Lunghi, Monia

Abstract Introduction: While newly diagnosed patients (pts) with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy have prolonged survival outcomes with venetoclax plus azacitidine (VEN+AZA) over AZA alone (2-year overall survival rate: 37.5% vs 16.9%), more can be done to further enhance outcomes (Pratz et al., 2024). CD123 is overexpressed on AML blasts and leukemia stem cells in AML. Pivekimab sunirine (PVEK) is a first-in-class antibody-drug conjugate comprised of a high-affinity anti-CD123 antibody, a cleavable linker, and an indolinobenzodiazepine pseudodimer payload. Previously, in pts with CD123-positive AML, PVEK combined with VEN+AZA demonstrated robust response rates with a manageable safety profile (Daver et al., 2023). Here we report a subgroup analysis from a preliminary cohort of frontline (1L)-treated pts with AML. Methods: Data are from the dose expansion phase of an ongoing, open-label, multicenter, fully enrolled, Phase 1b/2 study of PVEK+VEN+AZA in adults with 1L unfit AML deemed CD123-positive by investigator. Unfit pts were aged ≥75 years (yr), or aged <75 yr with Eastern Cooperative Oncology Group performance status (ECOG PS) score 2–3, or ≥1 defined comorbidity. Pts received PVEK (0.045 mg/kg, intravenous [IV]) on Day (D) 7 plus VEN (400 mg equivalent, oral) daily in a 28-D cycle (cohort 1 received ≥14 D of VEN; cohort 2 received 28 D of VEN) plus AZA (up to 75 mg/m2, subcutaneous or IV) on D1–7. Bone marrow assessments were performed by D12–14 (cohort 1) or D18–21 (cohort 2) to determine VEN duration in cycle 1 and at the end of every subsequent cycle to assess responses and myelosuppression. The primary endpoint was antileukemia activity (complete remission [CR] rate) and measurable residual disease (MRD) assessments. Responses were determined using the modified European LeukemiaNet 2017 criteria (plus CR + partial hematologic recovery [CRh]). MRD-negativity was defined centrally as <0.1% using multiparameter flow cytometry. Safety was assessed as a secondary endpoint. Results: Among 1L unfit pts with CD123-positive AML (n=49), the median (range) age was 77 (58–85) yr, with most pts aged ≥75 yr (n=36 [74%]). Forty-two (86%) pts reported an ECOG PS ≤1, 14% (n=7) had secondary AML, and 20% (n=10) and 51% (n=25) had intermediate or adverse cytogenetic risk, respectively; 65% (n=32) and 35% (n=17) were reported as TP53wt or TP53mut, respectively. Eight (16%) pts bridged to stem cell transplant. The median (range) number of treatment cycles and duration of treatment were 4 (1–20) and 5.5 (0.7–22.7) months (mo), respectively, for PVEK; 4 (1–20) and 5.1 (0.9–22.9) mo for VEN; and 4 (1–21) and 5.7 (0.9–23.4) mo for AZA. For cohort 1 (n=10), the median (range) duration of VEN was 4.5 (2.1–22.9) mo, and for cohort 2 (n=39), the median (range) duration of VEN was 5.7 (0.9–15.2) mo. With a median (range) follow-up of 10 (1.2–26.7) mo, 63.3% (95% CI: 48.3%–76.6%) of pts achieved CR, 79.6% (95% CI: 65.7%–89.8%) achieved CR/CR with incomplete hematologic recovery (CRi), and 73.5% (95% CI: 58.9%–85.1%) achieved CR/CRh; morphologic leukemia free state was achieved in 4% (n=2) of pts. Of pts who achieved CR or CR/CRi with a MRD-evaluable sample, 92% (23/25) and 90% (27/30) achieved flow cytometry MRD-negativity (<0.1%) respectively. The most common (≥50% of pts) any grade treatment-emergent adverse events (AEs) were neutropenia/neutrophil count decreased and thrombocytopenia/platelet count decreased (both 69%); constipation (61%); and peripheral edema (51%). Three pts (6%) experienced AEs leading to discontinuation (myocardial infarction/soft tissue infection/thrombocytopenia) and 2 pts had AEs leading to death (respiratory failure/pancytopenia). Conclusions: Unfit pts with newly diagnosed CD123-postive AML demonstrated high CR rates with PVEK+VEN+AZA. These robust response rates were observed across the select mutational profiles tested. Follow up with duration of response and survival estimates among all pts, by molecular subgroups and MRD negativity status, are being evaluated. Triplet therapy in unfit 1L pts with CD-123–positive AML was well-tolerated, and no new safety signals were observed. These data highlight the need to further evaluate this regimen in a randomized trial.

