Identification of a Novel KIF5B-RET, ABHD17C-RET Double-Fusion Variant in Lung Adenocarcinoma and Response to Cabozantinib

Ret proto-oncogene (RET) fusion is an emergent driving oncogene in NSCLC, and kinesin family member 5B (KIF5B)-RET fusion is the most frequent type. With the rapid development and popularity of next-generation sequencing, an increasing number of uncommon RET fusion partners have been discovered, including coiled-coil domain containing 6, nuclear receptor coactivator 4, and tripartite motif containing 33.^, However, to date, there were no reported cases of two RET fusions detected simultaneously in a patient with NSCLC. Here, we present the first case of KIF5B-RET, abhydrolase domain containing 17C (ABHD17C)-RET double-fusion variant in a patient with lung adenocarcinoma who responded well to cabozantinib.

A 72-year-old nonsmoking woman consulted a local hospital with complaint of weakness in the right upper extremity in June 2019. The computed tomography scan revealed a mass in the upper lobe of the left lung. Thereafter, the patient was referred to our hospital. Multiple brain metastases were seen in a magnetic resonance imaging scan, but ¹⁸F-deoxyglucose on positron emission tomography scan did not reveal other distant metastases. Bronchoscopy biopsy revealed a poorly differentiated adenocarcinoma. Subsequent amplification refractory mutation system-polymerase chain reaction for EGFR mutation and fluorescence in situ hybridization for anaplastic lymphoma kinase and ROS1 rearrangements did not reveal a druggable target. Considering the presence of obvious central nervous system symptoms, the patient was first administered whole-brain radiotherapy. However, after the whole-brain radiotherapy, she was deemed unsuitable for the continuation of palliative chemotherapy because she had a performance status of three and weighed only 32 kg. After adequate communication with the patient, a biopsy sample was sent for a targeted next-generation sequencing panel of 295 genes to find a druggable target. The results indicated a double RET fusion—KIF5B exon 15-RET exon 12 and ABHD17C exon 1-RET exon 12. The patient was commenced on cabozantinib (60 mg, once daily) as the first-line treatment from August 24, 2019. Her clinical symptoms improved, and the longest diameter of lung mass decreased from 64 mm to 41 mm after 1 month of cabozantinib treatment (Fig. 1). Moreover, a marked cavitation of pulmonary lesion was noted. However, owing to the grade II palmar-plantar erythrodysesthesia, the dose of cabozantinib was reduced to 40 mg daily for the first time and to 20 mg daily for the second time. Even so, the patient remained intolerable to cabozantinib, which is why cabozantinib was discontinued after 3 months of treatment.

Although RET fusion is detected in only 1% to 2% of cases of lung cancer, RET inhibitors are developing rapidly. Cabozantinib and vandetanib are the two currently available targeted agents for RET fusion.^{,  ,}  The ABHD17C-RET fusion and its response to RET inhibitors have never been reported in previous literature. However, KIF5B-RET fusion is known to confer sensitivity to cabozantinib.^{,  ,}  In our case, we cannot exclude a predominance of the KIF5B-RET clone in the patient’s tumor, which led to a good response to cabozantinib.

In conclusion, this is the first report, to our knowledge, of two RET fusions detected simultaneously in a case of lung adenocarcinoma and the first description of clinical efficacy of RET inhibitor cabozantinib on NSCLC harboring a novel KIF5B-RET, ABHD17C-RET double-fusion variant.