pivekimab sunirine (IMGN632)

P1/2, N=218, Active, not recruiting, ImmunoGen, Inc. | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2

Pivekimab sunirine showed single-agent activity across multiple doses, with a recommended phase 2 dose of 0·045 mg/kg once every 3 weeks. These findings led to a phase 1b/2 study of pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive acute myeloid leukaemia.

Ongoing developments with SL-401, IMGN632, CD123 chimeric antigen receptor (CAR) T-cells, and bispecific antibodies (BsAb) show promising advancements. The exploration of combinations such as CD123-targeted immunotherapies with azacitidine and venetoclax is suggested to enhance antineoplastic responses and improve survival rates in BPDCN patients. In conclusion, this multifaceted approach offers hope for more effective and tailored therapeutic interventions against this challenging hematologic malignancy.

P1, N=30, Recruiting, Fred Hutchinson Cancer Center | Not yet recruiting --> Recruiting

P1, N=30, Not yet recruiting, Fred Hutchinson Cancer Center | Initiation date: Nov 2023 --> Feb 2024

Patients 1 and 3 received treatment with CD47AB (Magrolimab), 5'-Azacitidine (Aza), and Venetoclax (Ven); Patient 2 received IMGN632 (CD123-targeting ADC), Aza and Ven. Patient 4 received p97 Inhibitor CB-5339; Patient 5 received CD47 inhibitor (ALX148), Aza, Ven... This study establishes a genotype-phenotype connection through single-cell proteogenomic profiling of TP53-mutated AML, describing the clonal evolution and immunophenotypic dynamics during treatment while proposing a potential mechanism of resistance.

Importantly, we previously showed high synergy of IMGN632 combination with BCL-2 inhibitor venetoclax (VEN) and DNA hypomethylating azacytidine (AZA) in AML cell lines and xenograft models (ASH 2020, #617). Together, these results suggest that VEN, apart from its canonical inhibitory effect on anti-apoptotic BCL-2, exerts previously unrecognized ability to suppress DDR program in AML and augments activity of DNA damaging IMGN632. Failure of cells to sustain DDR in the presence of VEN constitutes a key aspect of high efficacy of IMGN/VEN/AZA combination in AML.

Encouraging CCRMRD- rates were observed across cytogenetic/molecular subsets, and the majority of responding pts achieved early and deep remissions, which may translate to improved clinical outcomes. The regimen was well tolerated with no new safety signals, and the addition of PVEK to the AZA-VEN backbone did not appear to meaningfully prolong count recovery.

Standard of care treatments for BPDCN patients are intense chemotherapy or tagraxofusp (Elzonris®)...Pivekimab sunirine was granted orphan drug and Breakthrough Therapy designation and is currently being tested for the treatment of BPDCN patients as monotherapy and, as a triplet therapy in combination with azacitidine and venetoclax for the treatment of AML patients...Pivekimab sunirine is a potent ADC targeting CD123 and is highly efficacious against an aggressive BPDCN cell line model. This finding reinforces the importance of its use for the treatment of BPDCN patients.

P1b/2, N=292, Recruiting, ImmunoGen, Inc. | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024

P1, N=30, Not yet recruiting, Fred Hutchinson Cancer Center

P1/2, N=0, Withdrawn, Children's Oncology Group | N=38 --> 0 | Not yet recruiting --> Withdrawn

P1/2, N=179, Active, not recruiting, ImmunoGen, Inc. | Recruiting --> Active, not recruiting

P1b/2, N=242, Recruiting, ImmunoGen, Inc. | Trial completion date: Jun 2022 --> Jun 2024 | Trial primary completion date: Jun 2022 --> Jun 2024

Capillary leak syndrome is an important adverse effect of tagraxofusp that requires close monitoring. Several clinical trials are underway to study other regimens for the treatment of BPDCN, including IMGN632 (pivekimab sunirine), venetoclax (alone and in combination with hypomethylating agents), CAR-T cells, and bispecific monoclonal antibodies.

