RET fusions have been identified as new driver oncogenes in non–small-cell lung cancer (NSCLC) and are observed in 1% to 2% of all NSCLC patients.1 Vandetanib is a multitargeted tyrosine kinase inhibitor with RET kinase activity. In a multicenter, single-arm phase 2 study to evaluate the efficacy and safety of vandetanib in patients with advanced RET-rearranged NSCLC who had failed at least one prior treatment with systemic chemotherapy, Seto and colleagues2 administered vandetanib 300 mg orally once daily in 28-day cycles. The primary end point was objective response rate (ORR) by an independent review committee. Secondary end points included progression-free survival (PFS), disease control rate, duration of response, overall survival (OS), and safety. A total of 19 patients (10 KIF5B-RET, 6 CCDC6-RET, and 3 unknown-RET) were enrolled in this study and 17 patients were eligible for efficacy analysis. All patients had adenocarcinoma and 68% were never-smokers. A majority (63%) had received 2 or more prior cycles of chemotherapy (range, 1-12). Among 17 eligible patients, median ORR was 53%, of which 9 partial responses met the primary end point, and the disease control rate was 90%. The median PFS was 4.7 months (95% confidence interval, 2.8-8.3). According to RET fusion subtypes, ORR and median PFS were 83% and 8.3 months in patients with CCDC6-RET versus 20% and 2.9 months in those with KIF5B-RET. The median OS was 11.1 months, with a 1-year OS of 47%. The safety profile of vandetanib was similar to that reported previously. The most common grade 3/4 toxicities were hypertension (58%), rash (16%), diarrhea (11%), and QTc prolongation (11%). This study showed that vandetanib demonstrates marked antitumor activity in patients with advancedRET-rearranged NSCLC. Interestingly, the CCDC6-RET subtype showed much higher sensitivity to vandetanib than other RET subtypes.
