ASH 2021 | IMGN632 plus venetoclax and/or azacitidine for patients with CD123-positive AML
Naval Daver, MD, University of Texas MD Anderson Cancer Center, Houston, TX, discusses the preliminary results from a Phase Ib/II study (NCT04086264) investigating the safety, tolerability, and preliminary anti-leukemic activity of IMGN632, a CD123-targeting antibody-drug conjugate (ADC), in combination with venetoclax and/or azacitidine for patients with CD123-positive acute myeloid leukemia (AML). Preclinical studies have demonstrated promising efficacy for this combination in murine models, including in mice resistant to azacitidine and venetoclax. The Phase Ib/II trial reported manageable toxicity in patients with relapsed/refractory (R/R) AML, with common adverse events including infusion-related reactions, febrile neutropenia, and hypophosphatemia. In addition, efficacy was seen across all cohorts and all doses, with an objective response rate (ORR) of 55% and a composite complete remission (CCR) rate of 31%. Higher dosing of IMGN632 was associated with higher response rates. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.
Transcript (edited for clarity)
At this year’s ASH meeting, we will be showing data with a CD123 antibody drug conjugate called IMGN632. There have been many CD123-targeting approaches, including antibody drug conjugates bispecifics, CAR-Ts. One of the issues we have seen with many CD123 antibodies is that they cause capillary leak, veno-occlusive disease, and sometimes cytokine release. And one of the nice things with the single agent IMGN632, where we treated 70 plus AML relapse patients, was that we did not see a significant VOD or cytokine release or capillary leak...
At this year’s ASH meeting, we will be showing data with a CD123 antibody drug conjugate called IMGN632. There have been many CD123-targeting approaches, including antibody drug conjugates bispecifics, CAR-Ts. One of the issues we have seen with many CD123 antibodies is that they cause capillary leak, veno-occlusive disease, and sometimes cytokine release. And one of the nice things with the single agent IMGN632, where we treated 70 plus AML relapse patients, was that we did not see a significant VOD or cytokine release or capillary leak. Now, we did see VOD in two patients with the very high doses of IMGN, but in the further development we’ve actually used one-tenth or lower doses, so we have not seen VOD.
And that was why we’re excited about this antibody. We saw activity as a single agent about 25%, 30% response rates, which was okay, but not sufficient to develop it as a single agent. So that led to the combination of azacitidine with venetoclax, with the CD123 antibody drug conjugate IMGN. And at this year’s ASH, we’re showing some of the Phase I dose finding data from that triplet. And what we find is that the triplet is in general quite safe. The main thing that we saw with the IMGN was infusion reactions. These occurred in about 20% of the patients. And in all cases, these were predominantly grade 1, 2. I think we just had one or two grade 3. We do see peripheral edema, but in all cases, this was grade 1 or 2. We have not seen a true capillary leak or visceral edema. So the safety was overall pretty well managed. The myelosuppression is seen. It was very much in line with what we have seen with HMA VEN in relapsed AML. So it didn’t seem to be clearly increased myelosuppression.
And what was interesting is that we are seeing responses. So we looked at responses in two cohorts; prior VEN-exposed patients, which is a very difficult population, and prior VEN-naive relapsed patients. And in the prior VEN-naive patients, we’re seeing that the AZA VEN IMGN at the doses we were planning to expand is giving close to 70%, 75% response. And now, this is in relapsed/refractory settings, which is very impressive. And we’re happy about that, especially given that it’s a good safety profile. And even in the prior VEN exposed, where historically the response rate has been 15% to 20% with any treatments based on data published from our group, we’re seeing close to about 40%, 45% response. So definitely lower than the 70%, but not bad, especially if we’re trying to get them into a marrow response and to transplant. So the study now will be expanding, we will be going frontline, and we’re trying to finalize the recommended Phase II dose to expand it in the salvage. So hopefully by next year’s ASH, we’ll have much more confident data as to whether there is a true path for this moving forward.
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