Neuroendocrine Cancer Clinical Trial – Lutetium-177 OPS-201 (Satoreotide)

ops 201

What is Lutetium-177 OPS-201?

This is a ‘next generation’ Peptide receptor radionuclide therapy (PRRT) or more specifically the radiopharmaceutical that binds to both activated and unactivated somatostatin receptors which are upregulated on these tumours. There is far higher binding via this mechanism than standard octreotate. The technical name of the radiopharmaceutical is Satoreotide tetraxetan lutetium-177 (author’s note, I’m guessing but it could be a variant of Lanreotide).  It was once named JR11.

What’s the difference to the current approved therapy? 

Conventional PRRT (e.g. Lutathera, Lu177 Dotatate) is based on a somatostatin receptor ‘agonist’ approach, whereas 177Lu Ops 201 Satoreotide is a receptor ‘Antagonist’.  The differences are quite technical but in the most layman terms , the antagonist has the capability of attaching (binding) to more receptors, including those in a ‘resting’ or ‘inactive’ state, spends more time on the tumor than agonist based therapies. The result is a higher number of receptor binding sites and greater tumor uptake.  In addition it is said to show an improved tumor-to-kidney dose ratio compared to 177Lu-DOTA-TATE.

This would also be reflected in the theranostic use of the drug in Ga68 imaging (i.e. Ga68 Satoreotide).

Useful reading:

This presentation from Theranostics Australia

The Clinical Trial

The clinical trial is named “Study to Evaluate the Safety and Preliminary Efficacy of 177Lu-OPSC001 in NETs”.  The protocol involves 3 cycles 8 weeks apart of intravenous Lu-177 OPS-201. All patients will have baseline Ga-68 octreotate imaging performed.

The treatment is available for all NET patients with a histologically confirmed diagnosis of:

  • unresectable GEP NET (Grade I and Grade II according to WHO classification (2010, Annex 01), functioning and non-functioning).
  • unresectable “typical lung NET” or “atypical lung NET” are acceptable (with the exception of Large Cell Bronchial Neuroendocrine Neoplasms and Small Cell Lung Cancers).
  • malignant, unresectable pheochromocytoma or paraganglioma

Patients who have previously had Lu-177 octreotate (e.g. Lutathera) are not eligible. Patients may have had any other treatment including chemotherapy, radiotherapy or Somatostatin Analogues (e.g. octreotide, landreotide).

There are other inclusion and exclusion criteria to be found within the clinical trial document.  The trial is due to compete in May 2022.

Where is the Trial based?  

At the time of writing and according to the Clinical Trial document, Australia (Melbourne and Perth),  Austria (Vienna), Denmark (Aarhus), Switzerland (Basel), UK (Royal Free London).  Two sites are also listed in France (Nantes and Toulouse) but trial document currently marked as not yet recruiting.

I have anecdotal evidence to suggest one more UK site is possible in 2019, Windsor in UK, a private healthcare provider but it will be open to public and private patients.

What about USA?

I also found an additional trial based in Memorial Sloan Kettering New York designed to take a theranostic approach by using  Satoreotide (JR11) for the pre-treatment imaging, e.g. Ga68 satoreotide (JR11) and the 177Lu version for treatment. The clinical trial document indicates this trial is active but NOT RECRUITING and is entitled “Theranostics of Radiolabeled Somatostatin Antagonists 68Ga-DOTA-JR11 and 177Lu-DOTA-JR11 in Patients With Neuroendocrine Tumors”

Thanks for reading

You may also find these PRRT related articles useful:

PRRT Overview plus locations 

Phase 1 trial of Targeted Alpha-emitter Therapy (TAT) –  212 Pb-AR-RMX

COMPETE trial 177Lu Edotreotide-Solucin

PRRT and Chemo Trial

Ronny

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Expanding PRRT – Trial of 177Lu-Edotreotide (Solucin®) – COMPETE Phase 3 Clinical Trial

ITM_header_products_endolucinbeta
graphic courtesy of ITM AG

In the News.

On the heels of the approval of PRRT in USA and whilst we all wait on positive national announcements of PRRT approval in UK and elsewhere, here’s news of a new PRRT compound undergoing a phase 3 clinical trial.  Isotopen Technologien München AG (ITM), a specialized radiopharmaceutical company, today announced the enrolment of the first patient recruited in Europe for the COMPETE phase III clinical trial at the University Hospital Marburg, Germany. The CEO of ITM said “This marks the starting point of COMPETE in Europe, whereby we expect a rapid increase in the number of recruits.”  I actually met these guys at ENETS 2018 – sounds great.

What is the COMPETE trial?

