Phase 2 trial of regorafenib in recurrent/metastatic adenoid cystic carcinoma Journal Article
| Authors: | Desilets, A.; Vos, J. L.; Katabi, N.; Kuo, F.; Nadeem, Z.; Linxweiler, M.; Ostrovnaya, I.; Baxi, S.; Dunn, L. A.; Sherman, E. J.; Pfister, D. G.; Morris, L. G. T.; Ho, A. L. |
| Article Title: | Phase 2 trial of regorafenib in recurrent/metastatic adenoid cystic carcinoma |
| Abstract: | 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. © 2024 American Association for Cancer Research. |
| Keywords: | immunohistochemistry; adult; clinical article; human tissue; treatment response; aged; aged, 80 and over; middle aged; gene mutation; overall survival; genetics; lenalidomide; clinical trial; mortality; cisplatin; doxorubicin; drug dose reduction; hypophosphatemia; pyridines; nuclear magnetic resonance imaging; cancer grading; biological marker; carboplatin; cancer immunotherapy; metastasis; progression free survival; computer assisted tomography; phase 2 clinical trial; neoplasm recurrence, local; cell infiltration; protein kinase inhibitor; pathology; tumor marker; docetaxel; protein tyrosine kinase inhibitor; lymphocytopenia; protein kinase inhibitors; alanine aminotransferase; hyponatremia; maculopapular rash; lung metastasis; fluorescence in situ hybridization; tumor recurrence; radiosensitivity; adenoid cystic carcinoma; drug therapy; disease control; major histocompatibility complex; k ras protein; everolimus; carcinoma, adenoid cystic; disease exacerbation; lapatinib; pyridine derivative; recurrence free survival; nelfinavir; high throughput sequencing; regorafenib; phenylurea compounds; very elderly; carbanilamide derivative; humans; human; male; female; article; osimertinib; biomarkers, tumor; vinorelbine tartrate; metastatic adenoid cystic carcinoma; recurrent adenoid cystic carcinoma |
| Journal Title: | Clinical Cancer Research |
| Volume: | 30 |
| Issue: | 23 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-12-01 |
| Start Page: | 5281 |
| End Page: | 5292 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-24-1064 |
| PUBMED: | 39352719 |
| PROVIDER: | scopus |
| PMCID: | PMC11611652 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Alan L. Ho -- Source: Scopus |
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