ORLANDO – Despite missing its primary end point for complete cytogenetic response, a phase III trial suggests that the novel agent bosutinib has comparable efficacy to other drugs that were approved for first-line use in newly diagnosed chronic-phase chronic myeloid leukemia.
Dr. Carlo Gambacorti-Passerini
For most outcomes, bosutinib outperformed imatinib (Gleevec) in the multinational BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial reported by Dr. Carlo Gambacorti-Passerini at the annual meeting of the American Society of Hematology.
[Check out our comprehensive coverage of the American Society of Hematology's annual meeting.]
"Bosutinib may offer a new therapeutic option for patients with Philadelphia chromosome–positive CML," he concluded, after presenting mixed results from the open-label study sponsored by Pfizer Inc. The trial randomized 250 newly diagnosed patients to 500 mg/day of bosutinib and 252 patients to 400 mg/day of imatinib.
At 12 months, the major molecular response rate was superior with bosutinib (39%) compared with 26% with imatinib (P = .002) in an intent-to-treat analysis by Dr. Gambacorti-Passerini, professor of internal medicine and director of the clinical research unit in hematology at the University of Milan-Bicocca in Monza, Italy.
Treatment-failure rates were lower with bosutinib (3% vs. 10%), as were the rates of transformation to resulting from CML progression (1% vs. 3%).
The complete cytogenetic response rate was only slightly higher at 70% vs. 68%, however, and the difference did not reach statistical significance – a shortcoming Dr. Gambacorti-Passerini suggested may have been the result of 8%-9% of patients on bosutinib going off treatment before the first assessment.
What distinguished bosutinib from other tyrosine kinase inhibitors (TKIs) was its toxicity profile. GI side effects were more common, although not serious, and adverse events were the leading cause of treatment discontinuation, accounting for 19% in the experimental arm.
Dr. Gambacorti-Passerini attributed the discontinuations to most participating physicians’ unfamiliarity with bosutinib. Unlike imatinib and other approved TKIs, such as dasatinib (Sprycel) and nilotinib (Tasigna), bosutinib has not previously been used outside of clinical trials.
"I think we are paying ... the price of this relative lack of familiarity with the drug," he said, suggesting in an interview that at least part of the observed toxicity was because of poor management of side effects. "Patients in centers that had no previous experience with the novel drug had a 30% higher probability of dropping a patient for adverse events."
Paradoxically, bosutinib has a mild toxicity profile that is also different from those of the approved drugs, according to Dr. Gambacorti-Passerini. Patients in the experimental arm had significantly more diarrhea (68% of patients on bosutinib experienced this toxicity), vomiting, pyrexia, upper abdominal pain, and abdominal pain than did those in the imatinib arm. In contrast, patients on imatinib had significantly more bone pain, muscle cramps, and periorbital edema.
Except for diarrhea in patients who were treated with bosutinib, grade 3/4 events were uncommon. The median duration of diarrhea was 30 days, he noted, and no one dropped out as result. Moreover, more serious side effects such as arrhythmia and pleural effusions were not seen. Compared with imatinib, bosutinib was associated with less neutropenia and more transaminase elevation, but no liver injury was seen.
"I think the safety profile is the safest" among the second-generation TKIs, he said.
The toxicity profile "may or may not be a problem," according to session moderator Dr. Kimmo Porkka, a professor of hematology at Helsinki University. "We need to really learn to manage the different toxicities with these different agents. ... The toxicity profile may help determine which we will end up using," he said, noting the bosutinib seems similar in efficacy to the approved drugs.
Dr. Mark Shapiro, a hematology team leader with Pfizer, said that the company plans to apply for first-line approval in Europe based on the BELA trial and for second- and third-line approval in the United States based on phase II trials.