COMPETE is led as an international pivotal multi-center phase III clinical trial evaluating the efficacy and safety of (no-carrier-added) n.c.a.177Lu-Edotreotide (Solucin®) and the trial is comparing it to Everolimus (Afinitor). The trial runs until Dec 2020. The enrolment requires patients with inoperable, progressive, somatostatin-receptor positive neuroendocrine tumors of gastroenteric or pancreatic origin (GEP-NET). The primary endpoint is progression-free survival (PFS). The study will be conducted predominantly in Europe, North America, South Africa and Australia (ITM is waiting on FDA clearance to include North American locations in the trial). The first patient to be enrolled and treated was in Australia.  The clinical trial document (see references below) indicates its for non-functional GI tumours but for non-functional and functional pNETs. The list of locations can also be found in the clinical trial document. The usual inclusion/exclusion rules apply but the most notable would appear to be an exclusion for those with prior exposure to any PRRT or mTor inhibitor such as Everolimus (Afinitor).

What is 177Lu-Edotreotide (Solucin®) ?

The compound under investigation, Solucin®, is known as a Targeted Radionuclide Therapy (TRT) agent, which consists of the targeting molecule Edotreotide, an octreotide-derived somatostatin analogue and ITM´s EndolucinBeta® (no-carrier-added Lutetium-177). EndolucinBeta® is a synthetic, low-energy beta-emitting isotope of Lutetium, a recently EMA approved pharmaceutical precursor. The radiopharmaceutical Solucin® is administered as an intravenous infusion, specifically targeting and destroying the tumor cells with ionizing radiation. Solucin® received an Orphan Designation (EMA/OD/196/13) for the treatment of GEP-NET, based on early clinical experience, which has demonstrated a substantial clinical benefit with increased PFS and quality of life.

From ITM’s website … “Edotreotide contains DOTA which functions as a chelator for radioisotopes and TOC, a synthetic Somatostatin receptor ligand” (chelator and ligand are just fancy names for ‘bonding’ or ‘binding’). “The compound Edotreotide binds with high affinity Somatostatin receptors and retains both its receptor binding properties and its physiological function when labeled with 177Lu. Somatostatin receptors are predominantly overexpressed by neuroendocrine tumors. 177Lu-Edotreotide, upon binding to Somastotatin receptors in vivo is internalized and retained by tumor cells.” 

“Compared to 90Y-Edotreotide, 177Lu-Edotreotide Targeted Radionuclide Therapy in NET was found to be less haematotoxic and associated with a longer median overall survival. That was highly significant for patients with low tumor uptake as well as for patients with extra hepatic and solitary metastases. In a retrospective Phase II trial 177Lu-Edotreotide showed a low uptake/dose delivered to normal organs and very high tumor-to-kidney ratio.”

Other Spin offs from ITM

Interestingly the company is also working on a ‘theranostic pair’ for imaging and treating bone metastases – see graphic below.  It does not say whether this includes NET bone metastases but I don’t see why not given the connection with Solucin. However, please note this is some years away from fruition.

graphic courtesy of ITM AG

 

References:

1.  ITM News Release – click here

2. ITM Website – click here

3. Clinical Trials Document – click here

4. FDA authorises trial to go ahead in USA – click here

5. Useful video about the trial – click here

compete US trial locations

 

 

Thanks for listening

Ronny

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Lutetium Lu 177 dotatate (Lutathera®) – PRRT

prrt update

Short PRRT Primer

What is Peptide Receptor Radionuclide Therapy (PRRT)?

For those who are still not sure what it’s all about.  This is a non-surgical treatment which is normally administered intravenously.  It’s based on the use of somatostatin receptors to attract a ‘radiopeptide’.  The radiopeptide is a combination of a somatostatin analogue and a radioactive material. As we already know, somatostatin analogues (i.e. Lanreotide/Octreotide) are a NET cell targeting drug, so when combined with radioactivity, it binds with the NET cells and delivers a high dose of targeted radiation to the cancer while preserving healthy tissue.  In general, patients tend to receive up to 4 sessions spaced apart by at least 2 months. 

PRRT will not work on all NETs and not everyone will suited to this treatment. In general, for this treatment to be more successful, you must have somatostatin receptors in your tumors. Success rates are not 100% – it should not be considered a cure or ‘magic bullet’. However, the results are said to be pretty good.  The NETTER-1 trial data which has led to formal approval in Europe, USA and other areas, can be found here.

