The novel agentSY-1425 combined with azacitidine appears to be active in retinoic acid receptor alpha (RARA) superenhancer–positive newly diagnosed and relapsed or refractory acute myeloid leukemia (AML), according to the results of a phase II trial presented at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.1 SY-1425 is targeted to the RARA gene, a novel target in AML.
Eytan M. Stein, MD
“There are hints here that this therapy may find a place with the right patient population who has relapsed and refractory AML,” said lead author Eytan M. Stein, MD, a hematologist/oncologist and the Director of the Program for Drug Development in Leukemia at Memorial Sloan Kettering Cancer Center. “Because of this, we think the clinical activity supports the ongoing development of SY-1425 in RARA-positive myeloid malignancies.” RARA-positive AML accounts for a subset of about 30% of patients with AML.
The phase II, multicenter, open-label trial enrolled 28 patients with relapsed or refractory AML who tested RARA-positive in the peripheral blood. Patients were treated with azacitidine at 75 mg/m2 intravenously or subcutaneously on days 1 to 7 followed by SY-1425 at 6 mg/m2/d orally on days 8 to 18 for 28-day cycles. The primary endpoint was overall response rate according to International Working Group (IWG) criteria.
At baseline, median patient age was 74 years. Patients received a median of two prior therapies (range = 1–9 therapies). Two-thirds had received hypomethylating agent monotherapy; 32% received venetoclax combinations with a hypomethylating agent; 11% were favorable risk according to cytogenetics, 29% were intermediate risk, and 21% were poor risk (cytogenetic data were missing for 39%). Half of patients (n = 14) had previously received intensive induction treatment, and 21% (n = 6) had previously undergone stem cell transplant.
A total of 23 patients discontinued therapy: 10 for progressive disease, 4 for adverse events, 4 died, 2 for treatment failure, 1 for noncompliance, and 2 for other reasons. “Generally speaking, the combination was well tolerated with no increased toxicity compared with expected toxicity from either agent as monotherapy,” Dr. Stein said.
“Although the numbers are small, we saw responses in these heavily pretreated patients with relapsed/refractory AML,” Dr. Stein continued. Among 21 patients evaluable for response, there were 4 responses for an overall response rate of 19% (1 complete response, 2 complete responses with incomplete hematologic recovery, 1 morphologic leukemia-free state). Time to response was a median of 1.4 months, and two patients were continuing treatment with the novel combination at the time of the ASH Annual Meeting.
The combination enabled transfusion independence in 6 of 20 patients (30%) entered in the study, who did not require blood cell and platelet transfusion for an interval of 8 weeks or more on treatment. Of 11 patients, 3 (27%) who were transfusion-dependent at baseline converted to transfusion independence during treatment. Median overall survival was 5.9 months.
“Looking at a swimmer plot, all patients with stable disease seem to be surviving longer. We know these patients typically have very low survival. We are analyzing patients with stable disease to see if improvement in blood counts allowed them to survive longer without meeting the formal criteria for response,” Dr. Stein said.
The most commonly reported nonhematologic adverse events reported in 20% or more patients follow: pruritus, arthralgia, decreased appetite, vomiting, diarrhea, hypertriglyceridemia, constipation, fatigue, pyrexia, and nausea. “What stands out is that 21% of patients had grade 3 or higher hypertriglyceridemia, which is a known adverse event with SY-1425,” said Dr. Stein.
Hematologic adverse events of grade 3 or greater included neutropenia (4%), leukopenia (7%), thrombocytopenia (14%), anemia (14%), and febrile neutropenia (36%). Serious adverse events occurred in 19 patients, with febrile neutropenia reported most frequently (n = 7).
DISCLOSURE: Dr. Stein has received research funding from Bayer, Celgene Pharmaceuticals, Syndax, Novartis, and Daiichi Sankyo; has served on the board of directors or advisory committee for Genentech, Celgene Pharmaceuticals, Agios Pharmaceuticals, Syros, Novartis, PTC Therapeutics, Astellas Pharmaceuticals, and Daiichi Sankyo; and has served as a consultant for Genentech, Seattle Genetics, AbbVie, Amgen, Celgene Pharmaceuticals, Agios Pharmaceuticals, Syndax, Biotheryx, Novartis, Astellas Pharmaceuticals, and Daiichi Sankyo.
1. Stein EM, De Botton S, Cluzeau T, et al: Initial results from a biomarker-directed phase 2 trial of SY-1425, a potent and selective RaRα agonist, in combination with azacitidine in relapsed/refractory acute myeloid leukemia. 2020 ASH Annual Meeting & Exposition. Abstract 114. Presented December 5, 2020.
Jacqueline S. Garcia, MD
Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute, who was not involved in this study, agreed that “novel therapies for relapsed/refractory AML that are biomarker-directed are a dire unmet need and may help patients avoid ineffective therapies and unnecessary...