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Most patients with B-cell malignancies and intolerance to Bruton tyrosine kinase (BTK) inhibitors continued treatment without recurrence of intolerance after switching to the next-generation BTK inhibitor zanubrutinib (Brukinsa), a multicenter trial showed.

More than 70% of intolerance events did not recur, and most recurrences were less severe with zanubrutinib as compared with the original intolerance events with ibrutinib (Imbruvica) or acalabrutinib (Calquence). No recurrent events were more severe than the original intolerance, and no patient had grade 4 intolerance during treatment with zanubrutinib.

After a median follow-up of 12 months after the switch to zanubrutinib, the disease control rate was 93.8% and the overall response rate was 64.1%, reported Mazyar Shadman, MD, of Fred Hutchinson Cancer Center in Seattle, and colleagues, in .

"Patients intolerant of previous BTK inhibitors have limited treatment options," the authors concluded. "These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib."

Consistent Data

The findings add to existing evidence that zanubrutinib has a more manageable safety profile as compared with ibrutinib and extends the observation to include acalabrutinib, according to the author of an . However, the vast majority of patients had exhibited intolerance to ibrutinib, and follow-up on the initial BTK inhibitor and zanubrutinib was short.

"Notwithstanding these caveats, zanubrutinib was shown to be a better tolerated BTK inhibitor than acalabrutinib and ibrutinib across a range of expected adverse events in this study, including those of special interest," noted Shirley D'Sa, MD, of University College London Hospitals.

"Adverse events associated with zanubrutinib seem to be more tolerable and manageable for patients than those associated with other BTK inhibitors," she added. "These data suggest that robust dosing in terms of duration and dose intensity is more likely with zanubrutinib than with other BTK inhibitors, which should contribute to improved outcomes in this setting."

Moving forward, several actions can help improve understanding of differences among BTK inhibitors and optimize the drugs' use in B-cell malignancies, D'Sa said. These include a thorough patient history to gain details of pre-existing conditions and insight into adverse events that arise during treatment. Additional comparative clinical trials are feasible and needed. Standardization of assays can better characterize each drug's kinase selectivity and inhibitory activity, and improve treatment precision.

"Results of ongoing studies should be scrutinized closely, and strenuous efforts made to avoid premature conclusions and impulsive responses," she stated.

BTK inhibitors have proven highly effective in the treatment of B-cell malignancies, but , potentially related to off-target binding, has limited their use. One retrospective analysis showed that a majority of patients with chronic lymphocytic leukemia (CLL) discontinued ibrutinib during a median follow-up of 17 months because of toxicity, particularly atrial fibrillation.

Despite greater selectivity for BTK, acalabrutinib also is associated with toxicity-related discontinuation. A pooled safety analysis of nine clinical trials showed a 9% discontinuation rate because of toxicity during a median exposure duration of 24.6 months; half of the discontinuations occurred during the first 8 months of treatment.

Zanubrutinib's design reflects an effort to maximize tolerability by selectively binding BTK and limiting off-target kinase binding, Shadman and colleagues noted. A pooled safety analysis of almost 800 patients showed a 10% discontinuation rate because of toxicity. Though similar to data for acalabrutinib, substantially more patients in the zanubrutinib analysis had relapsed/refractory disease.

In clinical trials comparing zanubrutinib and ibrutinib in various hematologic malignancies, zanubrutinib consistently had lower rates of treatment discontinuation because of toxicity.

"Patients who discontinued BTK inhibitors due to treatment-related toxicities might benefit from the safety profile consistently observed for zanubrutinib across multiple studies," the authors stated.

Ongoing Trial

Shadman and colleagues reported findings from an ongoing, multicenter, phase II trial to evaluate the safety and clinical activity of zanubrutinib in patients with B-cell malignancies and intolerance to ibrutinib, acalabrutinib, or both. Data encompassed 67 patients enrolled at 20 U.S. centers, 57 with intolerance to ibrutinib and 10 with intolerance to acalabrutinib or both acalabrutinib and ibrutinib. CLL accounted for 43 of the patients, followed by Waldenström macroglobulinemia (n=11).

In the ibrutinib-intolerant group, median number of prior therapies was one as compared with three in the other group. Median time on previous BTK inhibitor therapy was 10.6 months in the ibrutinib group and 3.3 months in the ibrutinib/acalabrutinib group.

A total of 62 patients reported 115 ibrutinib intolerance events (n=38 grade 3; 4=grade 4). Ten patients reported 18 intolerance events with acalabrutinib (n=14 grade 2; n=4 grade 3), and two patients reported the same intolerance event with ibrutinib and acalabrutinib.

The most common grade ≥3 intolerance events with ibrutinib (N=62) were atrial fibrillation (11%), hypertension (10%), and fatigue (6%). The most common acalabrutinib intolerance events were arthralgia (n=4/10 patients) and myalgia (n=3).

After initiating treatment with zanubrutinib, 37 of 62 (60%) with prior ibrutinib intolerance events did not have a recurrence, accounting for 81 (70%) of the 115 total ibrutinib intolerance events. The most common were fatigue (n=5/13), arthralgia (n=4/10), rash (n=4/5), and hemorrhage (n=4/5). In 27 of 34 recurrent events, severity was lower than the original intolerance event. Of 38 grade 3 ibrutinib intolerance events, 13 (34%) recurred with zanubrutinib, and 12 of the 13 were at lower severity than the original event.

Seven of 10 acalabrutinib-treated patients did not have recurrences while on zanubrutinib, accounting for 15 of 18 (83%) acalabrutinib intolerance events.

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