Lenvatinib, a multikinase inhibitor with activity against RET fusions, showed clinical benefit in patients with RET fusion-positive adenocarcinoma of the lung who demonstrated a disease control rate (DCR) of 76%,according to phase II study findings presented on 9 October at the ESMO 2016 Congress in Copenhagen, Denmark.
RET fusions activate RET kinase and are seen in approximately 1% to 2% of patients with lung adenocarcinoma, prompting Vamsidhar Velcheti, Taussig Cancer Institute, Cleveland Clinic in Cleveland, USA and colleagues to investigate the efficacy of lenvatinib, a multikinase inhibitor with activity to RET, in an open label, phase II trial.
The study enrolled 25 patients with RET-positive lung adenocarcinoma, who were treated with lenvatinib at 24 mg per day in 28-day cycles until disease progression or unacceptable toxicity occurred. Previously treated patients were eligible for enrolment, including those receiving prior RET-targeted therapy.
The primary endpoint of the trial was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), overall survival (OS), DCR defined as complete response (CR) plus partial response (PR) plus stable disease (SD lasting for ≥ 7 weeks), clinical benefit rate (CBR) defined as CR plus PR plus durable SD (SD lasting for ≥23 weeks), and safety.
Tumour shrinkage was observed in the majority of patients
Of the 25 patients with RET-positive NSCLC, 13 patients showed KIF5B-RET fusion, and 12 patients had other RET fusion. Just 2 (8%) patients had received no prior treatment; 15 (60%) patients received ≥2 prior lines of therapy, and 7 (28%) patients had received prior RET therapy. The smoking status of the cohort included 16 (64%) never smokers, 1 (4%) current smoker, 7 (28%) former smokers, and 1 (4%) patient with unknown status.
Nearly half (48%) of patients showed a durable response. The primary endpoint ORR was 16% and consisted entirely of confirmed PRs in 4 patients. The DCR was 76% (19 patients). Of these, 12 maintained response for 23 or more weeks, yielding a CBR of 48%.
Median PFS in the entire study group was 7.3 months; 95% confidence interval (CI) 3.6, 10.2 months. Median OS was not reached; 95% CI 5.8 months, NE.
Subgroup analysis revealed that the 7 patients previously treated with a RET therapy showed the greatest response. In this cohort, The ORR was 14%, DCR was 86%, and CBR was 57% compared with 17%, 72%, and 44%, respectively, in patients not receiving prior RET inhibitors.
Acceptable safety profile with lenvatinib
The most commonly reported treatment-emergent adverse events (TEAEs) were hypertension, which occurred in 68% of patients, nausea in 60%, decreased appetite and diarrhoea, each occurring in 52%, proteinuria in 48%, and vomiting in 44% of patients.
TEAEs grade 3 or higher were reported in 23 (92%) patients. TEAEs requiring drug withdrawal occurred in 5 (20%) patients, dose reduction in 16 (64%), and dose interruption occurred in 19 (76%) patients.
Three deaths due to AEs occurred on study; one death from pneumonia was possibly related to lenvatinib.
Enriqueta Felip who discussed the study findings said that RET fusions are detected in 1-2% of lung adenocarcinoma. A number of genes, such as KIF5B, CCDC6, NCO4 and TRIMM33 can act as fusion partners. Lenvatinib is oral multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFR–alpha, and RET and KIT proto-oncogenes. At present, there are no specific RET inhibitors in clinical trials. Many potent RET inhibitor compounds have been initially designed to target other tyrosine kinase. There are case reports of activity of vandetanib, cabozantinib, lenvatinib, ponatinib, alectinib, sunitib, sorafenib, dovitinib in RET-positive patients.
Activity of vandetanib, lenvatinib and cabozantinib is described in phase II trials. In term of targeting RET in patients with RET-rearranged lung cancers, the results from a global registry have been reported at ASCO 2016 Annual Meeting. RET inhibitors in phase II trials are active in a subgroup of patients with RET-rearranged NSCLC with lower RR to that observed in EGFR-mutant/ALK patients. Dr. Felip emphasized that improved understanding of tumour biology and new therapeutic approaches is needed. Ongoing/planned clinical trials include testing of apatinib, cabozantinib, ponatinib, and alectinib in that patient population.
The investigators concluded that lenvatinib showed promising clinical activity in patients with RET-positive NSCLC, with most patients demonstrating tumour shrinkage and disease control. According to the investigators, toxicities were manageable in most patients with dose modification.
These results support for lenvatinib as a potential treatment for patients with RET-positive NSCLC.
Phase 2 study of lenvatinib (LN) in patients (Pts) with RET fusion-positive adenocarcinoma of the lung
V. Velcheti, T. Hida, K.L. Reckamp, J.C. Yang, H. Nokihara, P. Sachdev, K. Feit, T. Kubota, T. Nakada, C.E. Dutcus, M. Ren, T. Tamura
This study was funded by Eisai Inc.