Roxanne Nelson

June 15, 2011

June 15, 2011 (Chicago, Illinois) — Updated results have confirmed the efficacy of the experimental agent bosutinib (SKI-606) in the treatment of chronic myeloid leukemia (CML). At 18-month follow-up, bosutinib maintained superior rates of major molecular response (MMR) and cumulative complete molecular response, compared with the standard therapy, imatinib (Gleevec).

The results were presented here at the American Society of Clinical Oncology 2011 Annual Meeting.

What is the Optimal Choice?

Bosutinib is a third-generation tyrosine kinase inhibitor currently under development by Pfizer. It is an active dual-competitive inhibitor of the Src and Abl tyrosine kinases, with minimal activity against platelet-derived growth-factor receptor and c-KIT.

If it is approved, bosutinib will have to compete in the treatment of CML, not only against the first-generation agent imatinib, with which it has been compared in clinical trials, but also against the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel), which are both already on the market.

In a discussion during the meeting, Olatoyosi Odenike, MD, assistant professor of medicine at the University of Chicago Medical Center, Illinois, commented on this point.

What is the optimal choice for CML treatment?

"What is the optimal choice for CML treatment?," she asked. "Currently, there are 3 agents approved for frontline therapy — imatinib, nilotinib, and dasatinib. The optimal choice may depend on views of the long-term safety and efficacy of imatinib therapy."

"I believe that the long-term benefit of the second-generation tyrosine kinase inhibitors remains to be proven," she continued. "We need the data to tell us that progression-free survival and overall survival are distinctly superior."

There are other factors to consider, such as resistance, she added. "It is important to stress that the adverse-effect profiles are different, and of course there will be pharmacoeconomic issues when imatinib goes off patent," said Dr. Odenike.

Need to Identify Patients Who Will Benefit

The new data come from the Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial, a phase 3 study that is evaluating the effectiveness of bosutinib in newly diagnosed patients with chronic phase CML.

The 12-month analysis, which was presented at the 2010 annual meeting of the American Society of Hematology, and reported at that time by Medscape Medical News, failed to meet its primary end point of superior complete cytogenetic response (CCyR) at 1 year in the intent-to-treat population. However, the CCyR for bosutinib was higher than for imatinib in the evaluable population.

Now, an 18-month analysis from the study has shown that the CCyRs for bosutinib and imatinib are comparable (62% vs 67%). The new data also show that the MMR rate at 18 months was higher with bosutinib than with imatinib (46% vs 38%). These figures include patients who achieved complete molecular response (9% vs 4%). The MMR and complete molecular response rates were also higher for bosutinib at months 3, 6, 9, and 12.

The cumulative MMR rates at 18 months were 55% for bosutinib and 45% for imatinib; cumulative complete molecular response rates were 18% and 10%, respectively.

"Both the molecular remission and the cytogenetic responses are used as a proxy for more important points, such as mortality or progression of disease," explained lead author Carlo Gambacorti-Passerini, MD, professor of internal medicine and director of the clinical research unit at the University of Milano Bicocca, Italy. "We now have evidence that disease progression and mortality are impacted favorably by bosutinib, compared with imatinib."

"There is now a 4% increase in both event-free and overall survival in the bosutinib treatment group, compared with the imatinib group," he told Medscape Medical News. "That is in spite of the relatively high percentage that dropped out early because of adverse events."

The results seen at 18 months were expected. "Bosutinib produced responses faster, and therefore the tumor load is shrunk more quickly," said Dr. Gambacorti-Passerini. "The advantage is that the mass of leukemic cells from which a resistant clone can be selected is reduced."

He emphasized that the vast majority of patients are doing very well, whether they are treated with imatinib or bosutinib. "It will be important to identify in advance those patients who will do poorly with imatinib, as these patients will be the ones who will clearly benefit from bosutinib treatment," Dr. Gambacorti-Passerini explained.

He pointed out that if he was to treat all patients with bosutinib, without any selection process, not more than 4 or 5 out of 100 would benefit. "That applies to all second-generation tyrosine kinase inhibitors," he noted.

This is particularly important now that imatinib is about to come off patent, which could considerably lower the price of the drug. "From an economic standpoint, it is also important to be able to identify this group of patients," he added, "to justify the additional expense of treating with bosutinib."

Improved MMR, Similar CCyR

The BELA trial randomized 502 patients with newly diagnosed chronic phase CML to bosutinib (n = 250) or imatinib (n = 252). Baseline characteristics were well balanced between the 2 treatment groups.

The median duration of treatment was 19.3 months in the bosutinib group, compared with 19.5 in the imatinib group. Overall, bosutinib resulted in better rates of MMR than imatinib, and similar rates of CCyR.

CCyR and MMR Rates in the Intent-to-Treat Population

Months Bosutinib (%) Imatinib (%)
CCyR Rates    
3 50 25
6 59 49
9 63 55
12 70 68
18 62 67
Cumulative at 18 mo 79 79
MMR Rates    
3 7 3
6 28 11
9 35 19
12 41 27
18 46 38
Cumulative at 18 mo 55 45


The authors note that both MMR and CCyR were achieved faster in the bosutinib group than in the imatinib group, which correlates with a shorter risk period for disease transformation with bosutinib. The median time to first CCyR was 12.7 weeks with bosutinib, compared with 24.6 weeks with imatinib. The median time to first MMR was 36.9 weeks with bosutinib, compared with 72.3 weeks with imatinib.

In her discussion of the study, Dr. Odenike noted that the primary end point of this trial was CCyR, and that this was similar for both bosutinib and imatinib. However, she noted that a major molecular remission occurred faster and with a higher incidence earlier on with bosutinib than with imatinib.

Variation in Adverse Events

Fewer patients in the bosutinib group experienced treatment failure than in the with imatinib group (n = 9 vs 33; 4% vs 13%). Transformation to accelerated phase/blast phase CML was also lower in the bosutinib group than in the imatinib group (n = 4 vs 13; 5% vs 2%).

Deaths due to CML progression occurred in 5 patients in the bosutinib group and 9 in the imatinib group.

Bosutinib was associated with a higher incidence of gastrointestinal toxicities, including diarrhea, vomiting, and abdominal pain; imatinib was associated with a higher incidence of edema and musculoskeletal events. The most common adverse events were generally grade 1/2 in severity. Grade 3/4 diarrhea and vomiting were reported by more than 2% of patients in the bosutinib group, although diarrhea typically occurred during the initial month of treatment, and the majority of events resolved.

There were fewer cases of grade 3/4 neutropenia in the bosutinib group (11% vs 24%), and the incidences of grade 3/4 anemia and thrombocytopenia were similar between the 2 groups.

The study was sponsored by Pfizer. Dr. Gambacorti-Passerini reports receiving research funding from Pfizer. Dr. Odenike reports financial relationships with Amgen, Cephalon, Genzyme, Incyte, MGI Pharma, Celgene, TopoTarget, and Gloucester Pharmaceuticals.

American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting: Abstract 6509. Presented June 3, 2011.

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