Sustained response to brigatinib in a patient with refractory metastatic pheochromocytoma harboring R1192P anaplastic lymphoma kinase mutation: a case report from the Austrian Group Medical Tumor Therapy next-generation sequencing registry and discussion of the literature

Abstract

Metastatic pheochromocytoma and paraganglioma (PPGL) are rare diseases with dismal prognosis and standard therapies are lacking. We herein report the first case of a germline anaplastic lymphoma kinase (ALK) mutation in a patient with chemorefractory metastatic pheochromocytoma in the absence of mutations of known PPGL-associated predisposing genes. Therapy with the ALK inhibitor (ALKi) brigatinib led to dramatic and durable disease remission, despite previous disease progression on the ALKi alectinib. This case underscores the potential clinical use of molecular profiling in rare diseases with limited treatment options and suggests that the ALK-R1192P point mutation might predict sensitivity to brigatinib.

Trial registration: ClinicalTrials.gov NCT03301493.

Keywords: ALK; NGS; brigatinib; pheochromocytoma.

Conflict of interest statement

Disclosure FH declares honoraria from Lilly, Pierre Fabre, and Servier; consulting or advisory role for Lilly and Servier; research funding from Paracelsus Medical University; expert testimony for Lilly; and reimbursement for travel, accommodations, expenses from Servier, BMS, Roche, Merck, PharmaMar, and Pfizer. GH declares honoraria, consulting or advisory role, and reimbursement for travel, accommodations, expenses from MSD, Roche, AstraZeneca, Pfizer, and BMS. LC declares reimbursement for travel, accommodations, expenses from Amgen, Roche, and Celgene. GR declares consulting or advisory role for Pierre Fabre, Celgene, Roche, Novartis, Pfizer, Eli Lilly, Daiichi Sankyo, and MSD; participating in speakers' bureau for Amgen, AstraZeneca, Novartis, Bristol-Myers Squibb, Roche, Pfizer, and Eli Lilly; research funding from Roche; and reimbursement for travel, accommodations, expenses from Roche, Novartis, Amgen, Pfizer, and Bristol-Myers Squibb. TM declares honoraria, consulting or advisory role, speakers' bureau, expert testimony, and reimbursement for travel, accommodations, expenses from Roche, Takeda, MSD, Novartis, Merck, and BMS. LW declares honoraria from Roche, Bristol-Myers Squibb, Lilly, Novocure, Merck Serono, Amgen, and Pierre Fabre; consulting or advisory role for Bristol-Myers Squibb, Roche, Lilly, Novocure, Merck Serono, and Takeda; and reimbursement for travel, accommodations, expenses from Ipsen, Pfizer, Merck Serono, and AstraZeneca. RG declares honoraria and consulting or advisory role for Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, and Daiichi Sankyo, and reimbursement for travel, accommodations, expenses from Roche, Amgen, Janssen, AstraZeneca, Novartis, MSD, Celgene, Gilead, BMS, and AbbVie. All other authors have declared no conflicts of interest. Data sharing The authors declare that data supporting the findings of this study are available within the paper. The complete molecular report of the NGS analysis and primer sequences are available upon request from the corresponding author. Ethics declarations Written informed consent was obtained from the patient and from the patient's daughter for publication of this case report and any accompanying images. This analysis was performed within the next-generation sequencing (NGS) Registry of the Austrian Group Medical Tumor Therapy (AGMT) (NCT 03301493). This registry has been approved by the Ethics Committee of the provincial government of Salzburg (Nr.: 415-E/2129).

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Computed tomography images of the abdomen showing response of liver metastases to brigatinib. Red circles indicate locations of metastases.

Figure 2

(A) Timeline of patient's diagnosis of distant disease and treatments. (B) Normetanephrine levels during therapy. The arrows point at the start of the respective therapy. CTX, chemotherapy; MM, metachronous metastasis; NGS, next-generation sequencing; PD, progressive disease; PR, partial response; SD, stable disease.