Bosutinib: A Fourth Drug for Chronic Myeloid Leukemia

Roxanne Nelson

December 15, 2010

December 15, 2010 — (Orlando, Florida) — The investigational agent bosutinib has shown efficacy in the second- and third-line setting in the treatment of chronic myeloid leukemia (CML), but its role as a first-line option needs further study, according to data presented here at American Society of Hematology (ASH) 52nd Annual Meeting.

When bosutinib was tested as second- and third-line treatment in patients with Philadelphia-chromosome-positive chronic-phase CML, approximately a third of patients achieved a major cytogenetic response, with an acceptable safety profile.

But in a second study, in which bosutinib was used as a first-line therapy, it failed to meet its primary end point of superior complete cytogenetic response (CCyR) at 1 year, compared with imatinib (Gleevec).

In the intent-to-treat population, the rates were 70% for bosutinib and 68% for imatinib (P = .601). However, the CCyR for bosutinib was higher than for imatinib in the evaluable population, explained lead author Carlo Gambacorti-Passerini, MD, professor of internal medicine and director of the clinical research unit, University of Milano Bicocca, San Gerardo Hospital, Monza, Italy.

"Bosutinib treatment was able to also achieve a superior rate of [major molecular response] at 12 months," said Dr. Gambacorti-Passerini, adding that this was true for both the intent-to-treat and evaluable populations.

"Patients on bosutinib also had lower rates of transformation to accelerated or blast phase, lower rates of treatment failure, and lower rates of deaths due to CML progression," he told meeting attendees during his presentation.

Effective as Second or Third Line

Bosutinib is a third-generation tyrosine kinase inhibitor currently under development by Pfizer. At the American Society of Clinical Oncology (ASCO) annual meeting earlier this year, data were presented demonstrating bosutinib's efficacy in CML patients with either imatinib resistance or intolerance.

Two other studies of bosutinib were presented at the ASCO annual meeting. In one, bosutinib was found to be effective and well tolerated as a third-line agent in patients with chronic-phase CML who had failed both first-line imatinib and second-line dasatinib (Sprycel). The other, which evaluated bosutinib as second-line therapy in patients with accelerated-phase CML, blast-phase CML, or Philadelphia-chromosome-positive acute lymphoblastic leukemia, found that the agent was well tolerated and that responses were observed across a wide range of BCR-ABL mutations.

Meir Wetzler, MD, chief of the leukemia section at Roswell Park Cancer Institute in Buffalo, New York, told Medscape Medical News at that time that he believed it would be beneficial to have bosutinib approved for a first-line indication to give patients more therapeutic options.

The data are very impressive for second- and third-line therapy, said Dr. Wetzler. "If bosutinib is approved, we will have 4 different drugs to choose from" (imatinib, nilotinib, and dasatinib are already approved for use in CML).

New Studies at ASH

The first of the new studies presented at the ASH meeting was an open-label phase 1/2 trial that evaluated the safety and efficacy of bosutinib as third-line therapy in chronic-phase CML patients. "The patients in this trial had failed high-dose imatinib therapy (at 600 mg or higher)," said lead author Hanna J. Khoury, MD, from the Winship Cancer Institute of Emory University, Atlanta, Georgia. "The patients were also resistant or intolerant to more than 100 mg/day of dasatinib, and were resistant to nilotinib."

The cohort consisted of 114 adults with chronic-phase CML who had all failed treatment with imatinib and were resistant (n = 35) or intolerant (n = 51) to dasatinib, or were resistant to nilotinib (n = 28). The median time from CML diagnosis to the start of bosutinib was 7.3 years (range, 1.2 to 17.6), and the median daily dose of bosutinib was 446 mg (range, 140 to 563).

At week 24, 26% of patients achieved a major cytogenetic response. Of this group, 13% had a CCyR. The cumulative response rates were 34% for a major cytogenetic response and 22% for a CCyR, and 81% who achieved a major cytogenetic response retained it at a median follow-up of 23 months.