BPDCN currently has 1 approved therapy, tagraxofusp (TAG), with a median age of 68, CR/CRc rate of 57% and mOS of 15.8 mos (n=65; Pemmaraju JCO 2022). PVEK demonstrates compelling activity in frontline and R/R BPDCN pts, including durable responses in the R/R setting for pts who received prior TAG. PVEK safety was manageable with primarily low-grade IRRs and edema and no new safety signals were observed. Enrollment continues in the pivotal de novo frontline BPDCN cohort (NCT03386513) Antibody targeting, Monoclonal antibody, Myeloid malignancies

The PVEK+AZA+VEN triplet (Regimen C) is currently enrolling frontline unfit patients across sites in France, Germany, Italy, Spain, UK and USA. The PVEK+Magro doublet (Regimen E) is planned to be open for enrollment mid-2023 at sites in the USA. Clinical trial information: NCT04086264.

Recent advances in molecular biology and genetics have led to the development of targeted agents, such as tagraxofusp (a recombinant fusion protein targeting CD123), anti-CD123 CAR-T cells, XmAb14045, and IMGN632. Lastly, this review provides a comprehensive overview of pDC neoplasms.

The PVEK+Magro doublet (Regimen E) is planned to be open for enrollment mid-2023 at sites in the USA. Clinical trial information: NCT04086264.

Here, we report the biological activities, the efficacy and toxicities of humanized antibodies and antibody-drug conjugates that targets surface antigens as CD33 (gemtuzumab ozogamicine) or CD123 (pivekimab sunirine). We further explore mechanisms and effectiveness of medications that modify the microenvironment, such as glasdegib, or that harness the immune system against leukemia, such as CD47 antibody magrolimab, PD1/PDL1 inhibitors pembrolizumab and nivolumab, TIM3 inhibitor sabatolimab, T-cell and NK-cell engagers...In this scenario, a brief overview of the mechanism of action of target agents is provided, particularly with respect to their biological mechanisms. Overall, this therapeutic armamentarium will constitute the basis for multimodal and personalized combinations that, in the idea of precision medicine, will enormously benefit elderly AML patients.

Encouraging efficacy data were presented from first-in-human studies of two investigational menin inhibitors, SNDX-5613 and KO-539, in relapsed and refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangement or mutant NPM1, with overall response rates (ORR) of 53% (32/60) and 40% (8/20), respectively. The addition of the novel drug pivekimab sunirine, a first-in-class antibody-drug conjugate targeting CD123, to azacitidine and venetoclax in R/R AML resulted in an ORR of 45% (41/91), which rose to 53% in those who were venetoclax naïve. Additional novel triplet treatment combinations included the addition of magrolimab, an anti-CD47 antibody, to azacitidine and venetoclax, with an ORR of 81% (35/43) in newly diagnosed AML, including an ORR of 74% (20/27) in TP53 mutated AML. The addition of the FLT3 inhibitor gilteritinib to azacitidine/venetoclax was also featured, with an ORR of 100% (27/27) in newly diagnosed AML and an ORR of 70% (14/20) in R/R AML.

Some of these agents have shown promising results at the clinical level, including tagraxofusp (CD123 conjugated with diphtheria toxin) for the treatment of BPDCN and IMGN632 (anti-CD123 drug-conjugate), and flotetuzumab (bispecific anti-CD123 and anti-CD3 monoclonal antibody) for the treatment of AML. However, the therapeutic efficacy of CD123-targeting treatments is still unsatisfactory and must be improved through new therapeutic strategies and combined treatments with other antileukemic drugs.

IMGN632 exerted profound in vivo activity against pediatric ALL PDXs with varying CD123 expression levels, particularly those of B-lineage, inducing prolonged remissions at doses as low as 60 µg/kg. The significant difference in CD123 expression between B- and T-lineage ALL could have contributed to the difference in IMGN632 activity between the B-ALL and T-ALL models. These data strongly support the clinical evaluation of IMGN632 in B-lineage pediatric ALL.

