Longer follow-up is necessary to show whether these remissions are durable and whether they correlate with progression-free survival, she said.

For example, the recently reported ELEVATE-RR trial, comparing ibrutinib against acalabrutinib, showed early separation of the progression-free survival curve that disappeared with longer follow-up.2 Cardiovascular toxicity also occurred much later in ELEVATE-RR than in the ALPINE trial, though Dr. Barrientos cautioned that ELEVATE-RR enrolled higher-risk, more heavily pretreated patients, and conclusions should not be drawn from the cross-trial comparison.

“Based on the ALPINE data, zanubrutinib seems to be safer than ibrutinib, but we don’t know how it compares to acalabrutinib,” she concluded. Emerging data in a study presented at the EHA meeting by Shadman et al3 suggest zanubrutinib can be used in patients with ibrutinib and acalabrutinib intolerance; however, the study population was small and included patients with other B-cell malignancies, who may tolerate the drugs differently. “The study has a relative short follow-up and is still accruing but seems to confirm that zanubrutinib is a safer drug compared to ibrutinib and can be used to salvage ibrutinib- and acalabrutinib-intolerant patients.”

Dr. Barrientos added: “Although the results of ALPINE are promising, longer follow-up is needed to determine the impact of these findings in clinical practice outside of a controlled trial. At the end of the day, our goal is to offer our patients the opportunity to achieve excellent responses with durable remissions without affecting their quality of life.”

DISCLOSURE: Dr. Barrientos has received honoraria from Janssen; has served as a consultant or advisor to AbbVie, AstraZeneca, BeiGene, Genentech, Gilead Sciences, Innate Pharma, and Pharmacyclics; and has received institutional research funding from AstraZeneca, Oncternal Therapeutics, and Pharmacyclics.


1. Hillmen P, Eichhorst B, Brown JR, et al: First interim analysis of ALPINE study: Results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. EHA 2021 Virtual Congress. Abstract LB1900. Presented June 11, 2021.  

2. Byrd JC, Hillmen P, Ghia P, et al: First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. 2021 ASCO Annual Meeting. Abstract 7500. Presented June 4, 2021.

3. Shadman M, Sharman JP, Levy MY, et al: Preliminary results of the phase 2 study of zanubrutinib in patients with previously treated B-cell malignancies intolerant to ibrutinib and/or acalabrutinib. EHA 2021 Virtual Congress. Abstract EP642. Presented June 9, 2021. 


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