TPS6585 Background: Despite improved outcomes with azacitidine (AZA) and venetoclax (VEN) in newly diagnosed (ND) unfit acute myeloid leukemia (AML), only a subset of patients (pts) respond (CR 37%; CR/CRi 66%) and long-term survival remains inadequate (mOS <15m, DiNardo NEJM 2020). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). CD123 is expressed on the majority of AML blasts and leukemic stem cells while minimally expressed on normal hematopoietic stem cells (Kovtun Blood Adv 2018). Pivekimab sunirine (PVEK, IMGN632) is an antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The IGN payload alkylates DNA and causes single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. Clinical data from the first 50 pts in the dose expansion cohorts 1 and 2 with ND AML demonstrated a 76% (22/29) MRD negativity rate (by flow cytometry, negativity threshold <0.1%) (Daver ASH 2023), supporting the continued enrollment of the PVEK+AZA+VEN triplet and further evaluation of the regimen’s antileukemia activity and safety in consideration of potential registration-enabling trials. Methods: This is an open-label, multicenter, phase 1b/2 study of PVEK administered in a combination with AZA+VEN in pts with ND CD123-positive (CD123+ by flow cytometry or IHC) AML, with no prior treatment with hypomethylating agents (HMA). Pts will receive the recommended phase 2 dose of PVEK 0.045 mg/kg IV as a < 30-minute outpatient infusion on day 7, AZA 75 mg/m2 SC or IV daily on days 1 to 7, and VEN 400 mg PO daily for up to 28 days in a 28-day cycle. During cycle 1, a bone marrow evaluation at or around day 21 is required to inform VEN dose duration. Current eligibility criteria for continued enrollment of AML patients unfit for intensive chemotherapy include age ≥ 75 years old, or age < 75 years old with ECOG 2-3, or at least one defined comorbidity. The primary study objectives are to assess antileukemia clinical activity (composite CR [complete remission] rate, overall response rate, duration of remission) and MRD-negativity rates. Key secondary objectives are safety and tolerability, pharmacokinetics and immunogenicity. The PVEK+AZA+VEN triplet in pts with ND unfit AML is currently enrolling across sites in France, Germany, Italy, Spain, UK and USA. Clinical trial information: NCT04086264 .

Background In unfit patients (pts) with newly diagnosed (ND) AML, long-term survival remains short (mOS 14.7 months) despite improved responses (CR 37% and CR/CRi 66%) with azacitidine (AZA) and venetoclax (VEN) (VIALE-A, DiNardo NEJM 2020). In a pooled analysis of AZA-VEN in ND AML pts with poor risk cytogenetics the response rates were higher in TP53wt pts (CR/CRi 70%) compared with TP53mut pts (CR/CRi 41%) (Pollyea Clin Cancer Res 2022). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). Pivekimab sunirine (PVEK, IMGN632) is a first-in-class antibody-drug conjugate (ADC) comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The novel IGN payload alkylates DNA and causes single strand breaks without crosslinking (Kovtun Blood Adv 2018). Methods This is an ongoing, open-label, multicenter, Phase 1b/2 study of PVEK in combination with AZA +VEN in adults with ND CD123-positive AML (any CD123+ expression by local flow cytometry or IHC). Pts received the recommended phase 2 dose of PVEK 0.045 mg/kg IV on D7 + AZA 75 mg/m 2 SC or IV daily on D1-7 + VEN up to 400 mg PO daily for 14 to 28 days (based on cohort assignment) in a 28-day cycle. Bone marrow assessment was performed at D14 (cohort 1) or D21 (cohort 2) of cycle 1 to determine VEN duration. The primary endpoints are composite CR rate (CCR [CR+CRh+CRp+CRi]), MRD rate (assessed centrally [Hematologics, Inc.] by flow cytometry; &lt;0.1% defined as negative) and duration of remission. Key secondary endpoints are safety, pharmacokinetics and immunogenicity. Responses were determined using ELN 2017 criteria (with the addition of CRh) and a 14-day post-marrow count recovery window. Results As of July 17, 2023, data is available for 50 ND pts (n=25 per cohort) treated with PVEK+AZA+VEN and are aggregately reported here. The median age was 74 years (range, 46-83), 42% were ≥ 75 years old, 26% had secondary AML, 64% were ELN 2017 adverse risk, and 38% had a TP53mut. The most common non-hematologic treatment-emergent adverse events (TEAE) (all grades [grade 3+]) seen in &gt; 20% of all pts were febrile neutropenia (44% [38%]), constipation (42% [2%]), peripheral edema (36% [4%]), diarrhea (36% [2%]), hypophosphatemia (32% [0%], nausea (28% [4%]), and hypokalemia (24% [2%]). No veno-occlusive disease (VOD) events were reported. In responders, the median time to achieve absolute neutrophil count ≥500/µL and platelet count ≥50,000/µL was 35.5 days (range, 20-55) and 22 days (range, 20-55), respectively. The median post-remission cycle delay (beyond cycle day 28) was 14 days. Two pts discontinued PVEK due to a TEAE (edema; marrow aplasia). The 60-day mortality was 4%. In the ITT population (N=50) the CR rate was 52% (26/50), and the CCR rate was 66% (33/50). In pts ≥ 75 years old, the CCR rate was 76% (16/21). In pts known to be TP53wt, both the CR and CCR rate was 88% (22/25). Additional response subsets in Table 1. Twenty-one pts received 9-14 days of VEN, 9 pts received 15-21 days of VEN and 20 pts received ≥ 22 days of VEN in cycle 1; of those who received ≤ 14 days of VEN the CR rate was 71% (15/21) and the CCR rate was 76% (16/21). Of the 26 pts who achieved CCR and had an MRD-evaluable sample, 73% (19/26) achieved MRD negativity (CCR MRD-, &lt;0.1% residual blasts); notably all had undetectable MRD levels (lower level of detection is 0.02%). MRD-negativity was achieved rapidly with a median of 1.7 months (range, 0.8-4.5). CCR MRD- rates were high across major molecular subsets, including FLT3 (ITD/TKD) at 100% (7/7), IDH1/2 at 89% (8/9), and NPM1 at 89% (8/9), as well as ELN risk groups (intermediate 80% [8/10]; adverse 64% [9/14]). Conclusion With a manageable safety profile in pts with ND AML, the PVEK+AZA+VEN triplet demonstrated anti-leukemia activity with robust CR rates and early MRD negative responses in a cohort enriched for adverse disease characteristics (64% ELN adverse risk; 38% TP53mut). Encouraging CCR MRD- 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.