Results from ALPINE, a phase III trial, indicate that the second-generation BTK inhibitor zanubrutinib is superior to ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Besides having a better safety profile, zanubrutinib also improved progression-free survival.

In a head-to-head comparison, zanubrutinib (Brukinsa; BeiGene), a second-generation covalent inhibitor of Bruton tyrosine kinase (BTK), outperformed ibrutinib (Imbruvica; Janssen/Pharmacyclics) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Findings from the phase III trial, ALPINE, were presented during the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans, LA, December 10–13.

Ibrutinib, the first drug in this class, “has been transformative” for CLL/SLL, observed lead investigator Jennifer Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA. “However, it does have properties limiting its use, with up to 23% of patients discontinuing treatment due to toxicity.”

Enter zanubrutinib, “designed with greater specificity for BTK,” Brown said, as well as improved pharmaco-kinetics and pharmacodynamics “that should result in more sustained, complete inhibition, potentially increasing efficacy.” In ALPINE, 652 patients were randomly assigned to receive 160 mg of zanubrutinib twice daily or 420 mg of ibrutinib once a day. An interim analysis, published in November, indicated a higher objective response rate with the newer agent—78.3% versus 65.5% (J Clin Oncol 2022 Nov 17 [Epub ahead of print]).

At ASH, Brown disclosed that the estimated 2-year progression-free survival (PFS) was 79.5% with zanubrutinib and 67.3% with ibrutinib. In a high-risk subgroup—patients who lack part of chromosome 17 (17p deletion), which contains TP53—the magnitude of PFS benefit, 77.6% versus 55.7%, “was quite remarkable,” she said.

Patients with the 17p deletion generally respond well to the BCL2 inhibitor venetoclax (Venclexta; AbbVie/Genentech), but “they probably do even better with BTK inhibition, when we look at how long remission lasts,” said John Byrd, MD, of the University of Cincinnati in Ohio. “There hasn't been a trial directly comparing both types of agents in this population, however.”

Zanubrutinib had fewer side effects necessitating dose reductions or treatment discontinuation than ibrutinib, Brown reported. The rate of atrial fibrillation, a known ibrutinib toxicity, was lower with zanubrutinib, 5.2% versus 13.3%, “and whereas there were six fatal cardiac events in the ibrutinib arm, none occurred with zanubrutinib.”

Zanubrutinib is currently indicated for Waldenström macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Besides a strong performance in ALPINE, it has also proven superior to chemoimmunotherapy as a first-line treatment in the SEQUOIA trial (Lancet Oncol 2022;23:1031–43). As such, “we hope its approval is imminent” for CLL/SLL, Brown noted. Meanwhile, the drug has joined its second-generation counterpart acalabrutinib (Calquence; AstraZeneca)—which is greenlighted by the FDA—as a preferred CLL/SLL therapy, according to recently revised National Comprehensive Cancer Network Guidelines.

“Ibrutinib was a great drug,” Byrd remarked, “but both acalabrutinib and zanubrutinib are safer. I think my patients who are already on ibrutinib can continue treatment unless problems develop. For patients who haven't had a BTK inhibitor, however, I'll choose either of the newer drugs.”

Meanwhile, BTK candidates continue to emerge. For instance, NX-2127 (Nurix Therapeutics), which degrades rather than suppresses BTK and has shown early phase I efficacy, was also reported on at ASH. Reversible inhibitors are on the way too: Nemtabrutinib (Merck) and pirtobrutinib (Loxo/Lilly) are being evaluated in the phase II BELLWAVE-001 and phase III BRUIN-CLL-314 trials, respectively. Such options will be key to countering disease progression, Byrd said, “because existing agents have an overlapping mechanism of action, so resistance to one likely means resistance to the others.” –Alissa Poh

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