Panelists: Harry Erba, MD, PhD, Duke Cancer Institute; Naval Daver, MD, The University of Texas MD Anderson Cancer Center; Rami Komrokji, MD, H. Lee Moffitt Cancer Center; Mark Levis, MD, PhD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center; Dan Pollyea, MD, MS, University of Colorado Cancer Center
Harry Erba, MD, PhD: There are other drugs being developed for TP53, not so much in AML [acute myeloid leukemia] yet, but APR-246.
Rami Komrokji, MD: Right, absolutely. It does include a group of patients with AML, particularly the oligoleukemic. APR-246 is a drug that binds to mutant TP53, restoring its wild function of the protein. Originally, it had been tested to resensitize ovarian cancer for cisplatin because that’s part of the resistance there. We tested the drug preclinically originally, showing some additive effect with azacitidine. Particularly, it was given just before azacitidine.
Through the MDS [myelodysplastic syndrome] Clinical Research Consortium, we conducted the phase I and phase II studies. Those studies included MDS patients and oligoleukemic AML patients with TP53 mutation. Obviously, we can talk about TP53 all day, saying that those are the patients who have the worst outcomes. You alluded that they do have some higher responses to azacitidine or decitabine up front, but they relapse shortly. The median survival is 4 to 6 months.
What we’ve seen with the APR-246 at this year’s ASH [American Society of Hematology Annual Meeting & Exposition] is that there were 2 presentations: 1 from the US part and the MDS Clinical Research Consortium and 1 from our colleagues from the French group. Both included around 50 patients, all of them higher-risk, TP53 mutant. The response rates are in the range of around 80%, overall responses. Again, this is combining MDS and the AML. Around 50% plus CR [complete response] rates, around 17% or 18% marrow CR [complete response] plus hematologic improvement, somewhere around 40% to 50% of the patients became NGS [next-generation sequencing] negative for the TP53 mutation, and there is a subset that have MRD status achieved.
In the US study at least, around 19% to 20%, 19 patients who were able to go to transplant, went to transplant with this. There, survival seems in the range of 1 year plus at this point, so it’s very promising. This is already in phase III, randomizing patients to azacitidine, azacitidine–APR-246. The key there would be showing the durability of the response, or as you mentioned earlier, we’re going to be able to take more patients with TP53 to transplant. This is a very promising strategy.
Mark Levis, MD, PhD: We’re getting a couple of chinks in the TP53 armor.
Harry Erba, MD, PhD: It’s pretty exciting.
Naval Daver, MD: It’s slow and steady, yeah.
Harry Erba, MD, PhD: Dan, why don’t you finish this section? Tell us about combination with venetoclax, other than chemotherapy, more targeted agents.
Dan Pollyea, MD, MS: Well, Naval presented some nice data for venetoclax with the idasanutlin, which has a complicated mechanism. One of the exciting things is its ability to target MCL1 indirectly among other elements of the MDM2 pathway with some very promising results in the relapsed/refractory setting. That may be a good lesson for us: MCL1 is going to be a vital target in the relapsed setting or in the post-venetoclax relapsed setting. There are a lot of other opportunities there; they have been alluded to here already today with respect to FLT3 and other targeted therapies. There are pretty exciting opportunities.
Harry Erba, MD, PhD: That’s what we’ve discussed today: not only have there been a number of important drug approvals in the last couple of years, but a number of exciting new agents have been coming along very quickly as well. The challenge for all of us is to get back to work tomorrow to design the right clinical trials to show that these new agents truly have benefits for our patients, not only improving survival but looking at quality of life as well for our older patients. But let’s not forget that we can cure this disease with the tools we already have. This has been a great discussion. Thank you. On behalf of our panel, we hope you’ve found this OncLive® Peer Exchange® discussion to be useful and informative.