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).
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:
Theranostics is a joining of the words therapeutics and diagnostics. You may also see it conveyed as ‘Theragnostics’ and these terms are interchangeable. The basic aim of theranotistics is to find and then destroy the ‘bad guys‘. With Neuroendocrine Cancer, finding the tumours (the bad guys) can often be a challenge – they can be small and/or difficult to find – they are sometimes expert at camouflage. Moreover, once found, they can then be difficult to treat (destroy), as they can often prove resistant to conventional cancer drugs and many are inoperable due to sheer quantity, spread and positioning. When they are found and identified, it’s also really helpful to know from the intelligence gathered, how successful the destroy (therapeutic) part of the mission might be.
The nuclear scan uses the same targetin agent as the therapy, therefore if you cancer lights up on the nuclear scan, then the therapy will find its way to the cancer and hopefully work well. That is the beauty of theranostic pairing, i.e. the use of the same agent in the diagnostics – the ability to find, estimate likely success criteria and then hopefully destroy – or at least reduce the capability of the tumours and extend life.
A great example of an approved Theranostic Pairin Neuroendocrine Cancer, is the combination of the Somatostatin Receptor based Ga68 PET scan using NETSPOT or SomaKit TOC™ (US/Europe respectively) and Peptide Receptor Radiotherapy (PRRT) using Lutathera which both target NETs expressing the same somatostatin receptor, with PRRT intended to kill tumor cells by emitting a different kind of low-energy, short-range radiation than that of the diagnostic version. As mentioned above, the Ga68 PET scan can give a reasonably indication of therapeutic success using PRRT based on measurements taken during the scan (too complex for this article).
Nuclear medicine makes it possible by using the same molecular targeting compound to create diagnostic and therapeutic drugs, which work as theranostic pairings. Advanced Accelerator Applications’ theranostic platform is based on radiolabelling a single targeting molecule with either gallium Ga-68 for diagnostic use or lutetium Lu-177 for therapeutic use. AAA’s pipeline now includes several theranostic drug pairings for oncology indications including prostate and breast cancer; and gastrointestinal stromal tumors (GIST).
THERANOSTICS – FIND
Newer imaging agents targeting somatostatin receptors (SSTR) labelled with 68 Ga have been developed, namely, DOTATATE, DOTATOC and DOTANOC. They are collectively referred to as SSTR PET.
The main difference among these three tracers (DOTA-TOC, DOTA-NOC, and DOTA-TATE) is their variable affinity to SSTR subtypes. All of them can bind to SSTR2 and SSTR5, while only DOTA-NOC shows good affinity for SSTR3.
These agents have several benefits over In111-pentetreotide (Octreotide scan), including improved detection sensitivity, improved patient convenience due to the 2 hour length of the study (compared to 2 or 3 days with Octreoscan), decreased radiation dose, decreased biliary excretion due to earlier imaging after radiotracer administration, and the ability to quantify uptake. The quantification of the uptake can help decide whether a patient is suitable for PRRT. Eventually, all Octreotide scans should be replaced with SSTR PET. To confirm the advantages of SSTR PET over Octreotide scans, a study comprising 1,561 patients reported a change in tumour management occurred in over a third of patients after SSTR PET/CT even when performed after an Octreotide scan. Worth pointing out that SSTR PET is replacing the ageing Octreotide scan and not conventional imaging (CI). You can see the recommended scenarios for use of SSTR PET in this article published by the Journal of Nuclear Medicine
Ga68 PET scans have been in many locations for some time. Current excitement is focused on USA locations with Ga68 PET (NETSPOT) only recently approved (DOTATATE). Other countries/scan centres may use one of the other types of imaging agent.
Read much more about this scan in my detailed article on Ga68 PET here.
So SSTR PETs above have the ability to find and estimate likely success criteria for therapy. We are now in a position to move on to ‘THERApy’ – e.g. Peptide Receptor Radiotherapy or PRRT.
THERANOSTICS – DESTROY
Lutathera® (note the ‘THERA’ which makes up the brand name)
Europe Approval: LUTATHERA®(lutetium (177Lu) Oxodotreotide) is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEPNETs) in adults.
USA Approval: LUTATHERA® (lutetium Lu 177 dotatate) is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut and hindgut neuroendocrine tumors in adults.
