Initial safety and efficacy findings from an open-label, dose-escalation and expansion cohorts of the Phase 1b/2 study of pivekimab sunirine (IMGN632), a CD123 (Interleukin-3 alpha chain) -targeting antibody-drug conjugate, in combination with azacitidine (Vidaza®; Bristol Meyers Squibb/Celgene) and venetoclax (Venclexta®/Venclyxto®; AbbVie Inc. and Genentech) in patients with relapsed/refractory (R/R) and frontline acute myeloid leukemia (AML).
These findings were presented in an oral session at the 64th American Society of Hematology (ASH) Annual Meeting in New Orleans, Louisiana.
Acute myeloid leukemia (AML) is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems, and anemia. It is estimated that, in the US alone, more than 20,000 people will be diagnosed with AML and more than 11,000 will die from the disease this year.
Validated target
CD123, the interleukin-3 alpha chain, is expressed on multiple myeloid and lymphoid cancers including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myeloproliferative neoplasms. With limited expression on normal hematopoietic cells, rapid internalization, and expression on AML leukemia stem cells, CD123 is a clinically validated therapeutic target.
Because leukemic blasts and stem cells in acute myeloid leukemia (AML) express high levels of CD123 compared to normal hematopoietic stem and progenitor cells, CD123 has been recognized as a potential therapeutic target.
Pivekimab sunirine

Pivekimab sunirine is in clinical development for the treatment of hematological malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), and other CD123+ hematologic malignancies.

The investigational agent is being evaluated as monotherapy for patients with BPDCN, as a doublet with the investigational drug magrolimab (being developed by Gilead Sciences) in patients with relapsed/refractory AML, and as a triplet with azacitidine) and venetoclax in patients with frontline AML.

Pivekimab sunirine includes a humanized IgG1 antibody with high affinity to CD123 linked one of ImmunoGen’s novel indolinobenzodiazepine (IGN) payloads, which alkylate DNA and cause single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells. This payload has been observed in preclinical studies and clinical trials to have less toxicity to normal marrow progenitors than other DNA-targeting payloads.

Both preclinical synergy between pivekimab sunirine and azacitidine and/or venetoclax.

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In 2020 Kuruvilla, et all showed that pivekimab sunirine alone reduced leukemia burden and extended survival in all 4 CD123+ PDX models tested (median overall survival of 131 ± 74 days (range, 74-259) for pivekimab sunirine vs. 59 ± 7 days (range 49-69) for vehicle). The triple combination showed superior anti-leukemic efficacy in all four PDX models, compared to pivekimab sunirine or venetoclax+azacitidine alone (triple combination median overall survival of 152 days ± 99 days (range 41-313) vs. 131±74 days in IMGN632 (range 74-259) and 73 ± 22 days (range 51-110) in venetoclax+azacitidine. [2]. In addition, initial clinical data in R/R AML, presented by Daver at al during the 2021 annual meeting of the American Society of Hematology supported the continued clinical exploration of this triplet treatment option.

Orphan drug designation
The European Medicines Agency (EMA) granted orphan drug designation to pivekimab for the treatment of BPDCN in June 2020. Pivekimab sunirine also holds this designation in the US. In October 2020, the FDA granted pivekimab Breakthrough Therapy designation in relapsed/refractory BPDCN.

“While azacitidine and venetoclax have improved outcomes for patients with frontline AML, overall survival unfortunately remains poor in both this population and those with relapsed/refractory AML,” noted Naval Daver, MD, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.

“I am very encouraged by the broad anti-leukemia activity of this triplet, particularly the compelling CR/CRh rates in subgroups of relapsed/refractory AML including first relapse and those with IDH2 or FLT3 mutations as well the preliminary data showing encouraging tolerability and complete responses in the frontline setting,” Daver added.

“These data presented at ASH demonstrate this triplet’s encouraging anti-leukemia activity and tolerability, and reinforce our belief in pivekimab’s potential as a novel addition to the azacitidine and venetoclax regimen for AML,” said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen.

“Based upon the strong results from the first 10 frontline patients we have enrolled, we have moved forward with gathering more data for the triplet using 14 days of venetoclax and have opened a second cohort of up to 50 frontline patients with a goal of evaluating up to 28 days of venetoclax per cycle to optimize the duration of therapy. Tolerability and efficacy outcomes from these cohorts will guide pivotal development of the triplet in frontline AML.”

