Safety and efficacy of pivekimab sunirine in R/R AML: phase I/II study

CD123 is commonly overexpressed in patients with acute myeloid leukemia (AML).¹ Pivekimab sunirine is a novel antibody-drug conjugate comprising a high affinity CD123 antibody.¹

Here, we summarize the results from a phase I/II dose escalation and dose expansion trial (NCT03386513) investigating the safety and antileukemic activity of pivekimab sunirine in relapsed/refractory AML published by Daver et al.¹ in The Lancet Oncology.

Study design¹

• The dose escalation phase followed a 3 + 3 dose design.
  • In Schedule A, dosing started at 0.015 mg/kg of pivekimab sunirine and escalated five times to 0.45 mg/kg.
  • In Schedule B, dosing started at 0.015 mg/kg of pivekimab sunirine and escalated twice to 0.060 mg/kg. However, Schedule B was not pursued further.
• In the dose expansion phase, two doses from Schedule A were selected (0.045 mg/kg and 0.090 mg/kg).
• The primary endpoints of the trial were the maximum tolerated dose and the recommended phase II dose (RP2D) of pivekimab sunirine.
• Secondary endpoints included safety and antileukemic activity.

Key findings¹

• A total of 68 patients were enrolled in Schedule A at a median follow-up of 46.32 months.
  • 38 patients in the dose-escalation phase.
  • In the dose-expansion phase, 20 patients received 0.045 mg/kg and 10 patients received 0.090 mg/kg.
• The selected RP2D was 0.045 mg/kg once every 3 weeks; 29 patients received RP2D of pivekimab sunirine.

Safety

• During dosing Schedule A, there were three dose-limiting toxicities.
  • The most common Grade ≥3 treatment-emergent adverse events were febrile neutropenia (35%), and pneumonia (28%).
  • The most common Grade ≥3 treatment-related adverse event (TRAE) was febrile neutropenia (13%).
  • The 30-day mortality rate was 7%.
  • No dose-limiting toxicity-based maximum tolerated dose was reached.
• During the RP2D, treatment-emergent adverse events occurred in 97% of patients with the most common Grade ≥3 event being febrile neutropenia (Figure 1).
  • The most common Grade ≥3 TRAEs were febrile neutropenia (10%), infusion-related reactions (7%), and anemia (7%).
  • There were no deaths due to TRAEs.

RP2D, recommended phase II dose; TEAE, treatment-emergent adverse event.
*Adapted from Daver, et al.¹

 

Efficacy

• At RP2D, the overall response rate was 21% and the composite complete remission rate was 17% (Table 1).

Table 1. Efficacy endpoints of patients enrolled in dosing Schedule A and those treated with the RP2D of pivekimab sunirine *

Efficacy endpoint, % (unless otherwise stated)	Schedule A (n = 68)	RP2D (n = 29)
ORR	16	21
Complete remission	3	3
Composite complete remission rate	12	17
Median duration of ORR, months	2.0	2.6
Median duration of composite complete remission, months	2.2	2.3
Estimated median OS, months	2.99	5.85
ORR, overall response rate; OS, overall survival; RP2D, recommended phase II dose. *Adapted from Daver, et al.1

Key learnings
Treatment with pivekimab sunirine showed a manageable safety profile across a range of doses with a recommended phase II dose of 0.045 mg/kg once every 3 weeks. The favorable safety profile has also warranted the investigation of pivekimab sunirine + venetoclax + azacitidine in patients with newly diagnosed AML and ineligible for intensive chemotherapy (NCT04086264).