The FDA clinical reviewer responsible for the approval of this combination therapy discusses the data that led to the approval in May 2022.
The combination therapy of ivosedinib (Tibsovo; Servier Pharmaceuticals LLC) with azacytidine (Vidaza; Celgene Corporation) was approved in May 2022 based on compelling evidence of clinical benefit, including improved event-free survival (EFS), overall survival (OS), and durable complete response (CR) rate compared to azacytidine alone, explained Ashley Woods, MD, a clinical reviewer at the FDA responsible for the approval, during a presentation at the 64th American Society of Hematology (ASH) Annual Meeting and Exhibition in New Orleans, Louisiana. Woods said this combination received regular approval for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) aged 75 years or older or who have comorbidities that preclude the use of intensive induction chemotherapy.
Woods noted that ivosedinib, a small-molecule inhibitor of the IDH1 enzyme, works by decreasing abnormal production at the optimum metabolite 2-Hydroxybutyrate. Further, IDH1 mutations occur in 6% to 10% of patients with AML, explained Woods.
“The pivotal trial [NCT03173248] that led to the regular approval of ivosedinib in combination with azacytidine was a phase 3, double blind, randomized, placebo-controlled study of ivosedinib plus azacytidine vs placebo plus azacytidine in newly diagnosed patients with AML ineligible for intensive chemotherapy,” Woods said.
The primary endpoint was EFS, which was assigned as time from randomization until treatment failure, relapse or remission, or death from any cause, whichever occurred first. Woods explained that treatment failure was defined as failure to achieve CR by week 24. Patients who did not achieve a CR by week 24 were considered to have had an event at day 1. For the remaining patients with CR, the event time is either the time of disease relapse or death, whichever occurred first.
Key secondary efficacy endpoints of the trial were OS, rate of CR, rate of CR and complete remission with partial hematologic recovery (CRh), and overall response rate (ORR). Participants eligible for the study were randomized 1:1 to receive oral ivosedinib or matched placebo, both administered in combination with subcutaneous (SC) or intravenous (IV) azacytidine.
“The EFS was statistically significant, with patients receiving ivosedinib plus azacytidine having less events,” Woods said. “This is consistent with the [OS], with patients receiving ivosedinib plus azacytidine at a median [OS] of 24 months compared to 7.9 months for patients receiving placebo plus azacytidine.”
Further, Woods noted that the safety profile of ivosedinib plus azacytidine was found to be relatively tolerable, with the 30-day mortality higher in the placebo arm at 12% versus 7% in the ivosedinib plus azacytidine arm. Additionally, QTc prolongation, differentiation syndrome, and leukocytosis are known adverse events (AEs) of ivosedinib. These AEs were observed more frequently in the ivosedinib plus azacytidine arm than in the placebo plus azacytidine arm.
Dose interruptions and discontinuations were similar in both groups, with most of the discontinuations due to disease progression. Dose reductions were higher in the ivosedinib plus azacytidine arm, but 6 of the 10 cases were due to QTc prolongation. Additionally, there were 3 deaths due to AEs in the ivosedinib plus azacytidine, 2 deaths were due to differentiation syndrome, and 1 death was due to cerebral ischemia.
The clinical counterpart to Woods during the ASH presentation was Ehab Atallah, MD, professor of medicine and section head of hematological malignancies in the Medical College of Wisconsin Division of Hematology and Oncology. Atallah presented a patient case of a White woman, 76 years of age, who was admitted with new onset pancytopenia (workup acute leukemia). The patient was experiencing fatigue and easy bruising and had no significant past medical history but had an IDH1 mutation detected.
“What are the treatment options for this patient after this approval? The first option is ivosedinib plus azacytidine, the second option we already had was venetoclax plus azacytidine,” Atallah said. “We also have ivosedinib as a single agent and we have azacytidine or decitabine.”
After providing a review of the data, Atallah noted that both venetoclax plus azacytidine and ivosedinib plus azacytidine are acceptable options for the patient population represented by the patient described. However, this patient had a known IDH1 mutation detected, which doesn't always happen, Atallah explained.
“There are some logistical issues when you don't have the results of the IDH1 mutation in terms of some delay in therapy. The venetoclax plus azacytidine had higher risk of febrile neutropenia and the ivosedinib plus azacytidine has the higher risk of differentiation syndrome,” Atallah said. “So what next, what should we do? There’s some retrospective data with very a limited number of patients for such cases, so we need larger data.”
Woods A, Atallah E. Precision Medicine for Leukemias - Ivosedinib and Azacytidine for Newly Diagnosed Acute Myeloid Leukemia. Presented at: 64th ASH Annual Meeting and Exhibition in New Orleans, LA; December 12, 2022.