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