Effect of the RET Inhibitor Vandetanib in a Patient With RET Fusion-Positive Metastatic Non-Small-Cell Lung Cancer.

Introduction Aberrations of RET, the proto-oncogene that encodes rearranged during transfection (RET) transmembrane receptor tyrosine kinase, are associated with the development of several malignancies. Several RET rearrangements, specifically fusions, have been identified in non– small-cell lung cancer (NSCLC), including kinesin family member 5b (KIF5B) –RET, coiled-coil domain-containing protein 6 (CCDC6) –RET, nuclear receptor coactivator 4 (NCOA4) –RET, and tripartite motif-containing 33 (TRIM33) –RET. RET gene fusions occur in approximately 1% to 2% of unselected NSCLCs. RET fusions tend to occur in patients who are younger than age 60 years, former light smokers or never-smokers, with early lymph node metastasis and tumors that are poorly differentiated. RET fusions may be mutually exclusive, with activating mutations in EGFR, HER2, BRAF, and KRAS, as well as EML4-ALK and ROS-1 rearrangements, suggesting that these fusions may be targetable driver mutations. Vandetanib is an orally active small-molecule receptor tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), human epidermal growth factor receptor 2, epidermal growth factor receptor (EGFR), and RET, and is approved by the US Food and Drug Administration for treatment of medullary thyroid carcinoma. Previous trials of vandetanib in patients with NSCLC did not test for or select for RET mutations or fusions, and therefore the clinical efficacy of vandetanib in this subpopulation of NSCLC is currently unknown. Here we describe a patient with NSCLC with a known RET fusion who was treated with the RET inhibitor vandetanib and achieved a dramatic response that has continued for more than 5 months (at the time of submission of this article). Case Report A 36-year-old Asian woman, a never-smoker, with lung adenocarcinoma and RET rearrangement (CCDC6-RET fusion), who was found to have widely metastatic lung cancer, presented with a mass in the right neck and innumerable metastatic nodules in the lung. Computed tomography (CT) of the neck and chest revealed enlarged lymph nodes in the right supraclavicular region, right posterior triangle, and right internal jugular chain, with the largest lymph node measuring 1.5 cm in the right supraclavicular area. Innumerable noncalcified bilateral pulmonary nodules were found, with the largest measuring 1.3 cm in the right upper lobe, and mediastinal lymphadenopathy, including a 1.9-cm pretracheal retrocaval node and a 1.3-cm aortopulmonary window node, was also identified. Excisional biopsy of a right cervical lymph node revealed metastatic, poorly differentiated adenocarcinoma. Immunohistochemical studies showed positive staining for thyroid transcription factor-1 and napsin A and negative staining for thyroglobulin, paired-box gene 8 (PAX8), mammaglobin, and estrogen and progesterone receptors in the malignant cells. Depicted in Figure 1 is a hematoxylin and eosin– stained section showing the histologic appearance of the tumor (Fig 1A), an immunohistochemical preparation showing strong cytoplasmic positivity for napsin A (Fig 1B), and an immunohistochemical preparation demonstrating a lack of expression for thyroglobulin (Fig 1C). The histologic features of the tumor, together with the strong positivity for transcription factor-1 and napsin A and the negative staining for thyroglobulin and PAX8, supported the diagnosis of metastatic lung adenocarcinoma. Treatment with the EGFR tyrosine kinase inhibitor erlotinib was started while awaiting tumor DNA sequencing analysis of EGFR, which later revealed no evidence of an EGFR mutation. Restaging scans after 2 months revealed stable findings. However, because of poor tolerance, the treatment was changed to carboplatin, pemetrexed, and bevacizumab, which resulted in slight initial improvement of the metastases but was discontinued after 9 months because of progressive disease. The patient next received treatment as part of a clinical trial of an anti–interleukin-1 monoclonal