LATEST ON EXPANDED NETTER-1 TRIAL DATA.  “Novartis has announced presentation of a new analysis of Lutathera (lutetium Lu 177 dotatate) NETTER-1 data at the 2018 European Society for Medical Oncology (ESMO) congress examining the impact of Lutathera treatment on patients with low, medium or high liver tumor burden. The data show that Lutathera treatment results in significant improvement in progression free survival (PFS) regardless of the extent of baseline liver tumor burden (LTB), elevated alkaline phosphatase (ALP) liver enzyme or presence of large (>30mm diameter) lesion in patients with progressive midgut neuroendocrine tumors (NETs) compared to octreotide LAR alone.”

THERANOSTICS

Understanding the terminology is half the battle in understanding the latest developments. I’ve included Ga-68 PET scans within this section (or in more general terms Somatostatin Receptor PET (SSTR PET)) as the term ‘Theranostics‘ is becoming a commonly used theme.  Theranostics is a joining of the words diagnostics and therapy.

LUTATHERA is the radionuclide ‘mix’ for use in Peptide Radio Therapy Treatment (PRRT).  You may also see this drug called ‘Lutetium’ or ‘Lu-177 dotatate’, or just ‘Lu-177’ on its own. Yttrium 90 (Y-90) is a  radionuclide also used in PRRT. 

NETSPOT (USA) or SOMAKIT TOC (Europe) is not PRRT but it is the commercial names for the radiopeptide used in Gallium 68 (Ga-68) PET diagnostic scans.

Together they form a ‘theranostic pair’. Theranostics is apt as together (NETSPOT / SOMAKIT TOC and Lutathera), both target NETs expressing the same somatostatin receptor, with Lutathera intended to kill tumor cells by emitting a different kind of low-energy, short-range radiation than that of the diagnostic version.

Moreover, thanks to the theranostic approach that nuclear medicine allows, Novartis/AAA’s NETSPOT/SomaKit TOC products will be able to determine when Lutathera is the appropriate treatment.

Read more about Theranostics by clicking here.

Hasn’t the therapy has been in use for some time?

Of course, this therapy has been in use in Europe and some other places for some time but to be honest, they have been on a limited scale and never formally approved by national drug agencies.  Despite its extensive use, the EU approval in 2017 was actually the very first approval of PRRT anywhere in the world. For example, in UK, it was used for some time for those in need but was removed from routine availability through a ‘slush fund’ formally known as the Cancer Drugs Fund – to cut a long story short, the funding source was cut off, although there are still ways of obtaining the treatment pending formal acceptance by the NHS (certain criteria apply).

In the meantime, I constantly see stories of patients travelling to Switzerland, Germany, Netherlands, Sweden, Great Britain and others; mostly at their own cost.   However, it does indicate one thing, there is a huge unmet need in that many patients do not have access to the best treatments in their own country. I see this daily through many private messages.

What about Grade 3 (High Grade) Neoplasms?  

The main treatment for Grade 3 is chemotherapy, particularly poorly differentiated.  PRRT tends to work better with efficient somatostatin receptors (i.e. somatostatin receptor-positive tumors).  The European approval wording only covers Grades 1 and 2. The US FDA approval indicates “somatostatin receptor-positive tumors”.  It’s also worth noting that with Grade 3, are more likely to exist in Grade 3 well differentiated NETs, particularly in the lower Ki-67 readings. However, there’s an interesting study from Australia which might be useful to read – check out the abstract here (note the full version is not available free).

Merkel Cell Carcinoma.  Although not indicated for this type of Neuroendocrine Neoplasm, there is evidence to suggest that this skin Neuroendocrine Carcinoma does express somatostatin receptors.  Read more here.

merkel cell prrt ga68 images
Case Rep Oncol 2019;12:98–103
Merkel Cell Carcinoma
https://doi.org/10.1159/000496335

What about Pheochromoctyoma/Paraganglioma?

This article discusses the efficacy of PRRT in Pheo/para – click here.  There’s actually still a trial for Pheochromocytoma/Paraganglioma (Pheo/Para).  It is known that Pheo/Para can have somatostatin receptor tumors so a useful trial. The aim of the trial is to assess the safety and tolerability.  You can read about the trial here.

Where can I get PRRT?

global icon
Where can I get PRRT?

Regional Updates

The aim of this section is to update on a regional basis in order to inform an international community of followers and readers.

Background

I wanted a place to review what is happening globally given my following.  In many countries, however, I’m dependent on feedback from patients in those countries. Please note this is not intended to be a 100% complete breakdown on everything about PRRT or PRRT centres – it’s a summary.  It should be clear from below but please bear that in mind when reading.

