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Phase IB/II Study of Nivolumab with Azacytidine in Patients with Relapsed AML
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Dr. Naval Daver discusses Phase IB/II Study of Nivolumab with Azacytidine in Patients with Relapsed AML at ASCO 2017. For the ability to view on your mobile phone please visit us at

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My name is Naval Daver. I'm one of the leukemia faculty at MD Anderson Cancer Center in Houston, Texas. I am here presenting from the ASCO 2017 Meeting. I'll be telling you some of the highlights of one of my posters which is a combination of azacytidine and a PD-1 inhibitor nivolumab in patients with relapsed AML. As most of the oncology community is aware and excited, there has been an explosion of immune therapies including PT, PD1, CTLA-4, PD-L1 inhibitors showing excellent responses and durability in many solid tumors and hematological malignancies. We are one of the sites that have started investigating these in a large way in acute leukemias including AML, MDS and also in some forms of chronic leukemia such as CLL. One of the first things we had done as a background, before we started the clinical study, was to look at 100 patients with AML, half of these are relapse and half of these were newly diagnosed, to see what is the expression of PD1 on different T-cell subsets and we actually did find that there was increased PD1 expression on the CD8 cells as well as the T-regs and CD4 effectors in AML bone marrow aspirates as compared to healthy human donor bone marrow aspirates which was interesting indicating that there is an immune exhaustion or immune activation that happens in acute myeloid leukemia.

After this we went ahead to start the study which was a combination of standard azacytidine dose of 75mg/m2 days one through seven which would be what we would use as an HMA in AML and to that we added the PD1 inhibitor nivolumab on days one and 14. Initial part of the study had a safety run in with six patients and we saw that there were no major DLTs or concerns so the established dose was the combination of azacytidine and nivolumab both at their standard doses. We then went ahead to the expansion and went on to enroll an additional 64 patients so a total of six plus 64, 70 patients and that's the data we have presented over here. So as you can see, if you look at the poster, the background characteristics, these are elderly population. They have a median of two prior treatments so all of these patents were salvage AML. We did not include any frontline AML in this study, although there is an extension of this study now looking at frontline elderly AML.

Also, very similar to what we see at MD Anderson, we did have about 1/3 of the population that had adverse cybergenetics so these are usually difficult to treat people and we did have molecular profiling on all of these patients and we saw that the common mutations were TP53, ASXL1, DMNT3A, of which TP53 is important because it is a high-risk resistant mutation.

So what is important in this poster was what were the overall response rate and the durability of the responses. The response rate, as you can see, is about 32% which included a majority of CR/CRi, about 22% and then hematological improvements which we only included if they were durable for three months or more and that was about 11%. Another finding that we saw that has been well described in solid tumor was there was a subset of patients who did not achieve a CR/CRi or hematological improvement, but achieved stable disease and in some cases this has lasted more than one year without transplant which in a relapse CML population is quite unique and we are trying better to define how we would call stable disease in these heme diseases as we have done in other solid tumors with immunotherapies. We then compared what these outcomes looked as compared to using azacytidine or the decitabine alone in salvage AML and what we saw is that the overall response rate that we saw was about double so in our historical group at MD Anderson treated with azacytidine or decitabine alone in salvage AML, the response rate CR/CRi were 11-12% and in this group we had about 20-23%.

In addition, the median overall survival as well as the progression free survival of the next treatment was significantly improved and as you can see in figure 2 in the graphs, especially among patients who were salvage one AML, we saw a very encouraging median overall survival of almost 10 months. Now putting this into perspective, the frontline studies with azacytidine and decitabine, phase 3 studies have shown a median overall survival of 7-9 months. So to get a 10 month survival in a salvage AML population, again this is a single center experience, but it's quite encouraging and we think we need to develop this further.

We also did some immune correlatives and it seems that patients who had higher CD3 and CD8 infiltrate in the bone marrow aspirate to begin with were more likely to have a response which again, goes along with what has been shown in many solid tumor immunotherapy studies. So we expect that in the future we will be able to define maybe bio markers to select the patients who would benefit most and have a higher response rate allowing other patients who have less T-cell infiltrate at the baseline in their bone marrow to go to molecular or cytotoxic therapies. I will stop here and thank you very much.