Lenvatinib has just completed a Phase 2 trial in Gastrointestinal (GI) and Pancreatic Neuroendocrine Tumours. The trial was sponsored by Grupo Espanol de Tumores Neuroendocrinos (Spanish NET scientific organisation) and the manufacturers. A European venture with sites in Austria, Italy, Spain, UK. Headline: The responses are better than Everolimus (Afinitor) and Sunitinib (Sutent).
What is Lenvatinib?It is a type of targeted therapy known as a multikinase inhibitor. The brand name is ‘LENVIMA‘. These work by inhibiting multiple intracellular and cell surface kinases, some of which are implicated in tumour growth and metastatic progression of cancer, thus decreasing tumour growth and replication. A range of receptor kinases are involved in these processes, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (c-KIT), Flt3, fibroblast growth factor receptor (FGFR), which can be hyperactivated during tumour formation and progression. Tumour growth may be prevented by inhibiting the action of these hyperactivated receptor kinases, and as tumour progression usually involves the action of multiple kinases rather than just one, it is logical to target multiple kinases. The Lenvantinib mechanism of action is similar to targeted therapy drugs already in use (or in trial) for Neuroendocrine Tumours:
- Sunitinib (Sutent) – a targeted therapy receptor protein-tyrosine kinase inhibitor. It inhibits the actions of vascular endothelial growth factor (VEGF) and is an angiogenesis inhibitor (i.e. the development of blood vessels to supply the tumour with nutrients, which they need to grow). It is a mutlikinase in inhibitor. Click here
- Everolimus (Afinitor) – a targeted therapy kinase inhibitor that inhibits mammalian target of rapamycin (mTor) kinase, an enzyme required for cell growth and survival. By blocking this enzyme, the medication prevents cell division and, in turn, tumor growth. The medication can also interrupt angiogenesis. Click here
- Cabozantinib, an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL, and currently on trial for Neuroendocrine Cancer. Click here.
Anything special about Lenvatinib for Neuroendocrine Cancer?Recent reports from oncology conferences indicate that Lenvatinib showed significant antitumor activity and a favourable toxicity profile in progressive advanced NETs. This is the highest reported ORR with a targeted agent, confirmed by central radiology assessment in pancreatic NETs and Gastrointestinal (GI) NETs with promising progression free survival (PFS) in a pre-treated population; further evaluation is warranted. Adverse events were mild to moderate in 90% of patients, the most frequent being fatigue, diarrhea and hypertension. Lenvatinib showed the highest reported overall response rate (ORR) by central radiology assessment with a targeted agent in advanced NETs:
Average 29.2% pNETs: 40.4% (95% CI 27.3-54.9), GI NETs: 18.5% (95% CI 9.7-31.9. Worth noting that Everolimus and Sunitinib were approved with ORRs much less than these figures.
What’s next?Given the responses in comparison to other approved targeted agents, a phase 3 trial should be anticipated. Studies are “currently ongoing” and “further evaluation warranted”. I will keep this article live to provide updates.
New Trial using Lenvatinib and Everolimus in Treating Patients With Advanced, Unresectable Neuroendocrine TumorsUnder ClinicalTrials.gov Identifier: NCT03950609, there is a trial being setup at MD Anderson in Texas USA. Use of a combo of Lenvatinib along with Everolimus (Afinitor) in treating patients with advanced, unresectable Neuroendocrine Tumors (the word ‘Carcinoid’ is used in the trial documentation).
Reference material used in the compilation of this article:1. Annals of Oncology – Efficacy of Lenvatinib in patients with advanced pancreatic (panNETs) and gastrointestinal (giNETs) grade 1/2 (G1/G2) neuroendocrine tumors: Results of the international phase II TALENT trial (GETNE 1509) 23 Oct 2018 – click here. 2. ESMO Congress 2018 – Efficacy of Lenvatinib in patients with advanced pancreatic (panNETs) and gastrointestinal (giNETs) grade 1/2 (G1/G2) neuroendocrine tumors – click here 3. Prime Oncology Slide Show – click here (useful) 4. Clinical Trials Document NCT02678780 – click here 5. Manufactures website – click here. 6. Clinical Trials Document NCT03950609 for the trial of combo treatment Lenvatinib and Everolimus. Click here. As at 15 May 2019, the trial was not recruiting but see document for contact details, quite often these documents can be behind in updating. Trial start date recorded as 30 June 2019.
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