Broad Activity for the Pivekimab Sunirine (PVEK, IMGN632), Azacitidine, and Venetoclax Triplet in High-Risk Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

BACKGROUND: Despite recent improvements with azacitidine (AZA) and venetoclax (VEN), long-term survival for these patients remains short (median overall survival 14.7 months) and rationally designed novel additions to this regimen are being evaluated to improve patient outcomes. CD123 is expressed on the majority of AML blasts and leukemic stem cells while minimally expressed on normal hematopoietic stem cells. 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. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. Both preclinical synergy between PVEK and AZA and/or VEN (Kuruvilla ASH 2020) and initial clinical data in R/R AML (Daver ASH 2021) supported the continued clinical exploration of this triplet. Here we report safety and anti-leukemic activity of PVEK+AZA+VEN from the higher-intensity cohorts and ongoing expansion cohort in patients with R/R AML.

METHODS: In this phase 1b/2 study, eligible patients with CD123-positive R/R AML received PVEK+AZA+VEN in a three-drug escalation over a 28-day cycle: PVEK 0.015 or 0.045 mg/kg day 7, AZA 50 or 75 mg/m² days 1-7, and VEN 400 mg (or equivalent with azole) for 8, 14, or 21 days. The higher intensity cohorts are defined as patients treated with PVEK on day 7, and either a PVEK dose at 0.045mg/kg or at least 14 days of VEN. Enrollment of relapsed and frontline patients is ongoing in the expansion cohorts of PVEK 0.045 mg/kg day 7, AZA 75 mg/m² days 1-7, and VEN 400 mg for at least 14 days.

Responses were determined using ELN 2017 criteria (with the addition of CRh and CRp) and a 14-day count recovery window.

RESULTS: As of June 20, 2022, preliminary safety data are available for 71 patients with R/R AML treated in the higher-intensity cohorts as defined above. The median age was 68 years (range, 25-82), 30% had secondary AML, 32% had primary refractory disease, 44% had received prior VEN, 25% had prior allogeneic stem cell transplant, and 54% of the patients were ELN 2017 adverse risk. Fifty-two percent of the patients had received ≥ 2 prior lines of therapy.

The most common treatment-emergent adverse events (TEAE) (all grades [grade 3+ events]) seen in >20% of patients were febrile neutropenia (30% [24%]) and infusion-related reactions (IRRs, 21% [3%]). Pneumonia was reported in 16% of patients [grade 3+ 11%]. Overall, 10% of patients discontinued PVEK due to a TEAE (mostly unrelated to PVEK). Cytopenias and infections were consistent with those observed with HMA+VEN in patients with R/R AML. 30-day mortality was 3%.

Response data were available for 61 patients with R/R AML. The objective response rate (ORR [CR, CRh, CRp, CRi, MLFS) was 51% with a composite complete remission (CCR [CR, CRh, CRp, CRi]) rate of 31%. VEN-naïve patients had an ORR and CCR of 62% and 47% compared with 37% and 11%, respectively, in patients who had prior VEN exposure. Of note, responses were observed in 9 of 11 patients with FLT3-ITD AML with an ORR of 82% and a CCR of 64%. Table 1 displays response data from sub-groups of interest. Additionally, maximum best change in bone marrow blasts is depicted in Figure 1.

CONCLUSION: 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.