Early Results From A Biomarker-Directed Phase 2 Trial Of Sy-1425 In Acute Myeloid Leukemia (Aml) And Myelodysplastic Syndrome (Mds) Demonstrate Dhrs3 Induction And Myeloid Differentiation Following Sy-1425 Treatment

Abstract Introduction: A novel patient (pt) subset defined by RARA pathway activation was identified by super-enhancers (SEs) at the RARA and IRF8 gene loci in AML and MDS. These SEs correlated with mRNA expression of each gene, as well as preclinical tumor cell differentiation and in vivo efficacy response to SY-1425 (tamibarotene), a potent and selective oral RARα agonist approved for treatment of relapsed/refractory (r/r) APL in Japan. This discovery formed the basis of a biomarker-directed phase 2 clinical study of SY-1425 as monotherapy and in combination with azacitidine for AML and MDS pts (NCT02807558). Methods: Pts were screened with a novel biomarker test using qPCR for RARA and IRF8 mRNA on blasts or clonal hematopoietic cells from peripheral blood to determine eligibility for treatment. The test evaluated RARA pathway activation, and the positivity cutoff was set using functional models for SY-1425 response and retrospective analyses of pt expression databases. A sample set from screening (biomarker-positive and negative) was also tested for ex vivo differentiation response to SY-1425. Pts positive for RARA pathway biomarkers who satisfied other eligibility criteria initiated continuous treatment with SY-1425 at 6 mg/m2/day in divided doses. PK data were collected to confirm adequate exposure and consistency with prior results in APL patients. Two direct RARα target genes were tracked for target engagement and mechanistic response: DHRS3 mRNA, measured in tumor cells and PBMCs, and CD38, a cell surface marker expressed by differentiating myeloid cells after exposure to SY-1425. DHRS3 was assessed on day 1 (pre- and post-dose) and on day 15. CD38 was assessed at screening and after 4 weeks at C2D1 using local clinical immunophenotyping of marrow aspirates. Results: Of 215 pts screened to date (65% AML, 35% MDS), biomarkers were positive in 39.5% of pts, consistent with results of prior mRNA expression analyses in AML and MDS cells. The biomarker was positive for RARA in 27% AML and 31% MDS, for IRF8 in 7% AML and 3.5% MDS, and for both RARA and IRF8 in 18% AML and 31% MDS pts. The cutoff was confirmed by a statistically significant separation of biomarker-positive and negative pts using two independent differentiation analysis methods. To date, 48 biomarker-positive pts have enrolled in the monotherapy arms of the study: 29 with r/r AML or higher-risk MDS, 18 with lower-risk MDS, and 1 with newly diagnosed AML. PK data in 36 pts showed SY-1425 plasma levels similar to those observed in Japanese APL studies based on day 1 and day 15 Cmax (mean steady-state Cmax of 71 and 75 ng/mL, respectively). In 28 PD evaluable pts, upregulation of DHRS3 at 5-8 hours was found in 89% (25/28), including a greater than 2-fold increase in 10/12 AML and 4/5 MDS pts. Marrow aspirate immunophenotyping at C2D1 versus baseline revealed increased CD38 expression in response to SY-1425 in 11 of 13 evaluable pts, consistent with induction of myeloid differentiation. Conclusion: A novel subset of AML and MDS pts with evidence of RARA pathway activation was identified, providing rationale for a biomarker-directed clinical trial with SY-1425. The novel biomarker test prospectively identified 39.5% positivity for RARA, IRF8 or both. Dosing of SY-1425 achieved plasma exposures sufficient to elicit a PD response with RARα target engagement of the DHRS3 gene providing proof of mechanism in pts. Consistent with preclinical studies, differentiation of cells was observed. The biomarker cutoff confirmed by ex vivo differentiation of biomarker positive and negative pt screening samples, supports the predictive value of the biomarker test for pt selection. Immunophenotyping of pt marrow aspirates revealed evidence of differentiation with increased CD38 expression, consistent with downstream biological effects of SY-1425 on blasts. As previously reported, SY-1425 induced CD38 expression confers daratumumab dependent tumor cell death and NK cell activation in ex vivo experiments. The induction of the CD38 in pts treated with SY-1425 supports the planned evaluation of SY-1425 in combination with CD38 therapeutic antibodies. Taken together, these data support the ongoing investigation of the efficacy and safety of SY-1425 as monotherapy and in combination with azacitidine, a standard of care agent. Clinical exploration of novel combinations using CD38 targeted therapies based on SY-1425 induced myeloid differentiation is also warranted. Disclosures Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Research Funding; Astellas Pharma, Inc: Research Funding; Alexion Pharmaceuticals: Consultancy; Syros Pharmaceuticals: Research Funding; Amgen: Consultancy; Forma Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding; Genentech: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Kura Oncology: Research Funding; Merck: Consultancy. Raza: Janssen RD Celgene Inc.: Research Funding; Syros Pharmaceuticals: Research Funding; Novartis: Speakers Bureau; Onconova Therapeutics: Research Funding, Speakers Bureau; Genoptix: Speakers Bureau; Kura Oncology: Research Funding. Stein: Constellation Pharma: Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; GSK: Other: Advisory Board, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Seattle Genetics: Research Funding. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Rizzieri: Shire: Research Funding; Erytech: Research Funding. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Steensma: Onconova: Consultancy; Pfizer: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Incyte: Equity Ownership; H3 Biosciences: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cook: Syros Corporation: Membership on an entity's Board of Directors or advisory committees. McKeown: Syros Pharmaceuticals: Employment. Waters: Syros Pharmaceuticals: Employment. Stephens: Syros Pharmaceuticals: Employment. Volkert: Syros Pharmaceuticals: Employment. Di Tomaso: Syros Pharmaceuticals: Employment. Roth: Syros Pharmaceuticals: Employment. Cortes: BMS: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding; Sun Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding.