TY - JOUR
T1 - AML-262 Pivekimab Sunirine (PVEK, IMGN632) Triplet With Azacitidine and Venetoclax Shows Broad Activity in Adverse Genetic Subsets of Relapsed/Refractory Acute Myeloid Leukemia and Reduced Infusion-Related Reactions
AU - Daver, Naval
AU - Montesinos, Pau
AU - Aribi, Ahmed
AU - Martinelli, Giovanni
AU - Altman, Jessica K.
AU - Wang, Eunice S.
AU - Roboz, Gail J.
AU - Burke, Patrick W.
AU - Gaidano, Gianluca
AU - Walter, Roland B.
AU - Thomas, Xavier
AU - Jeyakumar, Deepa
AU - DeAngelo, Daniel J.
AU - Erba, Harry P.
AU - Todisco, Elisabetta
AU - Begna, Kebede
AU - Advani, Anjali
AU - Gastaud, Lauris
AU - de la Fuente, Adolfo
AU - Curti, Antonio
AU - Mendez, Lourdes M.
AU - Vyas, Paresh
AU - Boissel, Nicolas
AU - Vey, Norbert
AU - Recher, Christian
AU - Longval, Thomas
AU - Platzbecker, Uwe
AU - Kapp-Schwörer, Silke
AU - Schliemann, Christoph
AU - Konopleva, Marina
AU - Torres, Laura
AU - Sallman, David A.
AU - Marcucci, Guido
AU - Marconi, Giovanni
AU - Kantarjian, Hagop
AU - Sloss, Callum M.
AU - Malcolm, Karen E.
AU - Zweidler-McKay, Patrick A.
AU - Sweet, Kendra
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/10
Y1 - 2022/10
N2 - Context: Pivekimab sunirine (PVEK, IMGN632) is a first-in-class ADC comprising a CD123 high-affinity antibody, a cleavable linker, and an IGN (indolinobenzodiazepine pseudodimer) payload. PVEK with azacitidine (AZA) and venetoclax (VEN) is a novel triplet that has demonstrated anti-leukemia activity in relapsed/refractory AML patients. Objective: Evaluate the anti-leukemia activity in genetic subgroups of AML and safety of the triplet. Intervention: Patients with relapsed/refractory 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 for 8, 14, or 21 days. Results: Twenty-nine patients (median age 67 y, ELN adverse 62%, prior VEN 48%) were in higher-intensity cohorts (PVEK 0.045 mg/kg and/or VEN for 14 or 21 days). The overall response rate (ORR) was 59% (4 CR, 6 CRh, 1 CRp, 6 MLFS) and the composite complete remission rate (CCR, CR+CRh+CRp+CRi) was 38%. Higher rates are seen in patients with FLT3-ITD (n=9, ORR 89%, CCR 78%), IDH2 (n=4, ORR 75%, CCR 75%), and WT1 (n=7, ORR 57%, CCR 43%) mutations. Lower rates are seen in patients with monosomy 7/abn7q (n=6, ORR 17%, CCR 17%), TP53 (n=4, ORR 25%, CCR 25%), and ASXL1 (n=6, ORR 67%, CCR 17%) deletions or mutations. The safety profile for the PVEK triplet is similar to AZA+VEN. No VOD, TLS, or CRS was reported. IRRs were reported in 33% (n=17, one grade 4) of patients given 1 dose of dexamethasone (8 mg) as premedication (n=51); these IRRs were most frequently tachycardia and chills, with no anaphylactic reactions reported. Following the data cut-off, there was a second grade 4 IRR, and the prophylactic regimen was increased with two additional doses of dexamethasone on the day prior to the PVEK dose. The IRR rate has dropped to 8% (3 of 38), with no grade 3+; all were grades 1–2 that resolved with limited intervention (P<0.01). Conclusions: 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).
AB - Context: Pivekimab sunirine (PVEK, IMGN632) is a first-in-class ADC comprising a CD123 high-affinity antibody, a cleavable linker, and an IGN (indolinobenzodiazepine pseudodimer) payload. PVEK with azacitidine (AZA) and venetoclax (VEN) is a novel triplet that has demonstrated anti-leukemia activity in relapsed/refractory AML patients. Objective: Evaluate the anti-leukemia activity in genetic subgroups of AML and safety of the triplet. Intervention: Patients with relapsed/refractory 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 for 8, 14, or 21 days. Results: Twenty-nine patients (median age 67 y, ELN adverse 62%, prior VEN 48%) were in higher-intensity cohorts (PVEK 0.045 mg/kg and/or VEN for 14 or 21 days). The overall response rate (ORR) was 59% (4 CR, 6 CRh, 1 CRp, 6 MLFS) and the composite complete remission rate (CCR, CR+CRh+CRp+CRi) was 38%. Higher rates are seen in patients with FLT3-ITD (n=9, ORR 89%, CCR 78%), IDH2 (n=4, ORR 75%, CCR 75%), and WT1 (n=7, ORR 57%, CCR 43%) mutations. Lower rates are seen in patients with monosomy 7/abn7q (n=6, ORR 17%, CCR 17%), TP53 (n=4, ORR 25%, CCR 25%), and ASXL1 (n=6, ORR 67%, CCR 17%) deletions or mutations. The safety profile for the PVEK triplet is similar to AZA+VEN. No VOD, TLS, or CRS was reported. IRRs were reported in 33% (n=17, one grade 4) of patients given 1 dose of dexamethasone (8 mg) as premedication (n=51); these IRRs were most frequently tachycardia and chills, with no anaphylactic reactions reported. Following the data cut-off, there was a second grade 4 IRR, and the prophylactic regimen was increased with two additional doses of dexamethasone on the day prior to the PVEK dose. The IRR rate has dropped to 8% (3 of 38), with no grade 3+; all were grades 1–2 that resolved with limited intervention (P<0.01). Conclusions: 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).
KW - ADC
KW - AML
KW - combination therapy
KW - pivekimab
UR - http://www.scopus.com/inward/record.url?scp=85138157209&partnerID=8YFLogxK
U2 - 10.1016/S2152-2650(22)01257-5
DO - 10.1016/S2152-2650(22)01257-5
M3 - Article
SN - 2152-2650
VL - 22
SP - S231-S232
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
ER -