Purpose: Recurrent or metastatic adenoid cystic carcinoma (R/M ACC) is a rare cancer often arising from the salivary glands of the head and neck. While effective therapies are lacking, preclinical models have suggested that retinoic acid agonists may inhibit ACC growth by blocking MYB binding at translocated gene enhancers. We conducted a phase II trial evaluating retinoic acid as a potential novel therapy for R/M ACC. Patients and methods: Patients with histologically confirmed R/M ACC of any primary site with measurable disease (RECIST v1.1), clinical or radiographic progression within 12 months prior to enrollment, and any number of prior lines of therapy were eligible. Cohort 1 (CH1) received ATRA 45 mg/m2 split oral daily dosing on days 1-14 of a 28-day cycle; cohort 2 (CH2) received the same dosing continuously; treatment continued until disease progression. The primary endpoint was best overall response: ≥5 patients in CH1 with disease in response (CR+PR) among N=25 (assuming ≥2 of N=14 accrued in first stage of a two-stage design had disease in response) provided 85% power to target a >10% response rate (one-sided 9% binomial test). Secondary endpoints: safety, progression-free survival (PFS), overall survival. Exploratory analyses: ATRA impact on MYB expression, define resistance mechanisms, and monitor circulating tumor DNA. All had targeted tumor sequencing prior to enrollment. Results: Between 8/2019 and 2/2020, N=14 enrolled in stage 1 CH1. Primary endpoint of response to continue accrual into stage 2 in CH1 was not met; by 5/2020, N=4 enrolled in CH2 when the trial closed to accrual (budget constraints). Among 18 patients, median age: 58, 61% (11/18) women; each patient had a median of 3 organs (range, 1-4) with metastatic disease. 39% had 2+ prior lines of therapy. Best overall response: CR+PR 0%; SD 61% (11/18); PD 28% (5/18); unevaluable 11% (2/18). Median duration of stability 3.5 months (range, 1-12.3+). One patient (CH1) remains on drug with SD >1 year. Half of those who received prior VEGFR therapy achieved SD (4/8). At a median follow-up of 7.9 months, median PFS was 3.2 months (95% CI, 1.8-3.9). N=1 required dose adjustment; N=1 came off drug for toxicity. There were no grade 3-4 adverse events (headache, dry skin were common); no deaths due to treatment. Median tumor mutational burden was 0 (range, 0-5). NOTCH1 was the most frequent alteration (4, 22%) with 2 evaluable NOTCH1-mutant patients exhibiting SD. Mutations in the PI3K pathway, TP53, and TERT promoter were common. Low MYB protein expression was associated with longer duration of stability (p<0.01). Conclusion: While the trial did not meet its prespecified overall response endpoint, SD was observed among R/M ACC patients with disease progression 12 months prior to enrollment. This combined with limited toxicity makes ATRA a treatment option for long-term growth stabilization alone, or worth exploring in combination with other agents for R/M ACC.

Citation Format: Glenn J. Hanna, Anne O'Neill, Jennifer M. Cutler, Michelle Flynn, Tushara Vijaykumar, John R. Clark, Lori J. Wirth, Jochen H. Lorch, Jong C. Park, Jeffrey Mito, Jens G. Lohr, Jeffrey Kaufman, Leonard I. Zon, Robert I. Haddad. A phase II trial of all-trans retinoic acid (ATRA) in advanced adenoid cystic carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT165.