Lenvatinib has 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 is 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.

Multikinase inhibitors such as Lenvatinib, may be used to treat advanced kidney cancer as well as other specific types of cancer (in my research I also noted that in addition to kidney cancer, the drug is already approved for liver and thyroid cancers).  Worth also noting that the 3 examples of targeted therapy above are not just in use/in trial for Neuroendocrine Cancer, they are also in use/in trial for others including Renal (Kidney) Cancer, Breast Cancer.  Often more than one single kinase inhibitor can be given as a combo treatment, perhaps in sequence, to tackle multi kinases.

In this multicenter, open-label study involving 111 patients, treatment with lenvatinib (Lenvima) led to an overall response rate (ORR) of 29.9%, with a particularly high ORR — 44.2% — in patients with pancreatic NETs, reported Jaume Capdevila, MD, PhD, of Vall Hebron University Hospital in Barcelona, and colleagues.

Worth noting that Everolimus and Sunitinib were approved with ORRs much less than these figures.

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.

ASCO Extract 2019

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.