Bosutinib (Bosulif) is an oral dual Src/Abl kinase inhibitor that is active against many Bcr-Abl mutations associated with imatinib (Gleevec) resistance and that has reduced activity against nonspecific molecular targets associated with toxicities reported for other second-generation kinase inhibitors. The drug was recently approved for treatment of Philadelphia chromosome–positive chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) in adult patients with resistance or intolerance to prior therapy.

The recently reported BELA trial has shown that bosutinib did not produce a better 12-month complete cytogenetic response rate compared with imatinib as first-line treatment of chronic phase CML, despite significant improvements in major molecular response rate and time to complete cytogenetic response and major molecular response. The study also showed that bosutinib was associated with a distinct safety profile.

Study Design

As reported by Cortes and colleagues in a recent Journal of Clinical Oncology article,¹ BELA was an open-label, multinational phase III trial in which 502 adults with Philadelphia chromosome–positive chronic phase CML diagnosed within the prior 6 months who had received no prior antileukemia treatment (apart from 6 months or less of anagrelide or hydroxyurea) were randomly assigned to bosutinib at 500 mg/d (n = 250) or imatinib at 400 mg/d (n = 252). An increase in dose of both agents to 600 mg/d was permitted for suboptimal response, and patients who could not tolerate a dose of 300 mg/d of either drug were discontinued from the study. The primary endpoint was complete cytogenetic response rate at 12 months.

For the bosutinib and imatinib groups, respectively, median ages were 48 and 47 years, 60% and 54% were male, 64% and 65% were white, median times since diagnosis were 23 and 22 days, and 74% and 72% had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Sokal risk was low in 35%, intermediate in 47%, and high in 18% of patients in each group. Median white blood cell counts in the bosutinib and imatinib groups were 21.7 and 23.5 × 10⁹/L, and median platelet counts were 386 and 451 × 10⁹/L.

Median duration of treatment for both groups was 13.8 months. A total of 4% of bosutinib patients and 12% of imatinib patients had their dose increased to 600 mg/d due to suboptimal efficacy. As of the data cutoff, 71% of bosutinib patients and 80% of imatinib patients continued to receive study medication.

Major Endpoints

At 12 months on intent-to-treat analysis, complete cytogenetic response rates were 70% in the bosutinib group and 68% in the imatinib group (P = .601). Median time to complete cytogenetic response was markedly reduced with bosutinib treatment (12.9 vs 24.6 weeks, P < .001), with the bosutinib group having significantly higher complete cytogenetic response rates at 3, 6, and 9 months. Cumulative complete cytogenetic response rates by 12 months were similar in the two groups (79% vs 75%).

The major molecular response rate was significantly higher with bosutinib treatment at 12 months (41% vs 27%, P < .001), as was the rate of complete molecular response (12% vs 3%, P < .001). The median time to major molecular response was significantly reduced with bosutinib treatment (37.1 vs 72.3 weeks, P < .001), and the cumulative rate of major molecular response was significantly increased (47% vs 32%, P < .001).

There were no significant differences between the bosutinib and imatinib groups in complete cytogenetic response rates at 12 months according to low (78% vs 75%), intermediate (69% vs 67%), or high (56% vs 56%) Sokal risk group. Major molecular response rate was higher with bosutinib than imatinib in the low-risk group (53% vs 28%, P < .001) and similar in the intermediate- (31% vs 24%) and high-risk (33% vs 28%) groups.

Fewer bosutinib patients had an on-treatment event-free survival event with bosutinib (4%) than with imatinib (7%) and fewer had on-treatment progression to accelerated or blast phase CML (2% vs 4%). In an analysis of event-free survival including death at any time or on-treatment progression to accelerated or blast phase, events were less common in bosutinib patients (2% vs 6%). Estimated overall survival at 12 months was greater than 99% in the bosutinib group and 97% in the imatinib group and estimated 12-month event-free survival was 94% and 93%, respectively. The study population continues to be followed to allow long-term assessment of bosutinib efficacy.

Different Safety Profiles

The most common adverse events of any grade (≥ 20%) were diarrhea, vomiting, nausea, and rash in bosutinib patients and edema, nausea, diarrhea, and muscle cramps in imatinib patients. Diarrhea (68% vs 21%), vomiting (32% vs 13%), and abdominal pain (11% vs 5%) were more common with bosutinib, whereas edema (11% vs 38%), bone pain (4% vs 10%), and muscle cramps (2% vs 20%) were more common with imatinib. Grade 3 or 4 adverse events occurred in 64% of bosutinib patients and in 48% of imatinib patients (P < .001); the most common (> 2%) were diarrhea (11%) and vomiting (3%) in bosutinib patients.

For grade 3 or 4 laboratory abnormalities, liver aminotransferase elevations were more common in bosutinib patients and neutropenia and hypophosphatemia were more common in imatinib patients. The most common grade 3 or 4 laboratory abnormalities (≥ 5%) were elevated ALT (22%), thrombocytopenia (14%), elevated AST (11%), neutropenia (11%), elevated lipase (9%), and anemia (6%) in bosutinib patients and neutropenia (24%), hypophosphatemia (15%), thrombocytopenia (14%), anemia (7%), and elevated lipase (5%) in imatinib patients. Drug-related cardiac adverse events occurred in 4% of bosutinib patients and 3% of imatinib patients.

Discontinuation of treatment due to adverse events occurred in 48 bosutinib patients (19%) vs 14 imatinib patients (6%), with 15 (31%) of the 48 bosutinib patients discontinuing treatment prior to the first post-baseline assessment at month 3. The investigators noted that these early discontinuations may have contributed to the lower rate of complete cytogenetic response in the intent-to-treat population, which included these patients as nonresponders. Treatment interruptions due to adverse events occurred in 61% of bosutinib patients vs 42% of imatinib patients, and dose reduction due to adverse events occurred in 39% vs 18%.

Four bosutinib patients died, three from CML-related causes and one from mesenteric embolism/intestinal necrosis. Ten imatinib patients died, eight from CML-related causes, one from cardiovascular disease, and one from lung embolism. None of the deaths was considered related to study treatment.

As summarized by the authors, “This ongoing trial did not meet its primary endpoint of [complete cytogenetic response] at 12 months, despite the observed higher [major molecular response] rate at 12 months, faster times to [complete cytogenetic and major molecular response], fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib…. Further follow-up is needed to provide long-term data on duration of response, transformation to accelerated/blast phase CML, and overall survival, as well as the tolerability profile of bosutinib in newly diagnosed [chronic phase] CML.” ■

Reference

1. Cortes JE, Kim D-W, Kantarjian HM, et al: Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: Results from the BELA trial. J Clin Oncol. September 4, 2012 (early release online).