Tamibarotene with venetoclax and azacitidine in RARA⁺ acute myeloid leukemia: results from the SY-1425-202 study

RARA overexpression defines a molecularly distinct subset of acute myeloid leukemia (AML). Tamibarotene, an oral selective RARA agonist, synergizes with azacitidine (AZA) but its addition to venetoclax (VEN) with AZA has not been assessed. SY-1425-202 was a multicenter, open-label, randomized study evaluating tamibarotene combined to VEN/AZA (TAMI/VEN/AZA) vs VEN/AZA alone in newly diagnosed RARA-positive, unfit AML. Part 1 assessed the safety of TAMI/VEN/AZA, part 2 randomized participants to TAMI/VEN/AZA vs VEN/AZA, and part 3 explored salvage therapy with TAMI/VEN/AZA after VEN/AZA failure in part 2. TAMI 6 mg twice daily was administered. Randomization occurred after confirmation of RARA positivity by cycle 1, day 8. The primary end point was complete remission (CR) + CR with incomplete hematologic recovery (CRi) in part 2 and part 3, and safety in part 1. In part 1 (n=10), overall response rate (ORR) was 77.8% (5 CR, 2 CRi). In part 2 (n=51), CR/CRi was 60.0% for TAMI/VEN/AZA and 69.2% for VEN/AZA. Median CR/CRi duration was 293 vs 253 days. ORR was 80.0% vs 73.1%, respectively. In part 3, 2 of 5 patients responded (CR, morphologically leukemia-free state). Grade ≥3 treatment-emergent adverse event occurred in 76% of patients. Deaths were attributed mainly to disease progression or known complications of therapy; none were attributed to TAMI. The study met prespecified futility criteria and was discontinued early. The addition of TAMI to VEN/AZA was tolerable but did not improve efficacy over VEN/AZA. These results did not demonstrate clinical benefit of TAMI in the frontline unfit RARA-positive AML setting receiving VEN/AZA. This trial was registered at www.clinicaltrials.gov as #NCT04905407.