All patients received either azacitidine 75 mg/m2 days 1-7 or decitabine 20 mg/m2 days 1-5 with Ven dose adjusted based on azole antifungal prophylaxis...After Ven+HMA failure, therapy was pursued in 11 of 71 (15%) patients with gilteritinib (n=6), ivosidenib (n=2), Ven+Gilteritinib (n=1), CPX-351 (n=1), and IMGN 632 clinical trial (n=1)...Conclusion The current study identifies presence of TP53 and K/NRAS mutations as predictors of inferior survival in patients with AML relapsed or refractory to front-line Ven+HMA. Additionally, we propose a practical three-tiered survival model based on TP53 and K/NRAS mutations and refractoriness to Ven+HMA.

With a manageable safety profile in patients with R/R AML, the higher-intensity cohorts of the novel PVEK triplet demonstrated anti-leukemia activity across several difficult-to-treat subsets of patients. Enrollment and follow-up in both relapsed and frontline patients are ongoing (NCT04086264). Additional and updated safety and efficacy data will be presented at ASH.

The PVEK triplet with AZA+VEN demonstrates anti-leukemic activity across multiple high-risk genetic subsets of relapsed/refractory AML. Prophylactic steroids added on day -1 have significantly reduced IRRs. Expansion cohorts are now enrolling for untreated and relapsed AML patients (NCT04086264).

Results N/A Conclusion Phase 2 expansion cohorts for patients with untreated /frontline and relapsed AML are enrolling to further characterize the safety profile and assess the antileukemic activity. NCT04086264

Results N/A Conclusion Enrollment continues in the pivotal cohort for frontline/untreated BPDCN patients. CADENZA, https:// BPDCNtrial.com, NCT03386513

In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD+ to MRD- and RFS in both fit and unfit AML subpopulations (NCT04086264). IMGN632 is also being tested as a monotherapy in a pivotal cohort for adults with frontline BPDCN (NCT03386513, https://BPDCNtrial.com).

An additional cohort is enrolling patients with relapsed/refractory BPDCN, which may have had up to 3 prior lines of therapy, including CD123-targeted therapies and prior hematopoietic stem cell transplant (after 120 days) and may have CNS involvement (if cleared with intrathecals), but who must not have prior history of veno-occlusive disease of the liver, or history of grade 4 capillary leak syndrome or non-cardiac grade 4 edema, and other eligibility. Both cohorts are enrolling patients at the RP2D (0.045 mg/kg IV Q 3 weeks) in the US and EU (NCT03386513, https://BPDCNtrial.com).

With a manageable safety profile in this R/R AML population, the novel IMGN632 triplet demonstrated compelling anti-leukemia activity. Ongoing escalation cohorts aim to optimize safety and efficacy of the triplet therapy. Expansion proof-of-concept cohorts are planned in both relapsed and frontline AML patients (NCT04086264).

P1/2, N=232, Ongoing, IMMUNOGEN, INC.

These data support the addition of a CD123-targeted ADC with a novel DNA-damaging payload to the standard of care, AZA+VEN in AML patients. The combination of IMGN632 and Venetoclax and/or Azacitidine is being tested in an ongoing Phase Ib/II clinical trial (NCT04086264).

In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD-positivity to MRD-negativity, in fit and unfit AML subpopulations. NCT04086264

In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD+ to MRD-, in fit and unfit AML subpopulations. Research Funding: ImmunoGen, Inc.

Expansion cohorts for unfit frontline and relapsed/refractory BPDCN, and relapsed/refractory ALL continue to enroll at the RP2D (0.045 mg/kg Q3W). Research Funding: ImmunoGen, Inc.

The patient with CR had previously had a partial response to SL-401, responded to CHOP, received a transplant and was refractory to decitabine with venetoclax: on IMGN632 this patient cleared bone marrow (28% to 0%) with one dose, and cleared skin (biopsy negative) and CT lesions with 2 doses... In this phase 1 trial, the novel CD123-targeting ADC IMGN632 demonstrated a manageable safety profile and broad therapeutic window in high risk R/R AML and BPDCN patients. The encouraging single agent activity and safety profile, along with supporting preclinical efficacy studies, have led to the subsequent development of IMGN632 as monotherapy in patients with R/R BPDCN and MRD+ AML, and in combination with azacitidine and/or venetoclax in patients with R/R and untreated AML. Figure 1.

IMGN632 monotherapy dosing in this cohort will be 0.045 mg/kg once every 3 weeks. The study is planned to open in October 2019.