P3.13-33 Lung Adenocarcinoma Harboring RET Fusion and Dramatic Response to Combination of Vandetanib (VAN) and Everolimus (EVE): A Case Report from Brazil

Abstract

The identification of oncogene addicted NSCLC and the development of target therapies lead to improvement in survival rates and quality of life. In addition to other drugable targets such as EGFR mutation and ALK translocation, RET fusion has been shown to be an oncogenic driver in 1 to 2% of patients with NSCLC. Here we report a 23-year old never-smoker male patient (Pt) diagnosed with lung adenocarcinoma, metastatic to lymph nodes, bones and lungs. Tumor biopsy was performed during broncoscopy. Tissue molecular testing was negative for EGFR (cobas) and ALK (FISH), and PDL-1 tumor proportional score (22C3) was 5%. Pt presented rapid disease progression after one cycle of cisplatin and pemetrexed, with pleural effusion and respiratory distress. Since initial tissue biopsy paraffin had been exhausted, next generation sequencing in cell-free tumor circulating DNA in plasma was performed (Guardant360). CCDC6-RET fusion and TP53 mutation (T256I) were identified. Based on promising activity of the combination of VAN with EVE previously reported, and the lack of clinical trials in this setting in Brazil, Pt started oral target therapy with VAN 300 mg and EVE 10 mg daily. He had unequivocal clinical improvement over the following weeks, with discontinuation of pain medications and relief of respiratory symptoms. After 30 days on treatment, restaging CT scans demonstrated a dramatic response. Adverse events were grade (G) 1 cutaneous rash, G1 stomatitis and G1 diarrhoea. Pt also presented G1 pneumonitis that resolved rapidly with EVE temporary discontinuation. He remained without disease progression at 4+ months. After 5 months, he presented pneumonitis recurrence with respiratory failure. VAN is a multi-targeted tyrosine kinase inhibitor of EGFR, VEGFR and RET, with limited activity in RET-rearranged NSCLC phase 2 trial. However, the concurrent inhibition of RET and the mammalian target of rapamycin (mTOR) has shown promising activity for RET-rearranged tumors in preclinical models. Among the 6 evaluable NSCLC patients with RET fusions treated with VAN and EVE in phase I trial, 5 achieved partial responses (83%) and 1 stable disease (16%). In particular, it has been suggested that CCDC6-RET subtype shows higher sensitivity to VAN. This case report corroborates the promising activity of combination of VAN and EVE in RET-rearranged NSCLC.