Clinical Activity of REM-422, a MYB mRNA Degrader, in recurrent/Metastatic Adenoid Cystic Carcinoma: Final Results from the Phase 1/2 Dose-Escalation Cohort

Background
Adenoid cystic carcinoma (ACC) is a malignant neoplasm characterized by dysregulation of MYB, with the majority of tumors containing a hallmark t(6:9) rearrangement resulting in a MYB:NFIB fusion oncogene, or aberrant MYB overexpression. There are no FDA approved systemic therapies for the treatment of ACC. REM-422 is a first-in-class, potent, selective, oral small molecule mRNA degrader of MYB.

Methods
This Phase 1/2 study aims to determine the safety, PK/PD and efficacy of REM-422 in patients (pts) with recurrent or metastatic (R/M) ACC. During Phase 1 Dose Escalation and Optimization, patients received oral REM-422 once daily (3-48mg) in 28-day cycles. Enrollment was biomarker-agnostic; MYB mRNA transcripts targetable by REM-422 (biomarker positive) were retrospectively assessed in tumor specimens.

Results
In the Phase 1 study, 69 pts were enrolled (median age 57 [range 20-82]); 75% received ≥1 prior line of systemic therapy. Fifty-nine pts were efficacy evaluable: 32 biomarker positive, 24 biomarker negative, and 3 unknown. Fifteen patients received REM-422 at the recommended phase 2 dose (RP2D) of 24 mg. REM-422 was generally well-tolerated. No dose-limiting toxicities were observed. The most common treatment-related adverse events at the RP2D included epistaxis (60%), fatigue (60%) and anemia (40%), all of which were grade 1 or 2. Pharmacodynamic analysis in peripheral blood and on-treatment tumor biopsy confirmed robust target engagement including reduction in MYB mRNA and protein at efficacious exposures. In the biomarker positive population, tumor regression was observed at doses ≥12mg, with 21/30 pts (70%) experiencing reduction in target lesions and 14/30 (47%) achieving at least ≥20% shrinkage. Clinical activity was seen across both molecular subtypes (ACC-I and II) and in pts previously treated with antibody-drug conjugates. At the RP2D of 24 mg, 3 PRs were observed among 7 biomarker positive pts (ORR 42%). Time to response ranged from 4-8 months with durations up to 12 months and ongoing at the data cutoff (07 January 2026).

Conclusions
REM-422 is the first small molecule MYB mRNA degrader to demonstrate clinical activity in R/M ACC and is generally well-tolerated. These findings support further evaluation of REM-422 in a biomarker-selected population. Accrual to the Phase 2 Confirmatory Cohort is ongoing. Clinical trial identifier: NCT06118086.