While it’s a long way off becoming reality, this is quite an exciting clinical trial. I have no idea if it will pick up Neuroendocrine disease but initially, patients with suspected oesophageal and stomach cancers will be asked to try the test. Later it will be extended to include prostate, kidney, bladder, liver and pancreatic cancers. It’s possible that Neuroendcorine tumours in these locations might be picked up or at least show up some abnormality that triggers further checks.
The fact that Cancer Research UK is involved gives me some confidence as they tend to back the strong horses.
I will keep this article live and track developments.
“A combination of two common immunotherapy drugs shrinks rare, aggressive neuroendocrine tumors, according to new research results presented at the American Association for Cancer Research Annual Meeting 2019, held March 29-April 3 in Atlanta“. See below under section: – Nivolumab (Opdiva) and Ipilimumab (Yervoy) in Treating Patients With High Grade Neuroendocrine Carcinoma
Immunotherapy for Neuroendocrine Neoplasms
There’s a lot of Immunotherapy stuff out there! However, I also wanted to break it down and perhaps see if I can pick up the what, when, why, where and how in regards to Neuroendocrine Cancer. It’s really difficult, not least because the picture is not clear and there is no general roadmap printed, let alone one for Neuroendocrine disease. Immunotherapy for NETs was discussed at ENETS 2017 in Barcelona. The presentation that sticks out was one given by Dr Matthew Kulke, a well-known NET Specialist in Boston. My reaction to the presentation was one of ‘expectation management’ and caution i.e. it’s too soon to know if we will get any success and when we will get it. He also hinted that it’s more likely that any success will first be seen in poorly differentiated high-grade Neuroendocrine Carcinoma (NEC). Dr Jonathan Strosberg also said similar in a post here. In fact, from below you will see that grade 3 poorly differentiated is where the bulk of trial activity is (…..but read on, there is some action around plain old well differentiated NETs). You will also see that there are disappointing results so far with single agent Keytruda.
Retain hope but just be cautious with some of the hype surrounding Immunotherapy
Immunotherapy is exciting, but we also need to be aware of the risks of taking the brakes off the immune system. We have seen and heard more and more stories about people with grim cancer diagnoses who became cancer-free after treatment with immunotherapy. This offers hope to those with cancer, but we need to be cautious when discussing immunotherapy. This treatment method is still new, and the cancer community is still learning about how it affects the body. An unfettered immune system may end up attacking healthy, functioning parts of a person’s body, causing unpredictable side effects that may be life-threatening EVEN if not treated early.
For Neuroendocrine Neoplasms, only Neuroendocrine Carcinoma of the skin (Merkel Cell Carcinoma) and Small Cell Lung Cancer (SCLC) has an approved drug (see below). Anything else is currently an experimental scenario (clinical trial). Before launching into what is out for with an interest in NET and NEC, it’s worth pointing out that Immunotherapy is not for everyone, does not work for everyone, and has side effects for everyone.
Let’s start with Pembrolizumab (Keytruda)?
‘Pembrolizumab’ is more famously known as ‘Keytruda‘. This drug crops up everywhere and it has connections to many different cancers. Before I talk about this trial called PLANET, it’s very useful to take a quick look at the history of Keytruda which was only really made famous after former US President Jimmy Carter was treated with it for metastatic melanoma. There was a lot of media hype surrounding what made his treatment successful as he was also given radiation for his brain tumours and his large liver tumour was removed by surgery. However, putting the hype and conjecture to one side, Keytruda’s CV is pretty impressive. Pembrolizumab (Keytruda) is currently approved to treat certain scenarios in Hodgkin lymphoma, Melanoma, Non-small cell lung cancer (NSCLC), Squamous cell carcinoma of the head and neck, Urothelial carcinoma, Microsatellite instability-high (MSI-H) related cancers (a very interesting development as it’s the US FDA’s very first approval on a tissue/site agnostic basis).
However, despite this excelent record, it’s worth also noting that NANETS 2018 reported limited use of Keytruda (see below) as a single agent to treat high grade Neuroendocrine Neoplasms.
Other approvals are anticipated.
So what about Neuroendocrine Neoplasms?
