Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer
Wim van Boxtel, Maike J M Uijen, Stefanie D Krens, Tim Dijkema, Stefan M Willems, Marianne A Jonker, Sjoert A H Pegge, Adriana C H van Engen-van Grunsven, Carla M L van Herpen, Wim van Boxtel, Maike J M Uijen, Stefanie D Krens, Tim Dijkema, Stefan M Willems, Marianne A Jonker, Sjoert A H Pegge, Adriana C H van Engen-van Grunsven, Carla M L van Herpen
Abstract
Aim: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC.
Patients and methods: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included.
Results: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively.
Conclusion: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate.
Trial registration: This trial was registered on ClinicalTrials.gov: NCT03729297.
Keywords: Adenoid cystic carcinoma; Cabozantinib; Salivary duct carcinoma; Salivary gland cancer; Tyrosine kinase inhibitor.
Conflict of interest statement
Conflict of interest statement WvB reported no conflict of interest to declare. MU reported no conflict of interest to declare. SK reported no conflict of interest to declare. TD reported no conflict of interest to declare. SW receives research funding from BMS, MSD, Pfizer, Roche, Nextcure, AstraZeneca, Bayer and Lily. MJ reported no conflict of interest to declare. SP reported no conflict of interest to declare. AvE reported no conflict of interest to declare. CvH: Advisory (institution): Bayer, Bristol-Myers Squibb, Ipsen, MSD and Regeneron. Research grant (institution): Astra Zeneca, Bristol-Myers Squibb, MSD, Merck, Ipsen, Novartis and Sanofi. Ipsen Pharmaceuticals: this funding source had no role in the design of this study and did not have any role during its execution, analyses and interpretation of the data. Ipsen provided courtesy review of the article for scientific accuracy and fair balance. The authors were free to accept or decline the feedback provided.
Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.
Source: PubMed