SY-1425 Combination Shows Promise in Acute Myeloid Leukemia Subgroup

Treatment with SY-1425 in combination with azacitidine induced a 62% complete response rate with incomplete blood count recovery rate among unfit patients with RARA-positive AML.

Treatment with SY-1425 in combination with azacitidine (Vidaza) induced a 62% complete response (CR) rate with incomplete blood count recovery (CRi) rate among unfit patients with RARA-positive acute myeloid leukemia (AML), according to updated data from a phase 2 trial presented at the European School of Hematology (ESH) 5th International Conference Acute Myeloid Leukemia “Molecular and Translational”: Advances in Biology and Treatment in Estoril, Portugal.1

Moreover, the combination yielded a 54% CR rate in RARA-positive patients with 7 CRs (3 molecular CRs and 3 cytogenetic CRs). The duration of these responses was up to 344 days, with 3 of the 8 patients who experience CR with Cri experiencing responses beyond 7 months at the time of data cutoff.

Lastly, 82% of RARA-positive patients achieved or maintained transfusion independence.

The combination appeared to be well tolerated with no evidence of increased toxicities beyond those already known. The most commonly reported adverse events (AEs) were nausea (38%), decreased appetite (38%), constipation (33%), fatigue (33%), and peripheral edema (30%), while grade 3 or higher AEs included thrombocytopenia (25%), anemia (23%), and febrile neutropenia (23%).

“SY-1425 in combination with azacitidine continues to demonstrate high complete response rates, rapid onset of action and a favorable tolerability profile in RARA-positive AML patients. As we study the combination in more patients, we are also seeing a high rate of transfusion independence and early evidence of durable responses,” David A. Roth, MD, chief medical officer of Syros, said in a press release.

The ongoing phase 2 trial is evaluating the safety and efficacy of SY-1425, a first-in-class selective retinoic acid receptor alpha (RARα) agonist, in combination with azacytidine, a standard-of-care hypomethylating agent, in patients with either the RARA (n = 13) or IRF8 (n = 4) biomarker, as well as in patients without the biomarkers.

All patients were treated with 75 mg/m2 azacitidine daily, intravenously or subcutaneously, for 7 days, followed by 6 mg/m2 SY-1425 daily, administered orally, divided in 2 doses, for the remainder of each 28-day cycle.

As of August 22, 40 unfit patients with newly diagnosed AML (median age, 76) had been enrolled in the trial and were eligible for the safety analysis. Syros will continue to follow patients enrolled in the trial to further characterize the overall profile of the combination, including safety, efficacy, and durability of response.

Roth noted that the company plans to report potential proof-of-concept data next year in patients with RARA-positive relapsed or refractory AML.

“I am very encouraged by these data. AML patients continue to need new treatment options, despite recent advances in the field, that are well-tolerated and can be used in combination to extend survival and improve quality of life,” trial investigator Stéphane de Botton, MD, head of acute myeloid malignancies at Institut Gustave Roussy, said in the release.

“These data show that SY-1425, a targeted therapy, in combination with azacitidine is highly active in a subset of patients that can be readily identified and that the combination is generally well-tolerated even in very sick AML patients,” he added. “I believe SY-1425 is a promising combination agent with the potential to provide a meaningful benefit for a subset of AML patients, and I look forward to its continued development.”

1. de Botton S, Vigil CE, Cluzeau T, et al. SY-1425, a Potent and Selective RARα Agonist, in Combination with Azacitidine Demonstrates High Response Rates and a Rapid Onset of Clinical Responses in RARA-Positive Newly Diagnosed Unfit AML. Presented at: European School of Haematology; October 24-26, 2019; Estoril, Portugal. Abstract 16081.
2. Syros Pharmaceuticals. Syros Announces New Data from Phase 2 Trial of SY-1425 in Combination with Azacitidine Demonstrating High Response Rates, Rapid Onset of Action and Favorable Tolerability Profile in RARA-Positive Newly Diagnosed Unfit AML Patients. Available from: Accessed October 30, 2019.