Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Authors: Pemmaraju Naveen , Martinelli Giovanni , Todisco Elisabetta , Lane Andrew A , Acuña-Cruz Evelyn , Deconinck Eric , Wang Eunice S. , Sweet Kendra L. , Rizzieri David A , Mazzarella Luca , DeAngelo Daniel J. , Montesinos Pau , Tarella Corrado , Erba Harry P. , Konopleva Marina , Kantarjian Hagop M. , Sloss Callum M , Malcolm Kara E , Zweidler-McKay Patrick A , Daver Naval 
Published: November 2020

BACKGROUND: BPDCN is a rare, aggressive hematologic malignancy characterized by poor overall survival and limited therapeutic options. Overexpression of CD123 (IL-3Rα) is present in all BPDCN cases, therefore establishing this marker as a rational target for therapeutic intervention. Despite the recent approval of tagraxofusp-erzs (Pemmaraju NEJM 2019), outcomes remain poor in the setting of R/R BPDCN. IMGN632 is a CD123-targeting ADC, comprised of a high affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN class. Preclinically, BPDCN patient-derived xenografts demonstrated high sensitivity to IMGN632 (Zhang 2018, Kovtun 2018), establishing a rationale for the clinical evaluation of IMGN632 in this patient population.
AIMS: Safety and efficacy of single agent IMGN632 in patients with R/R BPDCN.
METHODS: Adult patients with R/R BPDCN with no more than three prior lines of therapy were eligible. IMGN632 was administered IV at 0.045 mg/kg on day 1 of a 21-day cycle.
RESULTS: 23 patients with R/R BPDCN; median age of 73 years [19-82]; 74% male. Fifty-two percent of patients had at least 2 prior therapies, 52% had received prior intensive therapies (eg HyperCVAD, FLAG, CHOP), 22% had prior allogeneic stem cell transplant, and importantly 43% had prior exposure to tagraxofusp-erzs (n=10). At enrollment, 70% had skin involvement, 61% had bone marrow involvement, and 48% had lymph node involvement.
The most common treatment emergent adverse events (TEAEs) include: nausea (35% all grade; 0% grade 3+), peripheral edema (26% all grade; 0% grade 3+), and infusion related reactions (22% all grade; 4% grade 3+). There were no Grade 3+ treatment-related AEs observed in &gt;1 patient. No capillary leak syndrome (CLS) was reported; grade 3+ LFT elevations, neutropenia, and thrombocytopenia were all noted in 1 patient each, and there were no deaths within 30-days after last IMGN632 dose.
Seven of 23 patients had an objective response (2 CR, 2 CRc, 1 CRi and 2 PR) for an ORR of 30% (95% CI 13-53%) and a composite complete remission rate of 22%. The duration of response (DOR including time from PR) for the four CR/CRc patients were 9.2, 6.8+, 3.1 and 3+ months without transplantation (Figure 1A). Examples of responses are shown in Figure 1B-D. Of note, among the 10 patients with prior exposure to tagraxofusp (none had achieved a CR with tagraxofusp), 30% (n=3) achieved an objective response to IMGN632 (1 CR, 1 CRi, 1 PR). Two remarkable responders had received 3 prior regimens including tagraxofusp followed by intense and other therapies (CLAG-M/CLAG; or CHOP/allogeneic transplant/decitabine with venetoclax) and presented with diffuse disease involvement with skin, nodal, and bone marrow infiltration. After 1 and 2 doses respectively, both patients cleared all three disease compartments (CR/CRi) with one remaining in CR for 9.2 months. Additionally, among 12 patients who had bone marrow involvement and response assessment, 75% (9 of 12) had a reduction in bone marrow blasts, and 50% (6 of 12) achieved a bone marrow complete remission (&lt;5% blasts, grey bars), including 3 patients with prior tagraxofusp. (Figure 1E).
CONCLUSION: The current available therapy for patients with R/R BPDCN has limited efficacy and significant safety and tolerability concerns that underscore the high unmet need for this patient population. In heavily pretreated R/R BPDCN patients, including patients who had progressed following tagraxofusp, intense chemotherapies and transplant, IMGN632 demonstrated a 30% (n=7) ORR, with 4 CR/CRc responses with notable DORs. In addition, IMGN632 demonstrated a favorable safety profile that included limited grade 3+ TEAEs/SAEs, no cases of CLS, and no deaths. In addition, IMGN632 is given once every 3 weeks, without the need for hospitalization.
This clinical trial represents the largest-to-date prospective group of uniformly treated patients with R/R BPDCN and demonstrates promising activity and favorable tolerability in a cohort of heavily pretreated patients, including nearly half with prior anti-CD123 targeted therapy.
FIGURE: A) Swimmers plot for all responders (CR, CRc, CRi, and PR); ^ = HSCT, arrows indicate patients in ongoing remission. Examples of resolution of B) PET and C) skin lesions from one patient, and D) PET lesions from another patient. E) Waterfall graph demonstrating best bone marrow response, gray bars = blasts &lt;5%, arrows indicate prior exposure to tagraxofusp.

Disclosures
Pemmaraju: Pacylex Pharmaceuticals: Consultancy; Affymetrix: Other: Grant Support, Research Funding; Cellectis: Research Funding; Roche Diagnostics: Honoraria; Samus Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; DAVA Oncology: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support; Stemline Therapeutics: Honoraria, Research Funding; Plexxikon: Research Funding; Blueprint Medicines: Honoraria; LFB Biotechnologies: Honoraria; MustangBio: Honoraria. Todisco:Jannsen, Abbvie, Jazz: Membership on an entity's Board of Directors or advisory committees. Lane:Stemline Therapeutics: Research Funding; Abbvie: Research Funding; Qiagen: Consultancy. Deconinck:ImmunoGen: Consultancy, Research Funding; Stemline: Consultancy. Wang:Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Astellas: Consultancy; Macrogenics: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau; PTC Therapeutics: Consultancy. Sweet:Stemline: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Rizzieri:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees. Mazzarella:Tethis: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Agios: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Incyte Corporation: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Shire: Consultancy; Takeda: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Autolos: Consultancy; Amgen: Consultancy; Forty-Seven: Consultancy. Montesinos:Astellas, Novartis, Janssen: Speakers Bureau; Celgene, Pfizer, Abbvie: Consultancy; Pfizer, Abbvie, Daiichi Sankyo: Research Funding. Tarella:TG-therapeutics: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ImmunoGen: Research Funding. Konopleva:Stemline Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Ablynx: Research Funding; Rafael Pharmaceutical: Research Funding; Eli Lilly: Research Funding; Genentech: Consultancy, Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Kisoji: Consultancy; Ascentage: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Research Funding; Sanofi: Research Funding; Agios: Research Funding. Kantarjian:BMS: Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Immunogen: Research Funding; Sanofi: Research Funding; Abbvie: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding. Sloss:ImmunoGen, Inc.: Current Employment. Malcolm:ImmunoGen, Inc.: Current Employment. Zweidler-McKay:ImmunoGen, Inc.: Current Employment. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Results from a Phase 1/2 clinical trial using a non-approved experimental therapy