iwAL 2019 | ADCs for AML: potential alternatives to gemtuzumab ozogamicin

Naval Daver, MD: Now there have been a number of new antibody drug conjugates that have entered phase one, phase two development. Among those specifically, one that we’re working closely with is CD123 antibody, called IMGN-632. So this is an agent that now uses not a bacterial toxin, but a chemical toxin. And it was engineered with the idea that it would have much lower VOD, as well as much lower myelosuppression than was seen with gemtuzumab and some of the other bacterial toxin containing antibody drug conjugates.

Naval Daver, MD: We showed some of this data at ASH this year, and in the phase one dose escalation and the relapsed/refractory AML, we see an overall response rate of about 25 to 30%. These are CR, CRi’s, we didn’t look at partial responses and blast reduction. The good thing is that the drug seems to be very well tolerated. The main reactions were infusion reactions, these are manageable by using steroids and pre-medications. We did have out of the 33 patients treated, one patient with VOD. This was seen at the highest dose level, dose level six. So we are no longer exploring dose level five and six but looking at lower dose levels and combinations with azacitidine and with venetoclax with this compound are moving into clinic in the next few months. So we think that this will be potentially a very safe and effective drug. There’s no other drug that right now in very advanced development for CD123, so we’re looking forward to the data with this agent and potentially could be an important drug in AML.

Naval Daver, MD: There’s also another CD33 antibody drug conjugate that is hopefully going to be better than gemtuzumab. This is also an IMGN drug, 779. The initial phase one seemed to show some activity, but the response rates are less than 10%. So we’re not sure that this drug will be as good as the CD123. But the trials are ongoing, and we’re waiting for more mature data.

Naval Daver, MD: In addition at this year’s ASH, there was a CD70 non-conjugated antibody that has shown some very impressive early activity. Among the 12 patients treated with this, they found that 11 of 12 front-line, elderly patients had response. Now this drug was not given as a single agent, it was given in combination with hypomethylating agent, so it’s hard to know if this is truly the benefit of the drug alone, or the combination. But nonetheless, to get 11 out of 12 CR, Cri’s in an elderly front-line AML population, even with the combination, the HMAs, is quite exciting. So the drug is called cusatuzumab, it’s a CD70 non-conjugated antibody, and we think that this will be another one to look out for going forward.

Naval Daver, MD: And lastly, there’s a group of radionucleotide conjugated antibody drug conjugates that are now in development. One of them is actually in a phase three study, where this agent is used as a conditioning before taking people to transplant. This is called the SIERRA Phase 3 study. The drug, is a drug called Iomab-b, it’s basically CD45 antibody that is conjugated to a iodine 131 kind of toxic payload. And so far the early results of this phase 3 study on the first interim analysis with 38 patients, showed that the Iomab-b seems to be very very effective. 18 out of 19 relapse refractory patients who got this were able to go to transplant, and 16 of them engrafted within a month. And this compares favorably to the control arm of chemo where only five out of 18 patients could make it to transplant.

Naval Daver, MD: So at least to get patients to transplant, and for post-transplant engraftment, this seems to be a very viable strategy based on early data. And will this translate into improved CR duration, which is a primary endpoint of the study, and overall survival? We’ll have to wait and see.

Naval Daver, MD: So, these are the major antibody-based approaches that are being developed. There’s also a huge group of bispecific antibodies that will be talked about by some of my colleagues. And overall, I think the immunotherapy field in AML, compared to four or five years ago, has really blossomed, and is moving very very quickly. And we think that in the next one or two years, one or two of these drugs will potentially get approved based on phase two, phase three data.