In 2018, RadioMedix Inc. and Areva (parent company Orano Med) initiated the Phase 1 trial for AlphaMedixTM in patients with somatostatin receptor (SSTR) positive Neuroendocrine Tumors (NETs) – an NIH supported trial.
AlphaMedixTM is composed of a somatostatin analogue radiolabeled with 212Pb, an isotope used for Targeted Alpha-emitter Therapy (TAT). This open-label, dose escalation study’s objective is to determine safety, bio-distribution, and preliminary effectiveness of 212 Pb-AR-RMX in adult patients with differentiated (sic) NETs. “Targeted Alpha-emitter Therapy (TAT) is the wave of the future in nuclear oncology and has a tremendous potential to treat patients with NET and overcome some of the limitations of current Peptide Receptor Radionuclide Therapy (PRRT)” said Dr. Ebrahim S. Delpassand, Chairman and CEO of RadioMedix, sponsor of the trial. They further announced on 21 Feb 2018 that the first patients had undergone some treatment.
The funding for Phase 2 was granted by NIH on 22 Jan 2019.
What is Targeted Alpha-emitter Therapy? Targeted Alpha Therapy is based on the coupling of alpha particle emitting radioisotopes to tumour selective carrier molecules, such as monoclonal antibodies or peptides. These molecules have the ability to selectively target tumour cells even if they are spread throughout the body. They recognize the targeted cancer cells through antigens that are expressed on the cell surface and can bind selectively to these cells, similar a key fitting into a lock. In targeted alpha therapy these carrier molecules serve as vehicles to transport the radioisotopes to the cancer cells. This is called the “magic bullet” approach. Radioisotopes that emit alpha particles seem particularly promising to selectively destroy cancer cells. Alpha particles have a high energy in the range of 5-9 MeV and at the same time a very short path length in human tissue below 0.1 mm, corresponding to less than 10 cell diameters. Consequently, the use of alpha emitters allows the specific targeting and killing of individual malignant cells, while minimizing the toxicity to surrounding healthy tissue. Extracted from EU Science Hub
According to the clinical trials document, this drug addresses an unmet need in the field of peptide receptor radionuclide therapy (PRRT) for NETs. Substitution of an alpha emitter (²¹²Pb) for the beta emitters currently being used (i.e., 177Lu or 90Y) will provide significantly higher Linear Energy Transfer (LET) and a shorter path length. Higher LET particles should cause more tumor cell death. Shorter path length should result in less collateral damage of the normal tissue and therefore less side effects for subjects receiving the drug.
What is the difference between PRRT and TAT? From the scant ‘patient understandable‘ information currently available, it would appear that TAT has the potential to be more targeted and less toxic than PRRT – to me that seems like it would be able to target smaller tumors. I also noted that TAT is sometimes described as a ‘radioimmuotherapy’ or ‘alpha immunotherpy’, indicating the mechanism of action is significantly different to that of conventional PRRT. It was also described as a ‘Trojan Horse’ which would seem to hint at its immunotherapy credentials.
I noted that TAT is also being studied for use in Prostate Cancer and Leukaemia.
Announcement of Phase 1 Clinical Trial – click here – results to follow.
“Lutetium Lu 177 dotatate (Lutathera®) – PRRT” – click here.
“Expanding PRRT – Trial of 177Lu-Edotreotide (Solucin®) – COMPETE Trial” – click here.
“Theranostics – a find and destroy mission” – click here
“Ga68 PET Scans – into the unknown” – click here
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
In the last 12-24 months, there seems to have been announcement after announcement of new and/or upgraded/enhanced diagnostics and treatment types for Neuroendocrine Cancer. Scans, radionuclide therapies, combination therapies, somatostatin analogues, biological therapies, etc. Some of the announcements are just expansions of existing therapies having been approved in new (but significant) regions. Compared to some other cancers, even those which hit the headlines often, we appear to be doing not too badly. However, the pressure needs to stay on, all patients need access to the best diagnostics and treatments for them; and at the requisite time.There’s even more in the pipeline and I’m hoping to continue to bring you news of new stuff as I have been doing for the last year.