Safety:

  • 91 patients with CD123-positive R/R AML received pivekimab at 15 mcg/kg or 45 mcg/kg on day 7, azacitidine at 50 mg/m2 or 75 mg/m2on days 1-7, and venetoclax at 400 mg daily for 8, 14 or 21 days per 28-day cycle.
  • The triplet displayed a manageable safety profile in R/R AML patients.
  • The most common treatment emergent adverse events (all grades [grade 3+ events]) were febrile neutropenia (33%, [29%]), thrombocytopenia (23%, [20%]), dyspnea (22% [6%]), infusion-related reactions (22%, [2%]), hypokalemia (21% [2%]) and fatigue (20% [2%]).
    • Rates of cytopenias were similar to those observed with a hypomethylating agent and venetoclax.
    • No tumor lysis syndrome, veno-occlusive disease, capillary leak syndrome, or cytokine release syndrome were reported.
    • Discontinuations due to pivekimab-related adverse events were 5%.
    • 30-day mortality was 6%, with no treatment-related deaths.

Anti-leukemia activity:

  • In the R/R cohort, objective response rate (ORR [CR, CRh, CRp, CRi, MLFS) was 45% with a composite complete remission (CCR [CR, CRh, CRp, CRi]) rate of 25%.
    • Venetoclax-naïve patients had an ORR of 53% and CCR of 38%; in patients who had prior venetoclax exposure, the ORR was 36% and CCR was 11%.
    • Responses were observed in 9 of 11 patients with FLT3-ITD AML with an ORR of 82% and a CCR of 64%.
    • Enrollment in the R/R cohort is complete.
  • In the 10 frontline patients enrolled, pivekimab was administered at 45 mcg/kg on day 7, azacitidine at 75 mg/m2 on days 1-7, and venetoclax at 400 mg for at least 14 days per 28-day cycle.
    • 5/10 (50%) patients achieved a CR and 3/4 (75%) patients tested had a minimal residual disease (MRD)-negative CR.
    • At the time of data cut-off, 5 patients remain on treatment.
    • Enrollment in the frontline cohort continues in the US and EU.

Summary of the key findings of the study include:

Anti-leukemic Activity in R/R Patients with AML
NORRCCR
Efficacy (Evaluable Population)6151%31%
Previous treatment
Venetoclax Naive3462%47%
Prior venetoclax2737%11%
Prior azacitidine + venetoclax2232%14%
Prior Stem Cell Transplant1547%33%
Subset Analysis
De Novo AML4260%36%
ELN Adverse Risk3546%26%
FLT3-ITD1183%64%

 

Clinical trials
Study of IMGN632 in Patients With Untreated BPDCN and Relapsed/Refractory BPDCN – NCT03386513
IMGN632 as Monotherapy or With Venetoclax and/or Azacitidine for Patients With CD123-Positive Acute Myeloid Leukemia – NCT04086264
A Study of the Drug IMGN632 in Children With Leukemia That Has Come Back After Treatment or is Difficult to Treat – NCT05320380

Highlights of prescribing information
Azacitidine (Vidaza®; Bristol Meyers Squibb/Celgene) [Prescribing Information]
Venetoclax (Venclexta®/Venclyxto®; AbbVie Inc. and Genentech) [Prescribing Information]

Reference
[1] Daver N, Montesinos P, Aribi A, Marconi G, Altman JK, Wang ES, Roboz GJ, Burke PW, Gaidano G, et al.Broad Activity for the Pivekimab Sunirine (PVEK, IMGN632), Azacitidine, and Venetoclax Triplet in High-Risk Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML), Abstract #62. Presented during the 64th American Society of Hematology (ASH) Annual Meeting in New Orleans, Louisiana, held December 10 – 13, 2022.
[2] Kuruvilla VM, Zhang Q, Daver N, Watkins K,  Sloss CM, Zweidler-McKay PA, Romanelli A, Konopleva M. Combining IMGN632, a Novel CD123-Targeting Antibody Drug Conjugate with Azacitidine and Venetoclax Facilitates Apoptosis in Vitro and Prolongs Survival In Vivo in AML Models Abstract #2886. Presented at the 2020 American Society of Hematology (ASH), Annual Meeting, held December 7, 2020.
[3] Daver N, Konopleva M, Maiti A, et al. Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML. Abstract #371. Presented at the 2021 American Society of Hematology Annual Meeting, held December 12, 2021.

Featured image: American Society of Hematology (ASH) 64th Annual Meeting at the Ernest N. Morial Convention Center here today. Photo Courtesy: © 2022 ASH/Matt Herp. Used with permission.

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