Clinical Trial: Lenvatinib Efficacy in Metastatic Neuroendocrine Tumors (TALENT)



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.
  • 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.
  • 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.

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 Tumors

Under 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.

Thanks for reading

Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!



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Round up of NANETS 2017 – Let’s talk about NETs #NANETS2017

NANETS (North American Neuroendocrine Tumor Society) is one of the biggest NET conferences, bringing together NET Specialists from around the world to discuss state-of-the-art treatment modalities, new therapies, and ongoing controversies in the field of Neuroendocrine Neoplasms (Tumors and Carcinomas). This is fairly complex stuff but much of it will be familiar to many. I’ve filtered out several outputs from the conference which I think are both relevant and topical to patients. The list is below allowing you to easily peruse and read further via linkages if you need to read more.  Remember, some of these are extracts so do not contain all the details of the research or study – although some of the linkages will take you to in-depth information if that’s your bag. Where applicable, I’ve also linked to some of my blog posts to add context and detail in patient speak. The list comprises articles which were published in medical news media and for which I received alerts.  It does not comprise the entire schedule of NANETS 2017. I may add more to the list if other relevant and interesting articles are published downstream.

Please note:
Some of the output from the conference is in ‘study form’ and has not yet been published as peer-reviewed data (important notice to readers).

NANETS to Bring All Specialties in the NETs Community Together for 10th Annual Symposium

Interview with Michael Soulen MD.  Nice introduction.

https://goo.gl/tMT6KS
Location of Neuroendocrine Tumors in the Small Bowel Does Not Affect Survival

 

https://goo.gl/zf9k9j
Diagnosing and Treating NET-Related Diarrhea

 

Incorporated into my Diarrhea article – https://goo.gl/PwsXmX
Emerging Therapies, Biologic Discoveries, and Improved QoL on Horizon for NETs

 

https://goo.gl/p4cCyd
Retrospective Database Analysis Studies Somatostatin Analog Usage in NETs

 

https://goo.gl/KWM4p7
Regional Lymph Node Involvement and Outcomes in Appendiceal Neuroendocrine Tumors: A SEER Database Analysis. https://goo.gl/vfF4DA
Personalizing Therapy With PRRT and Improving Imaging With SSTR-PET Brings Novel Options to NETs Landscape

(new term SSTR-PET generically meaning any PET scan using somatostatin receptors), e.g. Ga68 etc.

https://goo.gl/s8sked
PFS and OS After Salvage Peptide Receptor Radionuclide Therapy (PRRT) with 177-Lu[Dota⁰,Tyr³] octreotate in Patients with GastroEnteroPancreatic or Bronchial NeuroEndocrine Tumours (GEP-NETs) – The Rotterdam Cohort https://goo.gl/yZ56YZ
Molecular Classification of Neuroendocrine Tumors: Clinical Experience with the 92-gene Assay in >24,000 Cases https://goo.gl/aqgfRf
Neuroendocrine Tumors: A Patient Survey

“Regarding their biggest challenges, patients reported fatigue as their biggest challenge followed by diarrhea, sleep disturbances, and pain.”

https://goo.gl/qEeNRM
Phase III Trial Needed to Confirm Clinical Benefit of Cabozantinib in NETs

 

Incorporated into my Cabozantinib article – https://goo.gl/mR2yFT
QOL Improvements in NETTER-1 Phase III Trial in Patients with Progressive Midgut Neuroendocrine Tumors. (I think this is well-known but no harm in repeating it!) https://goo.gl/UmKsFi

 

The full link to all poster abstracts for NANETS 2017 can be found here

Thanks for reading

Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

Neuroendocrine Tumor Drug Clinical Trial – Cabozantinib (includes news on Pheochromoctyoma and Paraganglioma)

What is Cabozantinib?

Cabozantinib is an oral drug which works by blocking the growth of new blood vessels that feed a tumour. In addition to blocking the formation of new blood cells in tumours, Cabozantinib also blocks pathways that may be responsible for allowing cancers cells to become resistant to other “anti-angiogenic” drugs. It is a type of drug called a growth blocker.  Cabozantinib has been studied or is already in research studies as a possible treatment for various types of cancer, including prostate cancer, ovarian cancer, brain cancer, thyroid cancer, lung cancer, and kidney cancer. During my research, I found that it has a connection to Medullary Thyroid Cancer (MTC) which is a type of Neuroendocrine Cancer, frequently associated with Multiple Endocrine Neoplasia (MEN).  Cabozantinib, under the brand name of ‘Cometriq’ was approved by the FDA in 2012 for use in MTC.  Read more about Cometriq here.  It’s also been approved by the FDA for advanced renal cell carcinoma (RCC) (branded as Cabometyx). I also discovered that there is an exclusive licensing Agreement with the manufacturers (Elelixis) and Ipsen (of Lanreotide fame) to commercialize and develop Cabozantinib in regions outside the United States, Canada and Japan

Growth blockers are a type of biological therapy and include tyrosine kinase inhibitors, proteasome inhibitors, mTOR inhibitors, PI3K inhibitors, histone deacetylase inhibitors and hedgehog pathway blockers.  Cabozantinib is a tyrosine kinase inhibitor (TKI).  They block chemical messengers (enzymes) called tyrosine kinases.  Tyrosine kinases help to send growth signals in cells so blocking them stop the cell growing and dividing.  Some TKIs can block more than one tyrosine kinase and these are known as multi-TKIs.

cabozantinib-picture
Example action of Cabozantinib

So Capozantinib is a tyrosine kinase inhibitor and is therefore a biological therapy and growth blocker just like Everolimus (Afinitor) and Sunitinib (Sutent) – some texts describe thelattero two as chemotherapy but this is just not accurate.