Some of these new diagnostics and treatments will benefit eligible patients who are in diagnosis/newly diagnosed and also those living with the disease. As we’re now in our awareness month, let’s recap:
Many NET Patients will undergo a nuclear scan to confirm CT results and/or to detect further neuroendocrine activity. Basically, a nuclear substance is mixed with a somatostatin analogue, injected into the patient who is then scanned using a 360-degree gamma camera. As gamma cameras are designed to show up radioactive activity; and as Neuroendocrine Tumour cells will bind to the somatostatin analogue, it follows that the pictures provided will show where Neuroendocrine tumours are located. Many people will have had an ‘Octreotide’ Scan (or more formally – Somatostatin Receptor Scintigraphy) which is still the gold standard in many areas. The latest generation of nuclear scans is based on the platform of the Gallium (Ga) 68 PET Scan. The principles of how the scan works is essentially as described above except that the more efficient radioactive/peptide mix and better scan definition, means a much better picture providing more detail (see example below). It’s important to note that positive somatostatin receptors are necessary for both scans to be effective. Europe and a few other areas have been using the Ga-68 PET scans for some time (although they are still limited in availability by sparse deployment). The latest excitement surrounding this new scan is because they are currently being rolled out in USA. Read about the US FDA approval here. You may hear this scan being labelled as ‘NETSPOT’ in USA but this is technically the name for the preparation radiopharmaceutical kit for the scan which includes a single-dose injection of the organic peptide and the radionuclide material. Take a look at a comparison of both scans here:
This slide from a recent NET Research Foundation conference confirms the power of more detailed scanning.
Peptide Receptor Radionuclide Therapy (PRRT)
Similar to above, this treatment has been in use in Europe and other places for some time but is also to be formally deployed in USA if, as is expected, the US FDA approval is positive at the end of this year (Read here). In the most basic terms, this is a treatment whereby a peptide is mixed with a radionuclide and is drip fed over a number of treatments (normally up to 4 spaced out over a year). The concept of delivery of the ‘payload’ to the tumours is actually very similar to the preparation for a radionuclide scan as described above, the key difference is the dosage and length of exposure whilst the tumours are attacked. Once again, receptors are important. The NETTER series of trials showed good results and this is an excellent addition to the portfolio for those patients who are eligible for this treatment. Fingers crossed for the US FDA announcement due by the end of this year. Also fingers crossed that PRRT returns to the NHS England & Wales portfolio of available treatments next year. The Carcinoid Cancer Foundation has an excellent summary of PRRT here.
PRRT and Chemo Combo
Whilst on this subject, I also want to highlight the innovative use of combo therapies in Australia where they are combining PRRT and Chemo (PRCRT). I blogged about this here:
Somatostatin Analogues and their Delivery Systems
Somatostatin analogues are a mainstay treatment for many NET Patients. These drugs target NET cell receptors which has the effect of inhibiting release of certain hormones which are responsible for some of the ‘syndromic’ effects of the disease. Again, receptors are important for the efficacy of this treatment. You can read the ‘geeky’ stuff on how they work here. These drugs mainly comprise Octreotide (provided by Novartis) and Lanreotide (provided by Ipsen). The latter has been around in Europe for 10 years and was introduced to North America earlier this year. Octreotide has been around for much longer, almost 17 years. When you consider these peptides have also been used to support nuclear scans that can detect the presence of tumours; and that studies have shown they also have an anti-tumour effect, they really are an important treatment for many NET Patients. I’ve blogged about new somatostatin analogues in the pipeline and you can read this here. This blog also contains information about new delivery systems including the use of oral capsules and nasal sprays (…….. very early days though).
Treatment for Carcinoid Syndrome
For maintenance and quality of life, the release of a Telotristat Ethyl for Carcinoid Syndrome is an exciting development as is the first new treatment for Carcinoid Syndrome in 17 years. This is a drug which is taken orally and inhibits the secretion of serotonin which causes some of the symptoms of the syndrome including diarrhea. It must be emphasised it’s only for treating diarrhea caused by syndrome and might not be effective for diarrhea caused by other factors including surgery. Read about how it works and its target patient group in my blog here.
The announcement of a clinical trial for the Oncolytic Virus (an Immunotherapy treatment)specifically for Neuroendocrine Tumours is also very exciting and offers a lot of hope. Click the photo for the last progress update.
Earlier this year, AFINITOR became the first treatment approved for progressive, non-functional NETs of lung origin, and one of very few options available for progressive, non-functional GI NET, representing a shift in the treatment paradigm for these cancers. It’s been around for some time in trials (the RADIANT series) and is also used to treat breast and kidney cancer. It’s manufactured by Novartis (of Octreotide fame). It has some varying side effects but these appear to be tolerable for most and as with any cancer drug, they need to weighed against the benefits they bring.
In technical terms, AFINITOR is a type of drug known as an ‘mTOR’ inhibitor (it’s not a chemo as frequently stated on NET patient forums). Taken in tablet form, it works by blocking the mTOR protein. In doing so, AFINITOR helps to slow blood vessels from feeding oxygen and nutrients to the tumour.
Check out Novartis Afinitor website for more detailed information. There’s an excellent update about AFINITOR rom NET expert Dr James Yao here. The US FDA approval can be found here.
………. and relax! Wow, I’ve surprised myself by collating and revising the last 12-24 months. Dr James Yao also agrees – check out his upbeat message in the attached2 page summary. You may also like another upbeat message from Dr Jonathan Strosberg by clicking here.
Neuroendocrine Cancer – who’d have thought it? ….. a bit of a dark horse.
Thanks for reading
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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.