For commercial purposes, the drug may be slightly different on a regional basis. For all intents and purposes it does the same job.
PRRT with LUTATHERA®
LUTATHERA® solution for infusion is a ‘radiolabelled somatostatin analog (SSA)’ comprised of a radionuclide (Lutetium-177) and a peptide (differs between Europe and USA)
The relevant SSA binds with high affinity to the somatostatin receptors (SSTR) overexpressed in malignant neuroendocrine cells such as the ones found in GEP-NETs.
Lutetium-177 is a β particle emitting radionuclide, with a mean penetration range of 0.67 millimetres in tissue (maximum penetration range of 2.2 mm) which is sufficient to kill targeted tumour cells with a limited effect on neighbouring normal cells.
The affinity for SSTRs and the specificity of binding ensures a high level of specificity in the delivery of radiation to the tumour. Before starting treatment with LUTATHERA®, imaging must confirm the presence of these receptors in tumour tissues.
As an example of how the drug is administered, please watch this short video from the European site:
Video courtesy of Advanced Accelerator Applications Please see the following post for a summary of PRRT activity worldwide. Please note this linked article is not designed to contain a list of every single location or country available – please bear that in mind when you read it – CLICK HERE
Don’t understand Somatostatin Receptors? Join the club! I got my head around the term ‘Somatostatin’ and ‘Somatostatin Analogues’ some time ago but the term ‘Somatostatin Receptor’ (SSTR) is still a bit of a mystery and it’s come to the top of my list of things to study. SSTRs do come up in conversation quite often and I’m fed up of nodding sagely hoping it will eventually become clear! On analysis it looks like a technical subject – and therefore a challenge 🙂
I’ve taken a logical approach working from ‘Somatostatin’ to ‘Somatostatin Analogue’ before commencing on the ‘receptor’ bit. It is intentionally brief and (hopefully) simplistic!
It’s important to understand this hormone and then why your ‘butt dart’ is generically called a ‘Somatostatin Analogue’.
Some Neuroendocrine Tumours secrete hormones and peptides that cause distinct clinical syndromes, including amongst others, carcinoid syndrome. Somatostatin is a naturally occurring hormone and a known inhibitor of some of these NET related hormones and peptides that can be over secreted and cause syndromes. For example, somatostatin from the hypothalamus inhibits the pituitary gland’s secretion of growth hormone (GH) and Thyroid Stimulating Hormone (TSH). In addition, somatostatin is produced in the pancreas and inhibits the secretion of other pancreatic hormones such as insulin and glucagon. However, the naturally produced Somatostatin does not have the lifespan to have any effect on Neuroendocrine Tumours which are over secreting these hormones and peptides. ……. cue manufactured versions that can!
Somatostatin Analogue (SSA)
These are manufactured versions of Somatostatin known as Somatostatin Analogues. These are designed to have a lasting effect to inhibit for much longer and therefore reduce the symptoms caused by the over secretion (i.e. the syndrome). Examples of Somatostatin Analogue include Octreotide (Sandostatin), Lanreotide (Somatuline) and Pasireotide (Signifor).
So how do Somatostatin Analogues actually work?
For the inhibition to work effectively, there needs to be a route into the over secreting tumours, normally via short or long acting injections or even intravenously. On the tumour cells, there are currently 5 known sub-types of ‘Somatostatin Receptors’ (SSTR) which are ‘expressed’ by most NETs. These are known as SSTR1 through to SSTR5. The naturally occurring hormone Somatostatin attempts to bind with all 5 but as above, it lacks the lifespan to make any impact to inhibit sufficiently in cases of overecretion. However, SSAs can overcome this with the longer lifespan. They can successfully in most cases bind with these receptors to inhibit the hormones and peptides causing the problems, particularly SSTR2 with modest affinity to SSTR5. Clearly it’s therefore advantageous to target SSTR2.
The subtypes expressed by NETs are variable and the efficiency of different SSAs in binding to each SSTR subtype also varies. For example the table below lists the variability of Somatostatin Receptor efficiency in different types of NET. Interesting to note that non-functional NETs might not have efficient SSTRs but SSAs will still try to bind to them albeit it might not work or have a lesser effect.
