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Hello, my name is Jorge Cortes, from the Department of Leukemia at MD Anderson Cancer Center in Houston. I'm here at the ASCO Meeting 2017 in Chicago. And, I'm presenting a study on a randomized trial conducted, multi-center, multi-national of patients with newly diagnosed CML, randomized to receive either bosutinib or imatinib. And, this is on behalf of my colleagues that participated in this trial. As you know, bosutinib is a very potent tyrosine kinase inhibitor. It's very active against ABL. Although it does not have any activity against c-kit or PDGF receptor.
And the drug has demonstrated clinical activity, and it's actually approved in many parts of the world for patients with CML in all stages of the disease that have received prior therapy. And, there was a prior randomized study comparing it to imatinib for front line setting. And, although the primary endpoint was not met, the primary endpoint being complete cytogenetic response in that study. All of the other efficacy end-points were met. And, it showed earlier responses and deeper responses and fewer transformations.
The objective of this study was to further assess the efficacy and the safety of bosutinib in this setting of newly diagnosed patients with chronic myeloid leukemia in the chronic phase.
The design of this study is very similar to these other prior studies. That study was called the BELA trial, this one we call the BFORE trial. There are two primary differences between this study and the prior study. The first one is the dose of bosutinib that was used. Here, we're using 400 mg daily. The dose that is approved for the salvage setting is 500 mg daily. The other important difference is the primary endpoint. Here, we focused on major molecular response at 12 months. And, this is in keeping with our modern approach to CML, where we focus more on these deeper responses. So, patients were randomized 1:1 to receive bosutinib, 400 mg daily or imatinib, 400 mg daily. A total of 536 patients were randomized with 268 each on these arms. There are a number of secondary endpoints that have to do with efficacy and safety. And, they're all the usual end-points for this disease.
The populations were very well balanced. This is a median age of a little over 50 years. This is a little older than other studies that have been done in this setting. Randomized studies of imatinib versus other drugs. There's about a 20% of the population that have high-risk Sokal scores. And, other than that, this is a very typical population for this setting.
The primary end-point in this study was met. The rate of major molecular response at 12 months was 47% for the patients that received bosutinib as initial therapy. Compared to 37% for the patients that received imatinib. That difference is statistically significant. The odds ratio is 1.55. So, this was clearly better for patients receiving bosutinib. Importantly, this is true in all Sokal risk groups. There was a benefit in the low, in the intermediate, and in the high-risk.
And, it is also very important that these molecular responses at 3 months that we care too much about, less than 10% transcripts. It was also significantly better for the patients that received bosutinib. We had 75% of patients achieving these results, compared to 57% of patients treated with imatinib.
The complete cytogenetic response by 12 months, although this time it was a secondary endpoint, it is important to emphasize that this end-point was also met in this study. So, we have 77% of patients in the bosutinib arm, compared to 66% patients on the imatinib arm.
Here, you can see that there is, over time, as we assess the responses at three and six and nine and 12 months, there is a significant benefit in favor of bosutinib. Not only for the major molecular responses, but you can see that there is numerical difference in favor of the deeper responses. The MR4 and the MR4.5s. And, by 12 months, we already see that these differences become statistically significant. So, for example, the MR4s, we have 21% of patients at 12 months on bosutinib having this response, compared to only 12% in the imatinib arm.
This is too early to assess formally event-free survival, but the number of events, the cumulative incidents of events that define event-free survival has been lower for the patients receiving bosutinib, 3.7%, compared to the patient receiving imatinib, where 6.4% of these patients have already had an event.
The overall survival, again, is still, the follow up is short. And, as you can expect, the survival is good for both arms. It is 99.6% for the bosutinib treated patients and 97.9 for the imatinib-treated patients. There have been 1 death in the bosutinib arm, and 6 deaths in the imatinib arm trial.
There have been fewer transformations to accelerated and blast phase in the bosutinib arm. There's few in both arms, but fewer in the bosutinib arm, with 4 of them in bosutinib, 6 in imatinib, and most of these transformations have been to accelerated phase.
The safety profile is kind of expected for the two drugs. We know that diarrhea occurs frequently with bosutinib. 70% of patients had diarrhea. But, fortunately, very few of these were Grade 3 or 4. And, the lower dose helped minimize this. But very few patients discontinued therapy because of diarrhea. Two on each one of the two arms. We also know that liver toxicity, particularly elevation of transaminase was higher with the bosutinib. These were again, overwhelmingly Grade 1 or Grade 2. Few were Grade 3 and very few of these patients discontinued therapy because of liver toxicity. Most of these were transient and there were no associations with elevation of bilirubin. On the other hand, with imatinib, we see more muscular-skeletal symptoms and periorbital edema than we see with bosutinib.
So, in conclusion, this study demonstrates a significant benefit for bosutinib compared to imatinib as initial therapy for CML. The primary endpoint was met with a significantly higher rate of major molecular response at 12 months. In addition, other end-points such as the rate of complete cytogenetic response by 12 months was also significantly better. The responses are earlier with bosutinib, they are deeper. They are fewer transformations, and importantly, the safety profile is very manageable with bosutinib, with the most common toxicities being diarrhea and liver toxicity. But, most frequently Grade 1 and Grade 2, transient manageable and very seldom leading to treatment discontinuation. So, I think what these results show is that bosutinib may become a new and welcome treatment option for patients with newly diagnosed CML in the chronic phase. So, this ends my presentation and I thank you for your attention.