Harry P. Erba, MD: Let’s move on, then, and talk about the approval of the second-generation ABL TKIs in the newly diagnosed CML chronic phase patient. And there have been 4 trials, but 3 major trials have led to the approval—ENESTnd for nilotinib, DASISION for dasatinib, and the BFORE trial following the BELA trial for bosutinib. I’m going to start with ENESTnd, and that was a trial in chronic phase CML. About 280 patients in each arm were randomized between imatinib at 400 mg—you could argue about that as the baseline—or 2 doses of nilotinib at 300 twice daily, or the then-approved dose in the resistant and intolerant setting, 400 mg twice daily.

The primary endpoint in the study was major molecular response at 12 months, and it was statistically significant, 44% with nilotinib, 22% with imatinib. The other thing is we now have 5 years of update and 5 years of follow-up. And that study continues in follow-up for 10 years. What have we learned? We’ve learned that the rates of progression are lower with nilotinib than imatinib, especially again in the first year. We’ve learned that there’s no statistically significant difference in survival, but if you look at CML-related deaths, there was clearly a decrease in the number of CML-related deaths that was not offset completely by other non-CML-related deaths, including cardiovascular deaths.

We also found that with the second-generation drug, nilotinib at 300 mg twice daily, by 5 years, 54% or 55% of patients had an MR4.5 compared with 33% with imatinib. So, there were deeper responses at 5 years. But even in terms of my initial goal of therapy, which is to prevent progression, I think we do that by achieving a higher rate of MMR and also a higher rate of CCYR at 1 year, 80% versus 65%, nilotinib to imatinib. You also achieved higher rates of 3-month response: 91% with nilotinib achieved a BCR/ABL ratio of less than 10%, and it was 67% with imatinib. So, all these efficacy endpoints favored nilotinib. And in terms of discontinuations, they were similar because of adverse events, but there were actually fewer discontinuations on the nilotinib arm than imatinib because of a combination of efficacy and toxicity. In terms of preventing progression, that’s important. Now we have 5-year data saying that if we’re going to start thinking about treatment-free remissions, around half the patients got to that 4.5 and at least might be candidates for treatment-free remission. Let’s move on to the data for dasatinib in the DASISION trial.

Michael Mauro, MD: Pretty similar. Pretty good number of patients, over 500, randomized between imatinib and dasatinib. Same question, looking at major molecular remission, 5 years of follow-up. I think we had the similar conclusions. There were over 5 years of data. There were clearly more major molecular remissions, more deeper molecular remissions. There is some protection against progression. The race for cytogenetic response was equalized a little bit sooner in the DASISION trial. I think what’s most important is those advantages, when you look at the other important issues—being able to stay on drug, having adverse events, progression to overall survival—and the survival is similar across the study.

The new side effects that came through in DASISION were not surprising. Pleural effusions were noted as a new primary toxicity with dasatinib, although fortunately those aren’t limiting in most patients. I think it, again, shows the value of starting with a second-generation TKI with a good safety profile, with a specific side effect or a specific adverse event you needed to look out for, and the ability to hit all the buttons to achieve a deeper and faster molecular response to have some protection against progression—again, maybe not as clear as some of the other data. I’m intrigued by the fact that with dasatinib, like the other TKIs, we continue to look at the dose. I think there are recently published studies looking at even lower doses of dasatinib, which could even offer better risk-benefit ratios. So the story continues.

Harry P. Erba, MD: Yes. Before I move on to bosutinib, I did forget a very important long-term toxicity that came out in the ENESTnd trial, and that’s cardiovascular events. I believe the second-generation drugs in general have a higher risk of cardiovascular events, and whether that’s because imatinib is protective or second-generation drugs have a higher risk, I’m not certain. But in any case, about 9% of these events occurred on the nilotinib arm and 3% on the imatinib. Bosutinib and the BFORE trial were just presented at the ASCO meeting.

Jorge E. Cortes, MD: Yes. So, we just presented, at ASCO 2018, the 24-month follow-up. You mentioned there were 4 studies because there are 2 studies that have been done with bosutinib. I’ll briefly mention them because I think there’s some value there. The earlier study, which was the BELA trial, was randomized—the same design you had mentioned for the other studies, bosutinib versus imatinib. In that study, the dose of bosutinib was 500 mg, which is a standard dose for salvage setting, second-line setting. And that study and the primary endpoint was complete cytogenetic response at 12 months, which was not met. Everything else was met—major molecular response, transformation rate. All these other secondary efficacy endpoints were met but not the primary endpoint.

Part of the problem was the treatment discontinuation started early on. So, the subsequent study, the BFORE study, which is the recent one and the one that led to the approval, had 2 major changes. One was the dose of bosutinib, 400 mg daily, and the other one was a primary endpoint, major molecular response at 12 months. And that was met. That was presented at ASCO 2017. The drug was approved in December 2017, and we presented a 12-month follow-up. So, this is an earlier study. We have only 24 months, but the differences remain, as you would expect, 61% versus 51% rate of major molecular response. There’s a trend for fewer transformations in the bosutinib arm as well. So, I think it follows the same trend, and they find that there is a benefit in terms of earlier, deeper responses with the second generation.

For the toxicity profile with bosutinib, there are things to keep in mind. Diarrhea is very common but usually mild. About 80% of patients are going to have diarrhea, but it’s usually grade 1, grade 2. It is extremely rare that you have to discontinue therapy because of diarrhea. It’s very highly manageable, although most patients don’t even need management like medical intervention. The other toxicity to keep an eye on is liver toxicity. There is some elevation of transaminases, usually manageable with adjusting doses and that kind of thing. Few patients again have to discontinue therapy because of liver toxicity. There seems to be a bit less cardiovascular toxicity with bosutinib. The follow-up in this study is short with the BELA. There was about an equal incidence compared with imatinib. We’ll have to follow this study further.

Transcript Edited for Clarity