Case 2: CPX-351 Trial Data in AML


Naval G. Daver, MD:We’ll stop the discussion here and look at some of the data. Dr Rizzieri, if you could walk us through, please?

David Alan Rizzieri, MD:Sure. You had brought up the issue of CPX-351, so let’s look at that with our audience members in a little bit more detail.

This is a cytarabine/daunorubicin liposome using a nanoscale delivery complex. You see the picture of the liposome noted here where it’s a 100 nm bilamellar liposome. It’s a 5-to-1 molar ratio of cytarabine and daunorubicin, which in preclinical work was felt to be the synergistic ratio. The neat thing with this delivery mechanism is to take advantage of a ratio that is felt to be most synergistic in such a patient and also potentially increase the delivery of the agent to the area of concern, primarily the bone marrow.

You see that 1 unit of CPX-351 is equivalent to 1 mg of cytarabine and .4 mg of daunorubicin. We see the phase I data here, where the ratio was maintained for 24 hours. After the final dose, the drug exposure was maintained for a week, and with that, we found potent anti-leukemia efficacy and it was well-tolerated. That’s what led to the phase III study, as indicated here.

This is a phase III prospective randomized study of CPX-351 versus standard induction in older patients with newly diagnosed high-risk secondary AML [acute myeloid leukemia]. We do use a term secondary here, even though it’s been stricken from the current WHO [World Health Organization] classification, because at the time this study was conducted, that was still in our vernacular. The primary eligibility was to have patients who were previously untreated for AML, 60 to 75 years of age, and able to tolerate intensive chemotherapy.

Patients were stratified between those who had prior therapy-related AML, AML with a history of MDS [myelodysplastic syndrome] with or without prior HMA [hypomethylating agent] therapy, patients with AML with a history of CMML [chronic myelomonocytic leukemia], and de novo AML patients with MDS karyotype.

There was also an age stratification of 60 to 69 years of age, and 70 to 75. You see that patients could receive up to 2 cycles of induction, those with a remission then went on to receive consolidation therapy, and the primary endpoint was overall survival. You see the dosing as noted here for first induction and reinduction, and fairly standard dosing for 7+3 [cytarabine/daunorubicin], as well.

If we move on to the baseline characteristics, I’ll give you a second to look at that, but they are primarily very similar populations, and similar groups of patients by age range and performance status. If you look under the clinical characteristics, we may want to look at those with antecedent MDS with or without prior HMA therapy. This is a group that’s of some concern to many of us, and you can see that they were fairly well-balanced. Some had theFLT3mutation, and a little bit more withFLT3positivity in the CPX-351 arm, which is that high-risk group we’ve talked about before. Breakdown by white count and platelet count were similar, as well.

The overall response, noted in the next slide, was really encouraging. You see based on CR [complete remission] or Cri [complete remission with incomplete blood count recovery], that incomplete responding group, 37% to 47.7% CR or CRi rate in the CPX-351 group, versus 25.6% to 33.3% in the 7+3 [cytarabine/daunorubicin] group. That’s encouraging, but I think the other key here is, is it tolerable? We talked about these patients being primarily older. They may be more infirmed, and you can see in the next slide the early mortality rates—6% and 11%, respectively, at day 30, and 14% and 21% by day 60.

If we move to the meat of the primary endpoint—survival—in the next slide here, we can see patients with CPX-351 have a median survival of 9.56 months versus 5.95 months in those receiving 7+3 [cytarabine/daunorubicin]. That’s a statistically significant difference at .005. Importantly, when you look at those curves and the difference, I think that’s a clinically meaningful difference for our patients, as well.

Now, if you look at a Kaplan-Meier curve for overall survival and for those landmarked at the point of stem cell transplant, ITT [intention-to-treat] analysis population is noted here. The median survival of CPX-351 patients was not reached, and for those with 7+3 [cytarabine/daunorubicin], was 10.25 months, also with a clinically and statistically significant difference. This is as presented by Jeff Lancet [MD] at ASCO [the American Society of Clinical Oncology meeting] a couple of years ago.

Here’s a phase III prospective randomized study showing a survival difference, and I think we have very few of those in our specific field, so that’s very encouraging, but what cost does it come at? What are the [adverse] effects and toxicity? The next slide shows the febrile neutropenia, fatigue, pneumonia, bacteremia and sepsis issues that we follow. I think it’s very comparable in these objective measures for [adverse] effects in these 2 groups.

If we move to the next slide, in terms of count recovery, this is one of main differences that we’ve all noticed as we roll out CPX-351. It takes about an extra week to recover your counts. We really want to preach patience for these patients. Notably, if you’re used to doing a nadir marrow at day 14, you probably want to delay that as we did on study to day 21 or so. These patients will recover, but it’s just about a week delayed.

The conclusion from the phase III study of CPX-351 versus 7+3 [cytarabine/daunorubicin] is that older patients with high-risk secondary AML have longer overall survivals with CPX-351 than 7+3 [cytarabine/daunorubicin], and longer overall survival when even landmarked from patients undergoing transplant.

The post hoc analysis showed a greater proportion of patients with CPX-351 achieving a CR or CRi, that’s 47% versus 36%, and more of those patients underwent transplant. Patients receiving consolidation following successful induction also had longer survival with CPX-351 versus 7+3 [cytarabine/daunorubicin].

The last 2 slides of this looked at the safety of combination. It’s a fairly busy slide, and I’ll give you a minute to look at that. There really isn’t anything, when you look at all grades of toxicity, that jumps out at me as different in this particular presentation. I’ll be interested in my colleagues’ views of this, because all of us have a sense from treating a lot of these patients that it is better-tolerated. We’re talking about a lot more outpatient home therapy and, not for nothing, my patients love not losing their hair. Maybe that’s why they feel better when they look in the mirror, and that’s not a bad thing.

Transcript edited for clarity.

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