Outcomes in patients with therapy-Related AML who achieved remission with CPX-351 versus 7 plus 3: Phase 3 exploratory analysis

Dr Jeffrey Lancet - H. Lee Moffitt Cancer Center & Research Institute, Tampa, USA

There have been a couple of important updates with regard to CPX-351 at the ASH 2019 Annual Meeting. First off, CPX-351 is a novel liposomal formula that combines both cytarabine and daunorubicin at a fixed molar concentration ratio of 5:1 which is synergistic. It incorporates this concentration of both drugs into the same liposome allowing for much more efficient drug delivery of a synergistic drug combination. This particular compound has been studied extensively and most recently in a large phase III randomised trial in primarily older adults with secondary AML which demonstrated a survival advantage with CPX-351 compared to conventional 7 3 in this phase III trial. So that was the trial that led to the eventual FDA approval of CPX-351 for all patients with secondary or high risk AML.

Within the context of the phase III study we did a subgroup analysis of the group known as having therapy related AML. Therapy related AML is a difficult to treat type of secondary AML frequently associated with prior chemotherapy exposure for previous cancers – radiation therapy, immunotherapy. These are notoriously difficult to treat and associated with very poor outcomes, many times associated with a p53 mutation and other adverse markers.
So we wanted to assess whether this very high risk subgroup within the already high risk subgroup of the overall population also benefitted from the CPX-351 drug. So that was the purpose of this abstract and this presentation. What we found in this subset of patients was that the remission rates appeared to be somewhat higher for CPX compared to 7 3 amongst the patients who had therapy related AML in the study. Amongst the overall population of patients with therapy related AML who entered remission in both the 7 3 and the CPX group, the overall survival was clearly better with CPX. The median overall survival for that group of patients was not yet reached. So the numbers are relatively small because we’re talking about a subgroup of a subgroup, those patients that were already in remission, but those patients who achieved remission with therapy related AML seemed to have very good outcomes.

We also found that similar to the phase III overall population of patients the therapy related AML patients who were in remission who then went on to allogeneic transplant had a longer survival post-transplant in remission than those patients who were in remission with treatment that utilised 7 3, again in the therapy related AML subgroup.

So overall we found that the efficacy of CPX-351 in the therapy related AML subgroup held up; the benefit of CPX in this group held up similar to the way it performed in the overall population of patients so it was good to see that this high risk subgroup seemed to benefit proportionally as the rest of the overall group did.

The second important update with respect to the CPX-351 phase III clinical trial was a read-out of some of the baseline genetic characteristics of these patients that could predict for outcome to CPX-351 versus 7 3. There has been a lot of interest, of course, over the past few years in exploring genetic predictors of response to treatment so it’s no different for CPX-351. So we were able to gather the data, the pre-treatment data, for a high number of patients on this trial and looked at their next generation sequencing panel to identify mutations that were present and whether these mutations were associated with a differential response to either CPX or 7 3. What we found was that first off in the TP53 mutated AML patients there was no real difference in outcomes between 7 3 or CPX, not too surprising given the inherently resistant nature of TP53 mutated leukaemia.

However, in some of the other genetic subgroups such as the DNMT3A mutant subgroups, the TET2 mutant subgroups and the subgroups that contain what we call secondary-like mutations, these are mutations that are often seen in MDS that precedes AML. So in patients with these types of mutations that I’ve just mentioned there was clearly an overall survival advantage favouring CPX compared to 7 3 amongst the non-TP53 mutant genetic groups in general. So we learned a lot about the fact that these high risk genetic groups often associated with secondary AML to begin with are responsive to CPX-351 whereas the TP53 mutant are probably not and should be probably considered for other alternative and novel therapies. But the CPX-351 performed well within the genetic subgroups that I just mentioned.

So what we still need to learn more about is how deep these remissions are that are achieved in these types of patients with secondary-like or DNMT3 or TET2 mutations to understand how and why the CPX is performing better in these groups. Is it because you are achieving a better state of measurable residual disease? That’s the most likely explanation but those are data that still need to be validated.

Is genomic testing standard in these patients, or does that need to be approved?

Genomic baseline genetic and sequencing data are routinely performed now for AML patients in most centres and can be obtained within a matter of days to a couple of weeks. A lot of prognostic information can be gained from these panels and can often inform the treatment decisions moving forwards, so yes.