Pfizer's bosutinib fails to meet primary endpoint in Phase III study for chronic myeloid leukemia

However, Pfizer remains positive about drug as the data demonstrate early and meaningful response to bosutinib in patients with newly diagnosed chronic myeloid leukemia

Jeffrey Bouley
NEW YORK—It's good news/bad news for Pfizer as Phase III data emerge for investigational compound bosutinib that fail to reach the study's primary endpoint, but do point to some valuable characteristics of the drug nonetheless.

On Dec. 6, Pfizer announced that a significantly higher proportion of patients with newly diagnosed chronic myeloid leukemia (CML) who were treated with bosutinib (39 percent) experienced a major molecular response (MMR), a secondary endpoint, compared with patients treated with imatinib (26 percent) in the intent-to-treat (ITT) population.

However, the study failed to meet its primary endpoint of superior complete cytogenetic response (CCyR) rate at one year versus imatinib (70 percent vs. 68 percent, respectively,), in the ITT population.

Both sets of results come out of a Phase III study of bosutinib —the Bosutinib Efficacy and safety in chronic myeloid LeukemiA study, or BELA—as a first-line treatment in patients with Philadelphia chromosome positive (Ph+) CML, called.

Preliminary data show that fewer patients who took bosutinib progressed to an advanced phase of the disease (1.6 percent) compared to patients treated with imatinib (4 percent), and there were fewer deaths in the bosutinib arm (1.2 percent) than in the imatinib arm (3.2 percent). Patients responding to bosutinib achieved CCyR faster than those responding to imatinib (13 weeks vs. 25 weeks).

A pre-specified exploratory analysis also showed that bosutinib produced a higher rate of CCyR at one year compared to imatinib when CCyR was assessed only in the evaluable patient population (78 percent with bosutinib compared to 69 percent with imatinib). The evaluable population was different from the ITT population in that it included only those patients who received follow-up assessments for efficacy.

The most frequently reported all-grade drug-related adverse events with bosutinib were diarrhea (66 percent), nausea (27 percent), vomiting (25 percent), and rash (18 percent). The most frequent grade 3/4 adverse events with bosutinib included diarrhea (8 percent) and rash (2 percent), although no patients on the bosutinib arm discontinued therapy due to diarrhea. Gastrointestinal events associated with bosutinib had an early onset and usually subsided within the first four weeks of treatment. Most frequent grade 3/4 laboratory abnormalities with bosutinib included elevated ALT (21 percent), elevated AST (10 percent), and thrombocytopenia (7 percent).

More patients on bosutinib experienced serious adverse events (25.4 percent vs. 13.5 percent) and adverse events leading to discontinuation (19.4 percent vs. 5.6 percent) than on imatinib. Adverse events leading to discontinuation were most frequently due to liver enzyme elevations in the bosutinib arm and neutropenia in the imatinib arm. There were no deaths in the study due to treatment-related adverse events. The majority of patients on both treatment arms continued on study treatment after a median follow-up of 14 months.

"We are encouraged by these data, as they demonstrate early and meaningful response to bosutinib in patients with newly diagnosed CML," says Dr. Carlo Gambacorti-Passerini, professor of internal medicine and director, clinical research unit for the University of Milano—Bicocca, and the San Gerardo Hospital in Monza, Italy, who was a lead investigator of the BELA study. "Given the length of time these patients are treated for CML, we need more therapeutic options to choose from since each patient is different and has different needs. Based on my experience with bosutinib, I feel it would be an important option for patients with CML."

The BELA study is a global, open label, multicenter trial of 502 adult patients randomized to receive either bosutinib or imatinib. Although closed to enrollment, the study remains ongoing, and patients will continue to be followed for safety and efficacy outcomes. Bosutinib is also being studied as a single agent in patients with previously treated chronic phase CML in an ongoing clinical trial with over 500 patients, known as Study 200.

"Based on the totality of evidence from the bosutinib clinical development program, we are actively engaged in discussions with regulatory authorities which we hope will enable Pfizer to offer a new treatment option for patients with CML," says Dr. Mace Rothenberg, senior vice president of clinical development and medical affairs for Pfizer's Oncology Business Unit.

Bosutinib is an investigational oral dual Src and Abl kinase inhibitor. Researchers have posited that by dual inhibition of the Src and Abl tyrosine kinases, bosutinib may inhibit signaling in CML cells that allows the cells to grow, survive and reproduce. CML is one of the four main types of leukemia and accounts for 15 percent of all leukemias worldwide.


Jeffrey Bouley

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