RET rearrangements were identified as a new rare oncogenic alteration in NSCLC. Vandetanib is a multi-targeted tyrosine kinase inhibitor having RET kinase inhibitory activity.
This was a multicenter, single-arm phase 2 study to evaluate the efficacy and safety of vandetanib in patients with advanced RET-rearranged NSCLC who failed at least one prior chemotherapy. Vandetanib was administered orally at 300 mg once daily in 28-day cycles. RET positive-patients were screened by a nationwide genomic screening project with approximately 200 institutions in Japan participating (LC-SCRUM-Japan). The primary endpoint was the independently assessed objective response rate (ORR). Exploratory subgroup analyses for ORR and progression-free survival (PFS) were performed with the factors including sex, smoking status, and type of RET fusions.
With screening of 1536 advanced NSCLC patients in the LC-SCRUM-Japan, 34 RET positive-patients (2%) were identified. A total of 19 patients (10 KIF5B-RET, 6 CCDC6-RET, and 3 unknown) were enrolled in this study and 17 patients were eligible for primary efficacy analysis. Half of the patients had been heavily treated with 3 or more prior chemotherapy (range, 1 to 12). Among 17 eligible patients, ORR was 53% (90% CI, 31 to 74) of which 9 partial responses and no complete response met the primary endpoint. Of 19 patients in ITT population, disease control rate was 90% and median PFS was 4.7 months (95% CI, 2.8 to 8.5). In the subgroup analyses according to type of RET fusions, ORR and median PFS were 83% (5/6) and 8.3 months in CCDC6-RET, 20% (2/10) and 2.9 months in KIF5B-RET and 67% (2/3) and 4.7 months in unknown. There were no significant differences for ORR and PFS among sex and smoking status. The most common adverse events were hypertension (84%), diarrhea (79%), rash (63%), dry skin (42%), and QT corrected interval prolonged (42%).
Vandetanib demonstrated effective antitumor activity and manageable safety profile in patients with advanced RET-rearranged NSCLC. The exploratory subgroup analyses demonstrated that tumors with CCDC6-RET fusion showed greater response to vandetanib than those with KIF5B-RET fusion.
Clinical trial identification
Legal entity responsible for the study
Grants from an Japan Agency for Medical Research and Development (AMED) Practical Research for Innovation Cancer Control.
K. Yoh, M. Satouchi, M. Nishio: Honoraria: AstraZeneca. Research funding: AstraZeneca. T. Seto: Honoraria: AstraZeneca, Sanofi. Research funding: AstraZeneca. N. Yamamoto, H. Murakami, N. Nogami: Honoraria: AstraZeneca. S. Nomura: Mr. Nomura received personal fees from Japan Breast Cancer Research Group (JBCRG), and grants from Japan Agency for Medical Research and Development (AMED), outside the submitted work. JBCRG: €500 - €20’000 AMED: €500 - €20’000. K. Goto: Research funding: AstraZeneca. All other authors have declared no conflicts of interest.