ASH 2020 | IMGN632 is efficacious with venetoclax plus azacitidine in AML models
Marina Konopleva, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, TX, shares the findings of IMGN632 plus venetoclax and azacitidine triplet therapy efficacy in acute myeloid leukemia models in vitro and in vivo. IMGN632 is a novel antibody-drug conjugate, with an anti-CD123 antibody and a DNA single-stranded break-inducing alkylating payload. AML cells express high levels of CD123, making IMGN632 effective in AML treatment. Given preliminary results of synergy with venetoclax, a BCL-2 inhibitor, IMGN632 was investigated with the established combination of VEN + AZA. Cell line studies identified upregulation of apoptotic proteins and increased cell death with the triplet combination, compared to IMGN632 or VEN+AZA separately. The triplet also showed superior efficacy in AML patient-derived xenograft models. Additionally, in models refractory to the VEN + AZA doublet, the triple combination resulted in efficacy results exceeding those of IMGN632 alone. This indicates synergistic activity of the three agents. The pre-clinical results support the addition of IMGN632 to VEN+AZA, and a Phase Ib clinical trial has begun. This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020.
Transcript (edited for clarity)
So this was a pre-clinical study where my lab looked at the combination and efficacy of the anti-CD123 antibody-drug conjugate, IMGN632 were the standard of care ven + aza in the AML models. As we know, the ven + aza is a highly efficacious therapy, however, overall survival in the randomized Phase III study was only 14.7 months. So we have been looking for combinations that can increase the activity of this doublet and/or increase the longevity of the response...
So this was a pre-clinical study where my lab looked at the combination and efficacy of the anti-CD123 antibody-drug conjugate, IMGN632 were the standard of care ven + aza in the AML models. As we know, the ven + aza is a highly efficacious therapy, however, overall survival in the randomized Phase III study was only 14.7 months. So we have been looking for combinations that can increase the activity of this doublet and/or increase the longevity of the response.
CD123 is highly expressed on AML, including AML stem cells and on the majority of AML subsets and has been long identified as a potential target for therapeutic interventions. The single-agent IMGN632 has shown efficacy in patients with AML and in the relapse/refractory setting and also in patients with the BPDCN, the rare entity that has high levels of CD123.
For this particular study we have compared the efficacy of ven + aza IMGN or triple combination in the AML cell lines, that and also the AML primary derived xenografts. Now we show that the combination is synergistic in several cell lines so that we looked at the… With high induction of cell death and induction of the DNA, a damage was the several molecular markers associated with response.
Most importantly, in four different patient-derived xenografts of AML patients, the combination was clearly more efficacious than either of the ven + aza or IMGN632 alone. And the most importantly, it was also effective in two different PDXs that had the resistance and did not respond to ven + aza alone. This suggests that this combination must’ve been beneficial for translational therapy and in fact, the clinical trial that is testing this particular triple combination is already ongoing in the relapse/refractory AML patients.
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Disclosures
Consultancy (includes expert testimony): AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji
Equity ownership: Stocks, Reata Pharmaceuticals
Research funding: AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca
Patents and royalties: Reata Pharmaceuticals
