Phase 2 Trial of Regorafenib in Recurrent/Metastatic Adenoid Cystic Carcinoma.

PURPOSE: There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multitargeted VEGFR tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC. PATIENTS AND METHODS: Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The co-primary endpoints were best overall response and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants. RESULTS: Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR TKIs. No objective responses were observed. The 6-month PFS was 45%, and the median PFS was 7.2 months (95% confidence interval, 5.2-11.9 months). The presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS [HR 2.6; 95% confidence interval (CI), 1.1-6.1; P = 0.03]. Bulk RNA sequencing of pretreatment tumors revealed that regorafenib clinical benefit (CB; PFS ≥ 6 months; n = 11) was associated with the native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS < 6 months; n = 9) had greater expression of signatures related to cell-cycle progression (E2F targets, G2-M checkpoint). CONCLUSIONS: The trial failed to meet the prespecified 6-month PFS and best overall response targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, whereas programs promoting cell-cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR TKI should be considered.