The median duration of major cytogenetic response was 37 weeks (range, 6 to 185). The authors note that there were comparable rates of response across BCR-ABL kinase domain mutations, except for the T315I mutation.

Adverse events were similar to those previously observed. The most commonly reported adverse events (all grades) were diarrhea (83%), nausea (45%), vomiting (36%), rash (26%), headache (25%), and fatigue (22%); the incidence was generally similar for those with dasatinib resistance or intolerance and those with nilotinib resistance. Grade 3/4 hematologic effects included thrombocytopenia (23%), neutropenia (16%), and anemia (8%), but all were usually transient.

Ready for First Line?

In the second study reported at ASH, Dr. Gambacorti-Passerini and colleagues compared the activity and safety of bosutinib with that of imatinib in newly diagnosed patients with chronic-phase CML in an ongoing randomized phase 3 study. The cohort consisted of 502 patients who received treatment at 139 sites in 31 countries.

The patients were randomized to received either bosutinib 500 mg/day (n = 250) or imatinib 400 mg/day (n = 252). The primary end point was CCyR at 12 months. Secondary end points included major molecular response rate at 12 months, duration of CCyR, complete hematologic response, time to and rate of transformation to accelerated or blast phase, safety, and tolerability.

Median follow-up time was 16 months, and median duration of treatment was 13.9 months.

During the study, 81.4% of patients achieved a CCyR at or before week 48 (median time to CCyR, 24 weeks) and 82.6% achieved a complete hematologic response (median time, 8 weeks). For the 2 treatment groups, 40.6% of patients achieved a major molecular response at a median time of 49 to 61 weeks.

In the intent-to-treat population, CCyR rates were similar between the 2 groups. However, CCyR was superior with bosutinib in the evaluable group (78% vs 68%; P = .026). Rates for major molecular response were also higher with bosutinib for both the evaluable (43% vs 27%; P < .0001) and the intent-to-treat (39% vs 26%; P = .002) populations.

Dr. Gambacorti-Passerini pointed out that the median time to CCyR and major molecular response was considerably shorter for patients in the bosutinib group.

Time to CCyR and Major Molecular Response (MMR) in the Intent-to-Treat Population (P < .0001 for Both)

Time Bosutinib, weeks (range) Imatinib, weeks (range)
To CCyR 12.9 (12.6-13.4) 24.6 (24.3-25.6)
To MMR 37.1 (36.1-48.3 72.3 (61.1-NA)

A higher percentage of patients in the bosutinib group discontinued treatment because of adverse events (19% vs 6%). For both groups, the most common adverse events were diarrhea (43.7%), nausea (32.3%), vomiting (22.0%), rash (16.8%), pyrexia (11.6%), and fatigue (11.0%). Grade 3 hematologic events included neutropenia (14.2%), thrombocytopenia (12.4%), and anemia (5.8%).

Gastrointestinal events, such as diarrhea and vomiting, were more common in the bosutinib group, whereas bone pain and muscle cramps were more common in the imatinib group.

Moving Toward Approval

Based on the results of these studies, Pfizer is moving ahead and seeking approval for bosutinib in the United States and in Europe. They recently announced that they have begun the process of preparing a Marketing Authorization Application for submission to the European Medicine Agency. The indication will be for the treatment of patients with newly diagnosed Philadelphia-chromosome-positive CML.

In the United States, Pfizer has had discussions with the US Food and Drug Administration about a possible regulatory submission for the use of bosutinib in the treatment of previously treated Philadelphia-chromosome-positive CML patients.

Dr. Khoury reports receiving honoraria from Bristol-Myers Squibb and Novartis; coauthors report relationships with BMS, Pfizer, and Novartis. Dr. Gambacorti-Passerini reports receiving research funding from Pfizer; coauthors report relationships with Bristol-Myers Squibb, Novartis, Pfizer, Celgene, and Janssen-Cilag.

American Society of Hematology (ASH) 52nd Annual Meeting. Abstracts 892 and 208. Presented December 6 and 7, 2010.


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