lenvatinib and Neuroendocrine-Tumors

Approved systemic therapies for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown limited capacity to reduce tumor burden and no antitumor activity after progression to targeted agents (TAs). We investigated the efficacy and safety of lenvatinib in patients with previously treated advanced GEP-NETs.. This was a multicenter, single-arm, open-label, phase II trial with two parallel cohorts (ClinicalTrials.gov identifier: NCT02678780) involving 21 institutions in 4 European countries. Eligible patients had histologically confirmed advanced grade 1-2 pancreatic (panNET) or GI (GI-NET) NETs with documented tumor progression after treatment with a TA (panNET) or somatostatin analogs (GI-NET). Patients were treated with lenvatinib 24 mg once daily until disease progression or treatment intolerance. The primary end point was overall response rate by central radiology review. Secondary end points included progression-free survival, overall survival, duration of response, and safety.. Between September 2015 and March 2017, a total of 111 patients were enrolled, with 55 (panNET) and 56 (GI-NET) patients in each cohort. The median follow-up was 23 months. The overall response rate was 29.9% (95% CI, 21.6 to 39.6): 44.2% (panNET) and 16.4% (GI-NET). The median (range) duration of response was 19.9 (8.4-30.8) and 33.9 (10.6-38.3) months in the panNET and GI-NET groups, respectively. The median progression-free survival was 15.7 months (95% CI, 14.1 to 19.5). The most common adverse events were fatigue, hypertension, and diarrhea; 93.7% of patients required dose reductions or interruptions.. We report the highest centrally confirmed response reported to date with a multikinase inhibitor in advanced GEP-NETs, with a particularly strong response in the panNET cohort. This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other TAs, suggesting the potential value of lenvatinib in the treatment of advanced GEP-NETs.

Topics: Adult; Aged; Antineoplastic Agents; Europe; Female; Gastrointestinal Neoplasms; Humans; Male; Middle Aged; Neoplasm Grading; Neuroendocrine Tumors; Pancreatic Neoplasms; Phenylurea Compounds; Progression-Free Survival; Prospective Studies; Protein Kinase Inhibitors; Quinolines; Time Factors

Neuroendocrine neoplasms (NENs) are a rare group of tumors exceptionally heterogeneous, with clinical presentation ranging from well differentiated more indolent tumors to poorly differentiated very aggressive forms. Both are often diagnosed after the metastatic spread and require appropriate medical treatment. A high priority need in the management of this disease is the identification of effective therapeutic strategies for advanced and metastatic patients. The recent TALENT trial demonstrated the efficacy of lenvatinib, a multi-tyrosine kinase inhibitor, in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with no other treatment indication. Further development of this drug in advanced NETs is warranted.. We investigated potential clinical and molecular determinants of lenvatinib response in human primary cultures derived from patients with GEP-NET of different grades and sites of origin. We correlated response to treatment with patient clinical characteristics, with the mutational status of 161-cancer associated genes and with the expression levels of MKI-related genes.. Lenvatinib exerted a significant antitumor activity in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard frontline treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder showing a significant survival inhibition, and 5 as non-responder. We observed that the overexpression of HRAS in the original tumor tissue compared to the matched healthy tissue significantly correlated with responsiveness of primary cells to lenvatinib (p=.048). All 5 non-responder cultures showed normal HRAS expression, while of the 6 responder cultures, 4 had HRAS overexpression. Overexpression of HRAS was not associated with gene mutation. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) or molecular markers correlated with response.. Lenvatinib appears to be a highly effective drug for the treatment of NETs. The evaluation of HRAS expression in the tumor tissue might improve patient selection and optimize therapeutic outcome.

Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Stomach Neoplasms