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I'm Naval Daver from the Department of Leukemia at MD Anderson. I'm presenting on the highlights from ASH 2016 in the AML studies that were presented there of interest. I'll be going through five or six studies that I think are clinically relevant for acute myeloid leukemia clinical practice.
The first study is a study that was done by the SWOG group, S1203, presented by Dr. Guillermo Garcia-Manero from MD Anderson. This study looked at a large group of patients, 700 plus patients, to look at three different induction regimens, 7+3 versus IA with vorinostat versus IA alone. The details of the study are presented by Dr. Garcia-Manero, but the overview was that the response rates were very similar across all three induction strategies that were tried in the younger patients. More importantly, the overall survival analysis showed that the overall survival was extremely similar between 7+3 induction versus IA induction versus IA plus vorinostat induction in these younger patients, showing that at this time 7+3 still continues to remain a good regimen but we need to build on this further by adding molecular, immune or monoclonal antibody studies. These were also discussed in other presentations at ASH.
The second study is a study that was presented by Dr. Bruno Medeiros that highlighted on a new fixed dose liposomal formulation of cytarabine with idarubicin called CPX-351. This was a Phase 3 study that was completed last year. The study focused on patients 60 to 75 years of age who had specifically secondary or therapy-related AML. In the initial analysis that was presented at ASCO this year, Dr. Lancet and Medeiros showed that the CPX improved the overall survival in patients with secondary AML. In this analysis, they showed that the improvement in overall survival in secondary AML was maintained between different age groups, patients 60 to 69 through 70 to 75. Basically, this seems to be a very good drug, active choice for patients who are 60 to 75 years of age, specifically with secondary or therapy-related AML. We expect this drug to be reviewed and hopefully be approved by mid next year by the FDA, making it available in the open market, so that's an exciting development.
The third study was one that I presented. This is a combination of an immune checkpoint drug, nivolumab, with azacytidine. It's one of the first approaches to use immune checkpoint-based therapy in AML. What we saw was that the PD1 expression was high in AML patients, allowing us to try this approach. Overall, the response rate that we got when we combined the immune checkpoint inhibitor nivolumab with azacytidine was significantly better than what we see with azacytidine alone. Even more impressive, and I think the takeaway from this, is that those who achieve the response, those 35% patients, had a very, very durable response, which is unique and not seen routinely in patients with relapsed AML. I think we're now looking to find biomarkers just like people are doing in solid tumors to help identify patients who will respond to these immune checkpoint agents, because we believe that if we can get a response the response will be much more durable than we get with standard azacytidine or chemotherapy. A number of other immune checkpoint studies are being developed.
The next study was a very interesting study using a drug that many have heard about, those who do AML research, called venetoclax. This drug has been approved for CLL and there are two major studies that are ongoing with venetoclax in AML. One is a frontline venetoclax with decitabine or azacitidine and the second one, the one presented by Dr. Wei at this ASH, is venetoclax with low dose Ara-C. This combination was used in older patients, those above 65 years of age with acute myeloid leukemia who were not candidates for standard induction. What they saw is that when you use the combination of venetoclax and low dose cytarabine, the overall response rate was significantly improved to 61%. To put this in perspective, we've done a number of studies with low dose cytarabine alone as the randomized arm and usually the response rates or 12-15%. We see the response rates are going up 3-4 times by the addition of venetoclax, showing that this is a very, very active agent. Even more impressive was the survival curves that were shown by Dr. Wei where almost 60% of patients were alive at two year follow up. Again, putting this in perspective, in the older population we expect about 25, maybe 30% at most, to be alive at two year follow up with standard chemotherapy or hypomethylator-based approach.
These data, although in a small number of patients, are very, very exciting. Based on it, there will be a randomized Phase 3 study in older AML combining low dose Ara-C with venetoclax versus low dose Ara-C alone. That one should be opening next year, so very interesting study to consider enrolling your patients to if you have such patients who are not good candidates for intensive induction.
The third one touches upon the FLT3 inhibitors. The FLT3 inhibitors have been now used in clinical trials for the last five years. They've clearly shown to improve response rate over standard chemotherapy and they're much better tolerated. The first one was midostaurin, which showed positive data in a Phase 3 study that was shown last year and should hopefully be approved early next year for AML. This is the second one that has been in development called gilteritinib. Gilteritinib is a more specific FLT3 inhibitor than midostaurin. This study is an extension of the ongoing Phase 2 study of gilteritinib. They found that the most active dose was between 120 to 200 milligrams. What they saw here was that in salvage AML patients who were treated at the active dose of gilteritinib, the overall response rate which included CR as well as CR with incomplete recovery, was between 40 to 45%. This is important because we know that in salvage AML patients, even if you use a combination of high dose chemotherapy such as fludarabine Ara-C or mitoxantrone-based combinations, we expect response rate of 15 to 25%. This is double the response rate with the single oral pill with much less toxicity, highlighting the importance and activity of these FLT3 inhibitors.
Furthermore, what Dr. Perl, who presented this data at ASH, went on to show is that the activity was seen not only in the FLT3-ITD, but also patients who had a FLT3-ITD plus FLT3-D835. This is important because most of the FLT3 inhibitors that we have used such as quizartinib, sorafenib, have activity against FLT3-ITD, but here it appears that gilteritinib treatment may actually have some degree of activity against FLT3-ITD as well as FLT3-D835, making this a broader activity. We do have a number of these other FLT3 inhibitors that are now in development.
The last one touches on another major group of molecular targeted agents that are in development for AML called the IDH inhibitors. There are a number of IDH1 and IDH2 inhibitors that are in trial. The first among these that have gone into trials were the Agios drug. Dr. DiNardo from MD Anderson also presented an update on the IDH1 inhibitor. Both the clinical responses which continue to be encouraging with remission rates of about 25 to 38% in relapsed AML patients. What's interesting is that this, again, is a single oral agent and can produce a response rate of about 35% in patients who had multiple prior chemotherapies and has almost no toxicity. As a single agent this is very attractive, but I think the key is how it will do in combinations. A number of combination strategies with these drugs have now begun, including frontline combination in younger patients with 3+7 with IDH inhibitors and frontline combinations with azacitidine plus IDH inhibitors in older patients.
In this presentation, she focused on the role of molecular remissions and whether they have clinical value. What she showed is that patients who achieve a complete remission, not a partial remission or stable disease, had a good chance of completely clearing out the IDH1 mutation. Clearance was seen in about 1/3 of the patients who achieved a complete remission and clearance of the mutation was associated with a more durable response and overall survival. Similar to what we have seen previously with BCR-ABL, for example in CML or in Philadelphia-positive ALL, the people who get a complete molecular or major molecular response seem to have more benefit. This could be one of the tests that we could be checking. The IDH inhibitors are also going for an expedited approval and may become available next year depending on the FDA review.
There were a number of other studies but I think these were the highlights. I thank you very much for listening. Thank you.