This section of this article will cover each region, indicating where PRRT can be obtained (as far as I know). It is not designed to indicate whether this is through public or private facilities (this will depend to too many factors beyond the reach of this article). Please note this is not intended to be a 100% complete breakdown on every single PRRT centre – it’s a summary.  This actually should be clear from below but please bear that in mind when reading.

UNITED KINGDOM

On 29 August 2018. National Institute for Health Care Excellence (NICE) England has formally published that Lutetium (177Lu) oxodotreotide, within its marketing authorisation, is an option for treating unresectable or metastatic, progressive, well-differentiated (grade 1 or grade 2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (NETs) in adults.  CLICK HERE to read the approval.  Currently available in the following NHS locations:

  • London – at least 2 locations – Royal Free, Guys and St Thomas
  • Liverpool – The Royal
  • Manchester – The Christie
  • Sheffield – Weston Park
  • Bristol – Bristol Oncology Centre

Anecdotal mention of Leicester and Newcastle but waiting to hear confirmation.

On 9 July 2018. The Scottish Medicines Consortium (NICE equivalent) has approved lutetium 177Lu (Lutathera) for patients in NHS Scotland. Good news for Scotland once their hospitals have the capability to deliver. Scottish patients would then not need to travel to England for the NHS Scotland funded treatment. Read more here.

It is funded in Wales and Northern Ireland but is currently administered in England with inter NHS budget transfers.

Canada

On 7th Feb 2019, Health Canada approved Lutathera™ (lutetium (177Lu) oxodotreotide) for the treatment of unresectable (not removable by surgery) or metastatic, well-differentiated, somatostatin receptor-positive (expressing the somatostatin receptor) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults with progressive disease.  The treatment was previously available on a trial basis. Read more here.

Site update to follow but the following trial locations may be up and running first:

  • Juravinski Hamilton
  • LHSC London
  • PMCC Toronto
  • Sunnybrooke Toronto.

USA

PRRT was approved in USA on 26 Jan 2018. The approval is for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. CLICK HERE.

The extended access program (trial) is no longer offered but these locations should be ahead of the game in terms of provision, notwithstanding insurance and provision of sufficient nuclear material.

In the meantime, known USA sites offering routine “live site” insurance based PRRT treatment are as follows – please note information has been gleaned from US patients due to no other consolidated source of this information being readily available. It’s possible some patients got mixed up between trial locations and live locations so let me know of any omissions or additions/corrections – thanks in advance.

DRAFT – NOT YET COMPLETE – (as at 16 May 2019)

STATE LOCATION Due in Service? CONTACT DETAILS
Arizona Banner Now Dr Boris Naraev
California UCSF Medical Center Mission Bay San Francisco Now tbc
California – Antioch Kaiser Permanente Antioch Medical Center Now tbc
California Cedars Sinai Medical Center LA now tbc
California Stanford Medical Center Now tbc
California Kaiser Permanente Los Angeles Medical Center Now tbc
California Hoag Hospital Newport Beach Now tbc
California UCLA Health Now tbc
California Kaiser Santa Clara Medical Center Now tbc
California City of Hope LA Now tbc
California San Diego Now tbc
Connecticut Yale New Haven Medical Center Now tbc
Connecticut Hartford Hospital Now Salner, Andrew, MD
Radiation Oncology
Colorado Rocky Mountain Cancer Center Denver Now Dr Eric Liu
Colorado University of Colorado UC Health Denver Now tbc
Florida Moffat Tampa Now Dr Strosberg
Florida University of Miami Now tbc
Florida Mayo Jacksonville Now tbc
Florida Winter Park, Florida Radiation Oncology Orlando Now David Diamond MD
Florida Orlando Health Now tbc
Georgia CCTA Newnan, Atlanta Now Dr. Phan
Hawaii Queen’s Medical Center Now Dr. Marc Coel
Illinois Rush University Chicago Now
Illinois Northwestern Chicago now tbc
Illinois The University of Chicago Medicine now Xavier M. Keutgen, MD
Illinois Loyola University Medical Center Maywood now tbc
Illinois CTCA Chicago now tbc
Indiana Indiana University Health now tbc
Iowa University of Iowa now Dr T O’Dorisio
Kansas University of Kansas Medical Center Fairway now tbc
Kentucky University of Kentucky, Markey Cancer Center now tbc
Louisiana Ochsner now tbc
Maryland John Hopkins Baltimore now tbc
Massachusetts Dana Farber Boston Now tbc
Massachusetts Massachusetts General Hospital Now tbc
Michigan Ann Arbor Now tbc
Michigan Detroit – Karmanos Cancer Center Now tbc
Minnesota Mayo Rochester Now Dr. Thor Halfdanarson
Minnesota University of Minnesota Health Now tbc
Missouri Sara Canon Cancer Center Kansas City Now tbc
Missouri Siteman Cancer Center St. Louis/Barnes Jewish Hospital St. Louis Now tbc
Nebraska CHI Bergan Now Dr Samuel Mehr
Nebraska Nebraska Cancer Specialists Omaha Now Dr Samuel Mehr
New York Lenox Hill NYC Now tbc
New York Sloan Kettering Now tbc
New York Stony Brook University Cancer Center Long Island Now Nurse Navigator, Patty Zirpoli, RN
New York Roswell Park Buffalo Now Dr Iyer
New York Mount Sinai Now tbc
New York NYU Langone Now tbc
North Carolina Dukes Durham Now tbc
Ohio The James, Columbus Now Dr Shah
Oregon Oregon Health & Science University (OHSU) Now tbc
Pennsylvania UPMC Pittsburgh Now tbc
Pennsylvania Fox Chase Philadelphia Now Dr Paul Engstrom
Rhode Island Rhode Island Hospital Providence Now Dr Paul Engstrom
South Dakota Sanford in Sioux Falls now tbc
Tennessee Vanderbilt Nashville Now tbc
Texas MD Anderson Houston Now tbc
Texas Excel Diagnostics Houston Now tbc
Texas CHI St Lukes Houston Now tbc
Utah Huntsman Cancer Institute, Salt Lake City Now tbc
Vermont University of Vermont Medical Center Now Jay Kikut, MD, Director of Nuclear Medicine and PET
Virginia Carilion Clinic Roanoke Now tbc
Washington (State) Virginia Mason Seattle Now Dr. Hagen Kennecke
Washington (DC) VMedStar Georgetown University Hospital Now tbc
West Virginia VMU Cancer Institute Morgantown Now Shalu Pahuja, M.D
Wisconsin UW Health Madison, Carbone Cancer Center Now Noelle K. LoConte, MD Specialty: Medical Oncology Primary Location: UW Carbone Cancer Center (608) 265-1700 (800) 323-8942
 Wisconsin  Froedtert Milwaukee  Now  Dr Thomas

