SY-1425 Plus Azacitidine Continues to Show Durable Activity in RARA+ AML

In the phase II biomarker-driven trial combining retinoic acid receptor alpha (RARa) agonist SY-1425 with azacitidine (Vidaza), newly diagnosed adult patients with RARA-positive acute myeloid leukemia (AML) who were unfit for intensive chemotherapy continued to show responses to the combination and demonstrate tolerability of the regimen, according to a press release from Syros Pharmaceuticals.¹

“SY-1425 in combination with azacitidine continues to demonstrate high complete response rates, rapid onset of action, and a favorable tolerability profile in [patients with] RARA-positive AML. As we study the combination in more patients, we are also seeing a high rate of transfusion independence and early evidence of durable responses. We are gratified to see our discovery of this novel patient subset, as defined by our RARA biomarker, translating into clinical benefit,” David A. Roth, MD, chief medical officer, Syros, stated in the press release.

Reportedly, 62% of RARA-positive patients achieved complete response (CR) or CR with incomplete blood count recovery (CRi), as defined by Revised International Working Group criteria. Responses lasted for up to 344 days and treatment response had continued for 7 months in 3 of the patients at the time of data cutoff. Additionally, 82% of patients with RARA-positive AML reached or maintained transfusion independence.

In the press release, Roth also noted, “these results demonstrate the power of our gene control platform to identify which genes to modulate in which patients to maximize the chances of providing them with a profound benefit. We look forward to continuing to evaluate SY-1425 in our ongoing study and to reporting potential proof-of-concept data next year in [patients with] RARA-positive relapsed or refractory AML.”

The trial includes patients aged 18 years or older with either r/r non-acute promyelocytic leukemia (APL) AML who failed to response to standard induction therapy relapsed after responding, patients with r/r higher-risk myelodysplastic syndrome (MDS) who failed to respond on hypomethylating agents, or newly diagnosed treatment-naïve non-APL AML who were unlikely to tolerate intensive chemotherapy. Most patients required an ECOG performance status of 0, 1, or 2. However, patients under the age of 75 years old were required to have an ECOG of 0 to 3, and those who were aged 75 years or older had to have an ECOG performance status of 0 to 2.

Other study requirements include transfusion-dependent lower-risk MDS without the del 5q abnormality, lower-risk MDS, refractory to or ineligible for ESAs, and adequate organ function. Patients are excluded if they have acute promyelocytic leukemia, hyperleukocytosis, active malignancy, hypertriglyceridemia, clinically significant cardiac disease, active uncontrolled central nervous system or are refractory to platelet or packed red cell transfusions.

Patients receive SY-1425 (6 mg/m²/day) on days 1 through 28 of a 28-day cycles and intravenous azacitidine (75 mg/m²/day). The cycle for azacitidine was every week for 8 weeks, then every 2 weeks for 16 weeks, followed by every 4 weeks.

A total of 40 newly diagnosed AML patients were enrolled in the trial as of August 22, 2019, including 13 patients who were RARA-positive.

The combination has been well tolerated in all patients and the toxicities seen are consistent with the safety profiles of either drug alone, according to data released for the 40 patients with newly diagnosed AML. Most non-hematologic adverse events (AEs) were grades 1 and 2. The most common AEs reported were nausea (38%), decreased appetite (38%), constipation (33%), fatigue (33%) and peripheral edema (30%). Among the grade 3 or higher AEs, thrombocytopenia (25%), anemia (23%), and febrile neutropenia (23%) were the most common.

The results of this trial revealed an important fact about AML, which is that about 30% of patients who are diagnosed with AML are RARA-positive. The trial data also led Syros to their decision to use RARA as a biomarker for patient selection in SY-1425 clinical trials in the future. This decision was based on the fact that no IRF8-positive patients had a CR or CRi from treatment.

Syros plans to present these data at the European School of Hematology 5th International Conference Acute Myeloid Leukemia “Molecular and Translational”: Advances in Biology and Treatment in Estoril, Portugal and plan to report proof-of-concept from the r/r AML cohort in 2020. The phase II trial is ongoing and actively recruiting patients who meet the requirement for accrual.

Reference:

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 [press release]. Cambridge, MA; October 24, 2019; Syros Pharmaceuticals; https://bwnews.pr/31K01fd. Accessed October 25, 2019.