CLL Phase 3 Study: Zanubrutinib Bests Ibrutinib

Zanubrutinib (Brukinsa) demonstrated superior efficacy and safety over ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to results of the randomized, phase 3 ALPINE study.

Progression-free survival (PFS) was significantly higher for zanubrutinib versus ibrutinib, according to investigator Jennifer R. Brown, MD, PhD, director of the Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute, Boston.

Cardiac safety was also better with zanubrutinib, the second-generation Bruton’s tyrosine kinase inhibitor, compared to ibrutinib, the first-in-class Bruton’s tyrosine kinase inhibitor. Brown noted that ibrutinib has “transformed CLL therapy,” despite toxicity and pharmacokinetics issues which limit its use.

Even in patients with high-risk CLL, there was a clear benefit of zanubrutinib over ibrutinib, according to Brown, who presented final results of ALPINE in a late-breaking clinical trials session at the annual meeting of the American Society of Hematology.

“I am not aware of a patient population in which I would select ibrutinib as compared to zanubrutinib,” Brown said in a press briefing on the study at the meeting.

Although not currently indicated in CLL, zanubrutinib received Food and Drug Administration approval for treatment of relapsed/refractory mantle cell lymphoma in late 2019, followed by indications in Waldenström’s macroglobulinemia and relapsed/refractory marginal zone lymphoma in 2021.

But the choice of zanubrutinib over ibrutinib in relapsed/refractory CLL is already supported in current clinical practice guidelines, Brown said.

The most recent CLL guidelines from the National Comprehensive Cancer Network (NCCN), updated Aug 30, describe zanubrutinib as a “preferred” regimen, while ibrutinib falls into the category of an “other recommended regimen.”

The zanubrutinib recommendation is category 1, meaning that it is based on high-level evidence, with uniform consensus that the intervention in appropriate, according to NCCN.

Improved Safety, Efficacy

Side effects have proved to be an Achilles heel for ibrutinib, which first received an FDA approval in CLL in 2014.

Across CLL studies, between 16% and 23% of CLL patients have discontinued ibrutinib treatment because of toxicities, Brown, the ALPINE investigator, said at the ASH meeting.

In addition, pharmacokinetic data suggest that at certain times between doses, the amount of ibrutinib in a patient’s system may drop below the level needed to effectively inhibit the target protein, Bruton’s tyrosine kinase.

By contrast, zanubrutinib is designed to have greater specificity for that target protein, Brown said. Furthermore, the pharmacokinetic studies have demonstrated concentrations of drug consistently above the level needed for effective inhibition – an effect that suggests potential for greater efficacy.

In the ALPINE study, 652 patients with relapsed/refractory CLL/small lymphocytic lymphoma (SLL) were randomized to zanubrutinib 160 mg twice daily or ibrutinib once daily.

With a mean follow-up of 29.6 months, zanubrutinib PFS was significantly superior to ibrutinib, according to Brown, with a hazard ratio (HR) of 0.65 and 95% confidence interval (CI) between 0.49 and 0.86.

Estimated PFS at 2 years was 79.5% in the zanubrutinib arm and 67.3% for ibrutinib, according to the ALPINE data presented.

However, the difference in PFS in favor of zanubrutinib was even more pronounced in high-risk patients, according to Brown. Among patients with chromosome 17 deletion or TP53 mutation, the PFS at 2 years was 77.6% for zanubrutinib and just 55.7% for ibrutinib, with an HR of 0.52 and 95% CI of 0.30 to 0.88.

Zanubrutinib’s safety profile was superior to ibrutinib, with serious adverse rates of 42.0% and 50.0%, respectively, and significantly lower cardiac toxicity for zanubrutinib, according to the investigators’ presentation.

Only 5.2% of patients on zanubrutinib had atrial fibrillation/flutter on study, compared to 13.3% for ibrutinib (P = .0004), while rates of serious cardiac adverse events were 1.9% and 7.7% , respectively.

Impressive Benefit

The PFS benefit of zanubrutinib over ibrutinib was “quite impressive” in ALPINE, and in line with pharmacokinetic differences observed between Bruton’s tyrosine kinase inhibitors, said Stefan K. Barta, MD, associate professor of medicine at the University of Pennsylvania in Philadelphia.

“In the lab, [second-generation Bruton’s tyrosine kinase inhibitors] do hit the target better, but better doesn’t necessarily translate into good outcomes for patients – that’s a different question,” Barta said in an interview

However, the safety findings of ALPINE are particularly relevant, according to Barta, since today, many patients with CLL will receive treatment with Bruton’s tyrosine kinase inhibitors indefinitely.

In ALPINE results presented at ASH, zanubrutinib-treated patients had lower rates of atrial fibrillation and serious cardiac events, as well as zero deaths due to cardiac events, compared to six deaths in the ibrutinib group.

“Side effects make a big difference if you are on something for a long time,” Barta said. “It’s certainly a huge difference already, but then if you get the added bonus of also having an improvement in PFS, that’s a win-win.”

Brown reported disclosures related to Abbvie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Novartis, Pfizer, Rigel, Gilead, Loxo/Lilly, Verastem/Secura Bio, Sun, TG Therapeutics, Invectys, Grifols Worldwide Operations, Hutchmed, iOnctura, and Pharmacyclics.

This article originally appeared on, part of the Medscape Professional Network.

Source: Read Full Article