Europe (excluding UK which is listed above)

The European Medicines Agency (EMA) “market authorisation” received a positive indication on 20th July followed by EC approval on 29 Sep 2017.   The positive indication reads “Lutathera is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP NETs) in adults”. Of Course, the decision to fund the drug will be with national approval organisations.  Whilst I’m sure there are many more, these well-known centres have been making PRRT available for some years (but please note there are others):

Denmark – ‘Rigshospitalet’ since 2009. They have treated around 250 patients- and given 800 treatments.Netherlands – Rotterdam Treatment Centre – click here

Finland – Helsinki: Docrates Cancer Center

Germany:

– Zentralklinik Bade Berkaclick here

Uniklinikum Saarland Homburg

Berlin, Klinik für Nuklearmedizin

Italy – Milan, European Institute of Oncology

Netherlands – the combined NET centres of the UMCU Utrecht and AVL Amsterdam have an ENET certification and they both do PRRT.

UMCU – Utrecht
https://www.umcutrecht.nl/nl/Ziekenhuis/Ziekte/PRRT-behandeling-bij-NET-kanker
(only available in dutch)

AVL – Amsterdam
https://www.avl.nl/behandelingen/peptide-receptor-radionuclide-therapie-prrt/
(only available in dutch)

Poland – Poland, Maria Skłodowska-Curie Institute of Oncology, regional branch in Gliwice

Serbia –  Clinical Center Kragujevac, Centre of Nuclear Medicine

Slovenia – Ljubljana, University medical Centre Ljubljana

Sweden – Department of Endocrine Oncology Uppsala University Hospital – click here

Switzerland – University Hospital Basel, Radiology & Nuclear Medicine Clinicclick here

I’d be interested to hear from countries in Europe with their full list of centres or a link to it.

Australia

Australia seems to be ahead of the game or that is what I sense when I read output from there.  There’s a good section on the Australian effort – click here.

New Zealand

These guys have had to fight to get some progress on the provision of PRRT.  Currently New Zealanders have to go to Melbourne Australia for treatment – almost 50 New Zealanders with NETs are currently raising tens of thousands of dollars to pay for treatment in Australia because the life-prolonging treatment isn’t available locally. But this could change in 2018.  Unicorn Foundation New Zealand announced that Pharmac, the New Zealand government agency that decides which pharmaceuticals, have said that PRRT will be funded for patients with medium priority for the treatment of unresectable or metastatic, well-differentiated NETs (irrespective of primary site) that express somatostatin receptors.