Somatostatin receptors are found in high numbers on the surface of NET’s. Most receptors are in the inactive state (based on something called the phosphorylation status). Traditionally, agents such as dotatate have only bound to activated receptors on the surface. Scientists are looking at ways to bind to inactive receptors to increase therapy success (for example see clinical trial OPS 201)
Table 1 – Somatostatin receptor subtypes in neuroendocrine tumours (mRNA) (See Copyright)
This table above clearly shows the variability of SSTRs when binding with different types of NETs. It follows that manufacturers of SSAs will be using this data in the formulation of their drugs. If you now look at the table below, you can see how efficiently the 3 well-known SSAs inhibit NETs on each SSTR.
Table 2 – Somatostatin receptor subtype-binding affinity of somatostatin analogues (See Copyright)
You can see from the data why Octreotide and Lanreotide target SSTR2 and to a lesser extent SSTR5 but Pasireotide (Signifor or SOM-230) is interesting as it appears to have affinity for SSTRs 1-3 and 5, probably why it has been approved for Cushing’s Disease (ATCH producing). However, to date, there has not been enough evidence showing that Pasireotide has a progression-free survival benefit over the other 2 therapies. It is also associated with hyperglycemia. You may find this video interesting as the doctor (Strosberg) is suggesting it could be used by NET patients in certain scenarios.
What about SSA labelled diagnostics?
The same principles apply. For example, an Octreotide Scan (actually known as ‘Somatostatin Receptor’ Scintigraphy (SRS)) works by taking pictures using a gamma camera which is designed to see radiation from a ‘tracer’. The tracer in question is a radio labelled with an Octreotide variant (such as pentetreotide) which will bind to somatostatin receptors on the surface of the tumour cells In the simplest of terms, this shows up where NETs are. The same principles apply to Ga 68 PET scans which are more advanced and more sensitive than SRS.
What about SSA labelled therapies?
With (say) Peptide Receptor Radiotherapy (PRRT), there is a similar binding mechanism going on. In PRRT, Octreotide or a variant, is combined with a therapeutic dose of the radionuclides, e.g. Yttrium 90 (Y-90) and Lutetium 177 (Lu-177). It binds with the SSTRs on the tumour cells and the therapeutic dose attacks the tumour having been brought there by the binding effect. Simple isn’t it?
Do Somatostatin Receptors work for everyone?
Unfortunately not. Some people have more sensitive receptors than others and the figure of 80% appears to be the most common statistic indicating one-fifth of all NET patients may not be able to respond correctly to SSA treatment or get the right results from Octreoscans/Ga 68 PET and/or PRRT. However, that needs to be taken into context and probably applies to midgut NETs measured against SSTR2 – the tables above tend to confirm this figure. During my research, I did read that higher than normal doses of SSAs may have some effect on those with less sensitive SSTRs. Also, SSAs seem to work much better with well-differentiatedtumours.
How do I know if my Somatostatin Receptors work?
When I was completing my NET checks after diagnosis, my Oncologist declared I was “Octreotide avid” shortly after my Octreoscan was compared with my CT. I’m guessing that is a simple and crude test and how most people find out they have working receptors. I also suspect that if your syndrome symptoms are abated somewhat by SSA injections, then you there is a good chance your SSTRs are working normally. I also suspect those who show clear signs of tumour on CT but not on Octreoscan or Ga 68 PET, could have a receptor issue.
The advent of modern PET scanning (e.g. Ga68) has meant more accurate methods of working out if someone has the right receptors for PRRT through analysis of something known as standardized uptake values (SUV).
A more modern approach is to use a ‘Theranostic Pair” where the same radiolabelled tracer is used with the advantage that the diagnostic element can predict suitability for the therapy component – read more here
Somatostatin Receptor Research – Interest Point
I was please to see a piece of research ongoing to look at the issues with lack of somatostatin receptors. The research is looking at novel imaging agents for NETs which do not have working receptors. Read more here.
I hope this gives you a very basic outline of why Somatostatin Receptors are important to support the diagnosis and treatment of NETs.
Preclinical and clinical studies have indicated that somatostatin receptor (SSTR)expressing tumors demonstrate higher uptake of radiolabeled SSTR antagonists than of the currently approved SSTR agonist versions. See clinical trial OPS 201 for an example of the next generation of somatostatin receptor based theranostics where the use of a somatostatin antagonists.
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:
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.
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.
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
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.