Comparison of BTK Inhibitors Shows Promising Results for Zanubrutinib Over Ibrutinib in CLL/SLL

Article

An interim analysis of the phase 3 ALPINE study showed stronger results for patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma on the next generation BTK inhibitor zanubrutinib than standard of care ibrutinib.

In comparison with ibrutinib (Imbruvica), zanubrutinib (Brukinsa) showed superior efficacy and cardiac safety results for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to data published in the Journal of Clinical Oncology.1

Results from an interim analysis of the global, randomized, open-label phase 3 ALPINE study (NCT03734016) conducted approximately 12 months after the enrollment of the first 415 patients showed that the next-generation Bruton tyrosine kinase (BTK) inhibitor zanubrutinib outperformed the standard BTK inhibitor based on the overall response rate (ORR).

At a median of 15.3 months of follow-up, in the zanubrutinib group (n = 207) the ORR was 78.3% (95% CI, 72%-83.7%) compared with 65% (95% CI, 55.5%-69.1%) in the ibrutinib group (n =208), which was significantly better (P < .001). However, based on independent central review (ICR), the ORR met noninferiority standards but not superiority (P = .0121). When looking at the concordance rate between the ICR and investigator findings of a best overall response, partial response (PR) or higher, they found that zanubrutinib was higher at 94.2% compared with 93.3% with ibrutinib.

A consistent ORR benefit was seen in favor of zanubrutinib vs ibrutinib in all patient subgroups, which the researchers highlighted among patients with a del(17p)/TP53 mutation in their disease at 80.5% vs 50% (95% CI, 10.5%-50.5%), respectively. This was also observed in patients with a del(11q) mutation in their disease as patients on zanubrutinib achieved an 83.6% ORR compared with 69.1% among patients on ibrutinib.

Overall, there were 4 complete responses (CRs) in the zanubrutinib arm compared with 3 in the ibrutinib arm, but 158 PRs in the zanubrutinib arm vs 127 in the ibrutinib arm. There were more patients with a PR that also had lymphocytosis and stable disease in the ibrutinib arm vs the zanubtuitinib arm at 39 patients vs 21 patients and 28 patients vs 17 patients, respectively. Progressive disease was seen in just 1 patient compared with 2 patients on ibrutinib.

CLL, Zanubrutinib, SLL, Ibrutinib, survival, ORR

On the ALPINE study, patients were randomized 1:1 to either 160 mg of zanubrutinib given twice daily or 420 mg of ibrutinib given once a day until progressive disease of unacceptable toxicity. Eligible patients had a confirmed diagnosis of CLL or SLL and relapsed after, or were refractory to, 1 prior line of therapy.

Between both arms, the median age of patients was 67 years, and a majority had an ECOG performance score of 1 or more. Moreover, most patients had 1 prior line of therapy in the zanubrutinib arm (56%) and ibrutinib arm (52.9%). Among the patients, 19.8% in the zanubrutinib arm had del(17p)/TP53 mutation in their disease compared with 18.3% in the ibrutinib arm. Both arms also had a similar amount of patients with del(11q) in their disease at 29.5% in the zanubrutinib arm compared with 26.4% in the ibrutinib arm.

Among patients with a del(17p)/TP53 mutation in their disease, there were no CRs to either drug, but 33 patients had a PR to zanubrutinib compared with 19 in the ibrutinib arm. There were still more patients in the ibrutinib arm vs the zanubrutinib arm that had a PR with lymphocytosis and stable disease at 8 vs 3 patients and 8 vs 2 patients, respectively. Only 1 patient who had a del(17p)/TP53 mutation in their disease had progressive disease, and they were on ibrutinib.

These responses also yielded stronger progression-free survival (PFS) results for patients on zanubrutinib as the 12-month investigator assessed PFS was 94.9% (95% CI, 90.7%-97.2%) vs 84% (95% CI, 78.1%-88.5%) for patients on ibrutinib. This 12-month PFS rate remained favorable for patients regardless of their del(17p)/TP53 mutation status at 91.5% in the zanubrutinib arm vs 74.4% in the ibrutinib arm. Overall survival (OS) was also observed in the interim analysis, but both arms were similar at a 12-month OS of 97% in the zanubrutinib arm vs 92.7% in the ibrutinib arm (HR 0.54; 95% CI, 0.25-1.16). The HR for progressive disease or death was found to be 0.40 (95% CI, 0.23-0.69; P < .001) but not determined significant as a formal PFS event is being held until 205 PFS events are observed by researchers.

“Initial data support the hypothesis that complete/sustained BTK occupancy may improve efficacy outcomes and increased specificity may minimize off-target inhibition-related toxicities,” the researchers explained in the discussion of their data. “The interim analysis demonstrated a favorable benefit-risk profile for zanubrutinib in the treatment of patients with relapsed/refractory CLL/SLL.”

Between both drug arms, the median treatment of duration was similar at 15.3 months (range, 0.4-23) for patients on zanubrutinib and 14.6 months (range, 0.1-25.9) on ibrutinib. Overall, fewer patients on zanubrutinib experienced an adverse event (AE) that led to discontinuation of treatment vs those on ibrutinib at 7.8% vs 13%, respectively. Overall, more patients in the ibrutinib arm vs the zanubrutinib arm had AEs that led to a dose reduction and dose interruption at 12.1% vs 11.3% and 40.6% vs 39.7%, respectively. Of the AEs of interest to the research, infection events were the most common AE that led to discontinuation in either arm with 2.9% of patients experiencing them in both arms. Major hemorrhage was also experienced in 2.9% of patients in the zanubrutuinb arm compared with 3.9% in the ibrutinib arm.

The most common any-grade AE experienced in either the zanubrutinib or ibrutinib arm included arthralgia (9.3% vs 14%), anemia (13.2% vs 15%), diarrhea (16.7% vs 19.3%), upper respiratory tract infection (21.6% vs 14%), neutropenia (19.6% vs 15.5%), and hypertension (15.7% vs 13%). Slightly more grade 3 or greater AEs were observed in the zanubrutinib arm (55.9%) compared with the ibrutinib arm (51.2%), but more patients experienced serious AEs in the ibrutinib group (32.4%) than those on zanubrutinib (27.5%). The most common grade 3 or greater Aes included neutropenia (13.7% vs 10.6%), hypertension (10.3% vs 7.2%), and a decrease in neutrophil count (4.9% vs 4.3%).

Among the safety analysis of zanubrutinib, one of the key secondary end points was assessing atrial fibrillation and flutter, which was seen more in the ibrutinib arm vs the zanubrutinib arm at 10.1% vs 2.5%, respectively. Overall, cardiac disorder AEs occurred less for patients on zanubrutinib (13.7%) compared with patients on ibrutinib (25.1%).

“Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition,” the researchers concluded.

Reference

Hillmen P, Eichhorst B, Brown JR, et al. Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: interim analysis of a randomized phase III trial. J Clin Oncol. 2023 Feb 10;41(5):1035-1045. doi:10.1200/JCO.22.00510

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