Africa

South Africa:

Middle East, Asia and the Far East

Turkey – Istanbul, Dr.Levent Kabasakal.

IsraelHadassah Medical Center, Jerusalem – click to read

Lebanon – The American Hospital of Beirut – Dr Ali Shamseddine “We have started using Lu-177 here in Lebanon. So far, we have treated 3 patients, with good response. The operational cost is much less than in Europe”.  

Ali Shamseddine, MD, CHB Professor and Head of Division as04@aub.edu.lb

India – Mahatma Gandhi Cancer Hospital, Visakhapatnam. Recently started radionuclide therapy. Although only currently available privately, some patients have been sponsored by the companies that they work for. Point of contact is Dr. K. Raghava Kashyap. I’ve been assured by CNETS India that many locations have PRRT capability – contact them direct please.  Also – TATA Memorial Hospital Mumbai (waiting time is long, but cost is low: $200) and there are private clinics in Pune (cost is $1500) and Bengaluru (cost is around $6000).  (Info from Russian patient group).

Kuwait – Kuwait Cancer Control Center (KCCC) – read article here.

Malaysia

Sunway medical Centre

Beacon hospital

Pakistan – check out this article – click here

Singapore – Singapore General Hospital and National University Hospital.  

Philippines – St. Luke’s Medical Center, Global City, Taguig, Metro Manila.

South America

Chile – Instituto Oncológico Fundación Arturo López Pérez, Santiago

——————————————–

What’s next for NETs PRRT?

See this great summary from NET Research Foundation of what might be next plus basic facts about PRRT – click 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!


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Recent Progress in NET Management – Positive presentation from Jonathan R Strosberg MD

jonathan-strosbergI recently wrote a blog called Neuroendocrine Cancer – Exciting Times Ahead! I wrote that on a day I was feeling particularly positive and at the time, I wanted to share that positivity with you. I genuinely believe there’s a lot of great things happening. Don’t get me wrong, there’s a lot still to be done, particularly in the area of diagnosis and quality of life after being diagnosed. However, this is a really great message from a well-known NET expert.

In an interview with OncLive, Jonathan R. Strosberg, MD, associate professor at the H. Lee Moffitt Cancer Center in Florida, discussed his presentation on NETs at a recent 2016 Symposium, and shed light on the progress that has been made in this treatment landscape.

OncLive: Please highlight some of the main points from your presentation.

Strosberg: The question I was asked to address is whether we’re making progress in the management of NETs, and I think the answer is unequivocally yes. Prior to 2009, there were no positive published phase III trials.

Since then, there have been 8 trials, 7 of which have reached their primary endpoints. So it’s been a decade of significant improvement. And even though none of these studies were powered to look at overall survival as an endpoint, we’re certainly seeing evidence of improvement in outcomes.

OncLive: What are some of the pivotal agents that you feel have impacted the paradigm in the past several years?

Strosberg: The first group is the somatostatin analogs. We use them to control hormonal symptoms like carcinoid syndrome, but with the CLARINET study, we now know that they substantially inhibit tumor growth.

The next significant drug we use in this disease is everolimus (Afinitor), an oral mTOR inhibitor, which is now approved in several indications based on positive phase III studies. The first was in pancreatic NETs and subsequently, based on the RADIANT-4 trial, it was also approved in lung and gastrointestinal NETs. So that was an important advance.

The next important category of treatment is radiolabeled somatostatin analogs, otherwise known as peptide receptor radiotherapy. The one that’s been tested in a phase III trial is lutetium dotatate, also known as Lutathera. It was tested in patients with progressive midgut NETs and showed a very substantial 79% improvement in progression-free survival, and a very strong trend toward improvement in overall survival, which we hope will be confirmed upon final analysis.

OncLive: Are we getting better at diagnosing and managing the treatment of NETs?

Strosberg: Certainly. I think pathologists are better at making the diagnosis of a NET, rather than just calling a cancer pancreatic cancer or colorectal cancer. They’re recognizing the neuroendocrine aspects of the disease, and doing the appropriate immunohistochemical staining.

We also have better diagnostic tools. We used to rely primarily on octreoscan, and in many cases we still do, but there is a new diagnostic scan called Gallium-68 dotatate scan, also known as Netspot, which has substantially improved sensitivity and specificity. It’s not yet widely available, but it is FDA approved and hopefully will enable better diagnosis as well as staging in the coming years.

And, with the increase in number of phase III studies, we’re developing evidence-based guidelines, which will hopefully lead to more standardization, although knowing how to sequence these new drugs is still quite challenging.

OncLive: With sequencing, what are the main questions that we’re still trying to answer?