Very technical process but in the simplest of terms, Cabozantinib is designed to disrupt the actions of VEGF (a growth factor) and MET (a growth factor receptor) which promote spread of cancerous cells through the growth of new blood vessels.  Whilst we are on this subject, please note Everolimus (Afinitor) is an mTOR inhibitor and Sunitinib (Sutent) is a tyrosine kinase inhibitor. Many people think these drugs are a type of chemo – that is incorrect, these are targeted biological therapies.  See more on this by clicking here.

What is the current trial status of Capozantinib?

A Phase III trial is now recruiting entitled Cabozantinib S-malate in Treating Patients With Neuroendocrine Tumors Previously Treated With Everolimus That Are Locally Advanced, Metastatic, or Cannot Be Removed by Surgery”. 

The trial has 172 locations across the US (see link below). The primary study (final data) is scheduled Jan 1st 2021.

You can read the trial documentation by clicking here.

Progress report

  1. Poster submission for 2017 Gastrointestinal Cancer Symposium
  2. Onc Live output from the 2017 Gastrointestinal Cancer Symposium
  3. Output from NANETS 2017
  4. A funded piece of research by the NET Research Foundation – check it out herelooks like they are trying to figure out what patients might benefit from Cabozantinib using biomarker data to predict response.
  5. Dr Jennifer Chan speaking in 2018 about the drug potential.  (Apologies for the use of the out of date term ‘Carcinoid‘).
  6. Phase 3 Clinical Trial Document – click here

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UPDATED 2018 – There’s also another trial looking at unresectable metastatic Pheochromocytomas and Paragangliomas

A Phase 2 Study to Evaluate the Effects of Cabozantinib in Patients with Unresectable Metastatic Pheochromocytomas and Paragangliomas 

This part is from an article collaboration between MedPage Today® and the American Association of Clinical Endocrinologists

BOSTON — Cabozantinib (Cabometyx) may benefit patients with malignant pheochromocytomas and paragangliomas, according to results of a phase II trial presented here.

Patients receiving cabozantinib (Cometriq) treatment experienced notable tumor shrinkage in the lymph nodes, liver, and lung metastases, according to Camilo Jimenez, MD, of the MD Anderson Cancer Center in Houston, and colleagues.

Additionally, progression-free survival significantly increased after treated to 12.1 months (range 0.9-28) compared with just 3.2 months prior to treatment, they reported at the American Association of Clinical Endocrinologists (AACE) annual meeting.

Cabozantinib treatment was also tied to an improvement in blood pressure and performance status, as well as remission of diabetes among these patients.

“Malignant pheochromocytomas and paragangliomas are frequently characterized by an excessive secretion of catecholamines. [Patients] have a large tumor burden and they have a decreased overall survival,” explained Jimenez. “Tumors are frequently very vascular and frequently associated with bone metastases. In fact, up to 20% of patients who have malignancy of pheochromocytomas and paragangliomas may have predominant bone metastases.”

He added that “an interesting aspect of this tumor is that C-MET receptor mutation have been found in occasional patients with malignant pheochromocytomas and paragangliomas.”

Cabozantinib is an anti-angiogenic tyrosine kinase inhibitor, which also targets RET, MET, and AXL. It is approved for metastatic medullary thyroid cancer, and was more recently approved for first-line treatment of advanced renal cell carcinoma.

“MET pathway is also involved in the development of bone metastases. In fact, cabozantinib is a very effective medications for patients who have bone metastases in the context of cancer of different origins,” Jimenez said.

In order to be eligible for the trial, patients with confirmed pheochromocytoma or paraganglioma had to be ineligible for curative surgery, have ≥3 months life expectancy, no risk for perforation or fistula, and adequate organ functioning. Prior to cabozantinib initiation, patients could not receive chemotherapy or biologic agents within 6 weeks, radiation within 4 weeks, or MIBG within 6 months.

Following histological confirmation of disease progression >1 year according to RECIST 1.1, the trial included 14 patients with measurable disease and eight patients with predominant/exclusive bone metastases. Fifteen patients subsequently enrolled into the trial, six of whom had germline mutations of the SDHB gene.

All participants were all started at an initial daily dose of 60 mg of cabozantinib, which was subsequently reduced down to between 40 to 20 mg due to toxicity in 13 patients based on tolerance.

The majority of these patients with measurable disease experienced some level of disease response. Six patients reported a partial response, defined as over a 30% reduction, while three patients achieved moderate response, marked by a 15%-30% reduction. Five of the patients with predominant bone metastases reported disease stabilization, according to results of an FDG-PET scan. One patient experienced disease progression while on treatment.

Overall, cabozantinib was generally well-tolerated without any grade 4 or 5 treatment-related adverse events reported. Some of the most common adverse events reported included grade mild dysgeusia, hand and foot syndrome, mucositis, fatigue, weight loss, and hypertension, according to the authors.

  • Primary Source – American Association of Clinical Endocrinologists meeting – AACE 2018; Abstract 142. attended my Medscape writers

You can see the Pheo/Para clinical trial document by clicking here.

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Summary

I generated this blog article to add value rather than just post the outputs for your own perusal.  I hope you find it useful.

Please note that taking part in a clinical trial is a big decision and must be considered carefully in conjunction with your specialists if necessary.  This article is not suggesting this trial is right for you.  Please check the inclusion and exclusion criteria in the trials document carefully. (Pheo/Para patients see other clinical trial link above)