LURET study: Phase 2 study of vandetanib in patients with advanced RET-rearranged non-small cell lung cancer (NSCLC)

Background

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.

Methods

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.

Results

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%).

Conclusions

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

UMIN000010095

Legal entity responsible for the study

N/A

Funding

Grants from an Japan Agency for Medical Research and Development (AMED) Practical Research for Innovation Cancer Control.

Disclosure

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.