Strosberg: If we take, for example, NETs of the midgut, beyond first-line somatostatin analogs, physicians and patients often face decisions regarding where to proceed next, and for some patients with liver-dominant disease, liver-directed therapies are still an option.

For others, everolimus is a systemic option, and then hopefully lutetium dotatate will be an option based on approval of the drug, which is currently pending. Knowing how to choose among those 3 options is going to be a challenge, and I think there will be debates. Hopefully, clinical trials that compare one agent to another can help doctors make that choice. It’s even more complicated for pancreatic NETs. Beyond somatostatin analogs, we have about 5 choices—we have everolimus, sunitinib (Sutent), cytotoxic chemotherapy, liver-directed therapy, and peptide receptor radiotherapy. It’s even more challenging in that area.

OncLive: Are there any other ongoing clinical trials with some of these agents that you’re particularly excited about?

Strosberg: There’s a trial that is slated to take place in Europe which will compare lutetium dotatate with everolimus in advanced pancreatic NETs, and I think that’s going to be a very important trial that will help us get some information on both sequencing of these drugs, as well as the efficacy of Lutathera in the pancreatic NET population, based on well-run prospective clinical trials. I’m particularly looking forward to that trial.

OncLive: Looking to the future, what are some of the immediate challenges you hope to tackle with NETs?

Strosberg: One area of particular need is poorly differentiated neuroendocrine carcinomas. That’s a field that’s traditionally been understudied. There have been very few prospective clinical trials looking at this particular population, and we’re hoping that will change in the near future. There are a number of trials taking place looking at immunotherapy drugs. If these agents work anywhere in the neuroendocrine sphere, they are more likely to work in poorly differentiated or high-grade tumors, in my opinion, given the mutational profile of these cancers. So that’s something I’m particularly looking forward to being able to offer these patients something other than the cisplatin/etoposide combination that goes back decades, and is of short-lasting duration.

See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-24/expert-discusses-recent-progress-in-net-management#sthash.ypkilX2A.dpuf

Thanks for reading

Ronny

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PRRT and the NHS England Cancer Drugs Fund

cost cutting vs life cutting?
cost cutting vs life cutting?

As of 4 Nov 15, PRRT was delisted from the NHS England Cancer Drugs Fund. Appeals were made but were rejected, despite the glowing results from the NETTER-1 trial.  Although a replacement system is now in place, PRRT remains barred from routine NHS use.

Please see the following post for the very latest on PRRT worldwide – CLICK HERE

I was extremely disappointed to learn of the decision to remove PRRT (Lutetium or Yttrium) from the Cancer Drugs Fund (CDF) as reported by the NET Patient Foundation. You can read the detail of the decision here: CDF Statement.  PRRT has regularly been described by NET specialists and patients as the “magic bullet” due to its potential to shrink or kill tumours.

This is the second Neuroendocrine Cancer treatment to be withdrawn this year, after the earlier decision on Everolimus (Afinitor) in April . In fact, the recent cuts to the CDF were described in the media as a “massacre” as the list was reduced by two-thirds.  You can see the current CDF list by clicking here.

The timing of these cuts is extraordinary and when you look at the output from recent trial reports presented at the Europetwo-thirdsCongress (ECC) for both Neuroendocrine Cancer related drugs recently cut:

Everolimus

The RADIANT-4 trial said that Everolimus had a significant effect in non-functional NETs which are very difficult to treat.  This is particularly important for Lung NETs as no treatment currently exists.  The RADIANT-2 trial had already proven the efficacy of the drug for advanced carcinoid (in conjunction with Octreotide) and the RADIANT-3 trial proved good data for treatment with advanced functional pNETs.  Read the report here.

PRRT – 177Lu-DOTATATE

The ECC also reported a significant finding from the NETTER-1 trial.  Treatment with the novel peptide receptor radionuclide therapy (PRRT) Lutathera significantly increased progression-free survival (PFS) over Octreotide LAR (Sandostatin) in patients with advanced midgut NETs.  It shows a PFS that has never been shown before in this type of cancer adding that this was significant because these patients have a real unmet medical need.

Lutathera is a 177Lu-DOTATATE PRRT that targets somatostatin receptors, which are overexpressed in about 80% of NETs, to deliver cytotoxic radiation directly to the tumor – See more by clicking here.

To fully understand the background to the problem, you need to understand both PRRT and the Cancer Drugs Fund and a quick primer on both follows.

What is PRRT?

