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Treatment with the oral selective RARA agonist tamibarotene (formerly SY-1425) plus azacitidine (Vidaza) did not improve complete response (CR) rates compared with azacitidine plus placebo in high-risk patients with newly diagnosed, RARA-overexpressed myelodysplastic syndromes (MDS), failing to meet the primary end point of the phase 3 SELECT-MDS-1 trial (NCT04797780).¹

Efficacy assessment of the first 190 patients enrolled onto the intention-to-treat cohort of the study showed a numerically higher CR rate of 23.8% (95% CI, 16.7%-32.2%) in the tamibarotene plus azacitidine arm (n = 126) vs 18.8% (95% CI, 10.1%-30.5%) in the azacitidine plus placebo control arm (n = 64); however, this difference was not statistically significant (P = .2084).

Regarding safety, tamibarotene plus azacitidine appeared to be generally well tolerated among all enrolled patients (n = 245) and displayed an adverse effect profile in line with data from prior studies.

Syros Pharmaceuticals, the drug’s developer, disclosed that this outcome is considered an event of default under its secured loan facility with Oxford Finance LLC. The trial will accordingly be discontinued.

“We are deeply disappointed by this outcome, particularly for the high-risk [patients with] MDS who are seeking a new treatment option for this challenging disease,” Conley Chee, chief executive officer of Syros, stated in a news release. “We plan to stop the study, review the clinical data more thoroughly, and evaluate the next steps. We want to express our sincere appreciation for the patients, caregivers, and health care professionals who took part in the SELECT-MDS-1 trial and to all the employees of Syros for their exceptional work on the tamibarotene program.”

SELECT -MDS-1 Trial Overview

This multinational, randomized, double-blind, placebo-controlled trial assessed the efficacy of tamibarotene plus azacitidine vs azacitidine plus placebo in patients at least 18 years of age with newly diagnosed MDS, per World Health Organization classification, and RARA overexpression, as determined by an investigational blood test.2 Patients must have had very high–, high-, or intermediate-risk disease per Revised International Prognostic Scoring System for MDS classification; measurable disease with a bone marrow blast count greater than 5%; and an ECOG performance status of 2 or lower. Upon enrollment, patients were randomly assigned 2:1 to receive either tamibarotene plus azacitidine or placebo plus azacitidine.

The primary end point of the study was the proportion of the first 190 patients with a CR.¹ Secondary end points included overall response rate, event-free survival, overall survival, transfusion independence, duration of response (DOR), duration of CR, time to response, time to CR, and safety.²

Prior Findings and Next Steps

Previously reported findings from a phase 2 trial (NCT02807558) supported the initiation of SELECT-MDS-1 and showed a 61% CR/CR with incomplete hematologic recovery (CRi) rate with tamibarotene and azacitidine in patients with newly diagnosed acute myeloid leukemia displaying RARA overexpression.³

Tamibarotene was also evaluated in combination with azacitidine plus venetoclax (Venclexta) in the phase 2 SELECT-AML-1 trial (NCT04905407) of patients with untreated, RARA-overexpressed AML ineligible for induction therapy.⁴ Data presented at the 2024 SOHO Annual Meeting showed comparable response rates and CR/CRi rates with the triplet vs the azacitidine and venetoclax doublet, a low likelihood of superior CR/CRi rates at final analysis, and no new safety signals for the combination. Enrollment was discontinued following results from a prespecified interim analysis of the study in August 2024.⁵ Despite this, assessment of long-term DOR, survival, and salvage therapy in patients continuing the trial in follow-up is planned.⁴

References

1. Syros announces topline data from SELECT-MDS-1 phase 3 trial of tamibarotene in higher-risk myelodysplastic syndrome with RARA gene overexpression. News Release. Syros Pharmaceuticals. November 13, 2024. Accessed November 13, 2024. https://ir.syros.com/press-releases/detail/312/syros-announces-topline-data-from-select-mds-1-phase-3
2. SELECT-MDS-1. Syros Pharmaceuticals. Accessed November 13, 2024. https://d1io3yog0oux5.cloudfront.net/_558fbeda297744d95a698522efc34c60/syros/files/pages/patients/our-clinical-trials/SELECT-MDS-1_fact_sheet.pdf
3. Tamibarotene for HR-MDS. Syros Pharmaceuticals. Accessed November 13, 2024. https://www.syros.com/programs/tamibarotene
4. Borate U, McMahon C, Fenaux P, et al. SELECT-AML-1: phase 2 randomized trial of tamibarotene in combination with venetoclax and azacitidine in adult patients with previously untreated AML with RARA overexpression, who are ineligible for standard induction therapy. Presented at: 2024 SOHO Annual Meeting; September 4-7, 2024; Houston, TX. Abstract AML-347.
5. Syros provides update on SELECT-AML-1 phase 2 clinical trial. News release. Syros Pharmaceuticals. August 12, 2024. Accessed November 13, 2024. https://ir.syros.com/press-releases/detail/308/syros-provides-update-on-select-aml-1-phase-2-clinical-trial