Targeting RARA Overexpression with Tamibarotene, a Potent and Selective RARα Agonist, is a Novel Approach in AML

A super-enhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in approximately 30% of non-acute promyelocytic leukemia (non APL) acute myeloid leukemia (AML) and in approximately 50% of myelodysplastic syndromes (MDS). RARA overexpression is an actionable target for treatment with tamibarotene, an oral potent and selective RARα agonist. Sensitivity to the RARα agonist tamibarotene was demonstrated in RARA-high but not RARA-low preclinical AML models. The combination of oral tamibarotene plus azacitidine was evaluated in a Phase 2 clinical study in 51 newly diagnosed unfit AML patients identified as RARA-positive (N = 22) or RARA-negative (N = 29) for RARA mRNA overexpression in peripheral blasts with a blood-based biomarker test. In 18 response evaluable RARA-positive patients, complete remission/complete remission with incomplete hematologic recovery (CR/CRi) rate was 61%, CR rate was 50%, and time to initial composite CR was rapid at 1.2 months. Transfusion independence was attained by 72% of RARA-positive patients. In contrast, 28 response evaluable RARA-negative patients had response rates that were consistent with azacitidine monotherapy. Tamibarotene in combination with azacitidine was well-tolerated. The majority of non-hematologic adverse events (AEs) were low grade and hematologic AEs were comparable to single agent azacitidine, demonstrating that there was no additional myelosuppression when tamibarotene was combined with azacitidine. These results support further evaluation of tamibarotene-based treatment strategies in AML and MDS patients with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial is registered at www.clinicaltrials.gov as NCT02807558.