For those who are not entirely sure what PRRT is, here’s a quick primer from The Society of Nuclear Medicine and Molecular Imaging:

Peptide receptor radionuclide therapy (PRRT) is a molecular therapy (also called radioisotope therapy) used to treat a specific type of cancer called neuroendocrine carcinoma or NETs (neuroendocrine tumors). PRRT is also currently being investigated as a treatment for prostate and pancreatic tumors.

In PRRT, a cell-targeting protein (or peptide) called octreotide is combined with a small amount of radioactive material, or radionuclide, creating a special type of radiopharmaceutical called a radiopeptide. When injected into the patient’s bloodstream, this radiopeptide travels to and binds to neuroendocrine tumor cells, delivering a high dose of radiation to the cancer.

The cells in most neuroendocrine tumors have an abundance (called an overexpression) of a specific type of surface receptor—a protein that extends from the cell’s surface—that binds to a hormone in the body called somatostatin. Octreotide is a laboratory-made version of this hormone that binds to somatostatin receptors on neuroendocrine tumors. In PRRT, octreotide is combined with a therapeutic dose of the radionuclides. Yttrium 90 (Y-90) and Lutetium 177 (Lu-177) are the most commonly used radionuclides.  

What conditions are treated with PRRT?

PRRT may be used to treat NETs, including carcinoids, islet cell carcinoma of the pancreas, small cell carcinoma of the lung, pheochromocytoma (a rare tumor that forms in the adrenal glands), gastro-enteropancreatic (stomach, intestines and pancreas) neuroendocrine tumors, and rare thyroid cancers that are unresponsive to treatment with radioiodine.

PRRT is an option for patients:
• who have advanced and/or progressive neuroendocrine tumours
• who are not candidates for surgery
• whose symptoms do not respond to other medical therapies.

The main goals of PRRT are to provide symptom relief, to stop or slow tumor progression and to improve overall survival.

These video’s on Nuclear Medicine are by Professor Val Lewington – the UK’s most experienced person on PRRT.  I was at this presentation and she is absolutely amazing. It’s slightly dated but still very current.  This presentation also covers Octreotide and Gallium 68 scans under the heading of Nuclear Medicine – if you are still unsure about PRRT or Nuclear Medicine in general, these videos are definitely worth a watch.

The Role of Nuclear Medicine in NETs

Q&A Sessions

This is also a great source of information maintained by NET Patients in the USA.  Click here

What was the Cancer Drugs Fund?

The Cancer Drugs Fund was money the UK Government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. This may be because the drugs haven’t been looked at yet. Or it may be because NICE have said that they don’t work well enough or are not cost-effective. This was introduced as a ‘political statement’ by the then Conservative/Liberal Democrat coalition government in 2010/11.  The aim of the fund is to make it easier for people to get as much treatment as possible.

The Cancer Drugs Fund was for people who live in England. The governments of Scotland, Wales and Northern Ireland decide on how they spend money on health and so far haven’t decided to have a similar programme.

Worth noting that on 1 April 2013, NHS England took on responsibility for the operational management of the Cancer Drugs Fund (CDF). The NHS spends approximately £1.3 billion annually on the provision of cancer drugs within routine commissioning. The CDF was established as an additional funding source to this.

There was a national list of drugs available through the fund – you may have heard this called the priority list. If you met the conditions for a drug that was on the list, you should have been able to have it on the NHS if you live in England. The Fund would also have considered applications on behalf of individual patients for other drugs that are not on the list.  However, under the new system, Individual funding requests (IFRs) relating to cancer drugs will no longer be considered via the CDF process.  All IFRs relating to cancer drugs will now be considered using NHS England’s single, national IFR system, which was updated in January 2016.

The new system came info force on 29 July 2016 and you can read more if you click this link

Summary

Although the decision is shocking to most, it was not totally unexpected as the Government and NHS have been hinting for sometime that the costs of the fund need to be reined in.  In any case if was only ever a temporary arrangement until a another model could be put into place.  There is a political element as the fund was set up by David Cameron with healthcare experts suggesting that it made no sense as a response to rising drug prices.  Moreover, by topping up the fund, the same experts claimed this was making the manufacturers the real beneficiaries of the fund as they have been able to sell their drugs to the NHS at prices that are unaffordable (and therefore unsustainable) for the NHS.

UK NET patients who have advanced and/or progressive neuroendocrine tumours which cannot be removed by surgery and whose symptoms do not respond to other medical therapies, still need help.

Ironically, the UK seems to be intent on cutting provision of the treatment (at least for NHS patients) as the US is trying very hard to formally introduce it.  This is a disgraceful situation and advanced Neuroendocrine Cancer patients and those who may need this treatment in the future are being terribly let down.

I will keep this blog ‘live’ in order to add information as things progress.

Thanks for reading

Ronny
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