On December 12, 2022 Syros Pharmaceuticals, a leader in the development of medicines that control the expression of genes, reported a peer-reviewed publication of results from its completed biomarker-directed Phase 2 trial of tamibarotene in combination with azacitidine in newly diagnosed patients with acute myeloid leukemia (AML) who are not eligible for standard intensive chemotherapy (Press release, Syros Pharmaceuticals, DEC 12, 2022, View Source [SID1234625177]). These findings support Syros’ ongoing evaluation of tamibarotene for the treatment of AML and myelodysplastic syndrome (MDS) patients with RARA overexpression. The paper, titled "Targeting RARA Overexpression with Tamibarotene, a Potent and Selective RARα Agonist, is a Novel Approach in AML," was published online in Blood Advances on December 7, 2022 at View Source
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"We are excited to see a high CR rate and a rapid onset of response in newly diagnosed unfit AML patients with RARA overexpression treated with a combination of tamibarotene plus azacitidine. The biomarker test successfully identified AML patients positive for RARA overexpression who were enriched for response to tamibarotene and azacitidine relative to those patients who were negative for RARA overexpression. This observation further demonstrates that the activity of tamibarotene is dependent on the biology of RARA overexpression. In addition, the combination was generally well tolerated and provides the potential for a novel targeted treatment approach for patients with AML," said Stéphane de Botton, M.D., Head of Acute Myeloid Malignancies at Institut Gustave Roussy and a clinical investigator in the Phase 2 trial of tamibarotene.
"With approximately 30% of AML patients and 50% of HR-MDS patients positive for RARA overexpression, tamibarotene has the potential to contribute to a new frontline treatment paradigm for large, targeted patient populations," said David A. Roth, M.D., Chief Medical Officer at Syros. "These data, including the high CR rate in patients with low blast count AML, informed our ongoing SELECT-MDS-1 Phase 3 trial in newly diagnosed HR-MDS patients and SELECT-AML-1 Phase 2 trial in newly diagnosed unfit AML patients, from which we reported encouraging data from the safety lead-in portion at the ASH (Free ASH Whitepaper) Annual Meeting on December 10th."
In the SY-1425-201 trial, a total of 51 patients at 12 sites in the U.S. and France were enrolled into the newly diagnosed unfit AML cohort that evaluated the combination of tamibarotene plus azacitidine. Patients were screened with a novel blood-based clinical trial assay used to prospectively identify those with RARA overexpression. Based on RARA expression levels, each patient was classified as positive for RARA overexpression (22 patients) or negative for RARA overexpression (29 patients). Both groups were enrolled and treated with 28-day treatment cycles, including azacitidine dosed daily on Days 1 to 7, followed by oral tamibarotene dosed twice daily on Days 8 to 28.
A total of 18 patients with RARA overexpression were response evaluable and exhibited an overall response rate (ORR) of 67% (12/18), CR/CRi rate of 61% (9 CR, 2 CRi), CR rate of 50% and morphological leukemia-free state of 5% (one patient). Median time to initial composite complete remission for patients with RARA overexpression was 1.2 months and median duration of composite complete remission was 10.8 months (95% CI: 2.9, NE). Importantly, in patients with low blast count AML, which is similar to HR-MDS, data showed a 67% (4/6) CR rate. In the patients without RARA overexpression, the response rates were consistent with treatment with azacitidine alone. Additionally, correlative analyses of RARA expression levels identified an association of RARA overexpression with a monocytic gene expression signature that may be associated with resistance to venetoclax. These data also informed the strategy of evaluating the triplet combination of tamibarotene, venetoclax and azacitidine in the ongoing SELECT-AML-1 trial.
Importantly, the tamibarotene plus azacitidine combination was generally well tolerated in the patients treated. The rates of myelosuppression were comparable to azacitidine monotherapy in this population suggesting no added hematologic toxicity from tamibarotene when used in combination with azacitidine. The majority of non-hematologic adverse events (AEs) were low grade.