FDA granted accelerated approval to Avelumab (BAVENCIO) for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma (MCC). MCC is a Neuroendocrine Carcinoma of the skin. Avelumab is a programmed death-ligand 1 (PD-L1) blocking human IgG1 lambda monoclonal antibody. This is the first FDA-approved product to treat this type of cancer – CLICK HERE for more information.
In Aug 2018, the FDA granted Nivolumab (OPDIVO) accelerated approval for third-line treatment of metastatic small cell lung cancer (a type of Neuroendocrine Carcinoma. Read more – click here.
In Dec 2018, US FDA approves pembrolizumab for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Click here.
On March 18, 2019, the FDA approved Atezolizumab (TECENTRIQ) in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). Click here.
This trial is interesting. Nivolumab (Opdiva) and Ipilimumab (Yervoy) in Treating Patients With High Grade Neuroendocrine Carcinoma It’s a multiple cancer setup and includes several of the less common NET/NEC types including ‘Lung Carcinoid’, ‘Anal NEC’, ‘Gastic NEC’, ‘Pancreatic NEC’ ‘Esophageal NEC. Interesting because this is the drug combo that NEC patient Danielle Tindle has moved onto after Keytruda didn’t really work in the medium to long-term (see the Danielle Tindle story below). Looking at the list in the trial document, I’m thinking they might mean high-grade Lung Neuroendocrine rather than ‘carcinoid’. I could be wrong. It’s currently recruiting.
Update from 2019 AACR Annual Meeting.
The immune checkpoint inhibitor combination of nivolumab (Opdivo) and ipilimumab (Yervoy) induced a greater than 40% response rate and was well tolerated in patients with high-grade neuroendocrine carcinoma, according to findings from the phase II DART trial presented at the 2019 AACR Annual Meeting.
“DART is the first NCI-funded rare tumor immunotherapy basket study which we think is unique in its design scale,” lead author Sandip Patel MD, an associate professor of medicine at the University of California San Diego School of Medicine, said in a press briefing at the meeting. “We’re studying over 37 rare tumor types [using the] combination of ipilimumab plus nivolumab. The neuroendocrine cohort, the nonpancreatic cohort, had promising signs of benefit—[particularly] in patients with high-grade neuroendocrine carcinoma—independent to primary site,” added Patel.
I also have some evidence of the use of Pembrolizumab (Keytruda) by an Australian high-grade thymus patient – I posted something here (Danielle Tindle)
PDR001 (Spartalizamab) – see below.
UPDATE from NANETS 2018. “A preliminary trial of checkpoint blockade for neuroendocrine tumors (NETs) produced little evidence of activity, according to data reported here. Only one of 21 patients with high-grade NETs responded to treatment with pembrolizumab (Keytruda). Three others had stable disease. The trial had an objective response threshold of 5% as the definition of clinically interesting, as reported at the North American Neuroendocrine Tumor Society annual symposium. “Pembrolizumab, though generally well tolerated, showed limited activity as a single agent in high-grade neuroendocrine neoplasms (NENs) in this study,” Arvind Dasari, MD, of MD Anderson Cancer Center in Houston, and colleagues concluded.” More info.
Update from Gastrointestinal Tumor symposium 2019. “Disappointing results for single agent pembrolizumab (Keytruda) in well differentiated NET. Response Rate 3.7%. Not a viable option. Listen to Dr Jonathan Strosberg describe the poor results. Click here.
This is an interesting trial sponsored by Novartis (of Octreotide fame). PDR001 (anti-PD-1) is an investigational immunotherapy being developed by Novartis to treat both solid tumors and lymphomas (cancers of the blood). It is currently being trialled on many cancers including Neuroendocrine Neoplasms both well and poorly differentiated. Click here:Clinical Trial SPARTALIZUMAB – Immunotherapy for Neuroendocrine Neoplasms (PDR001)
NET Research Foundation
Please also see the wonderful work done by NET Research Foundation who are using their funds to explore the use of Immunotherapy in NETs – check out their update by clicking here.
But what about just plain old well differentiated low or moderate grade NETs?
I found the following:
Pembrolizumab (Keytruda) in combination with Lanreotide
According to the trial documentation, it’s for patients with non-resectable, recurrent, or metastatic well or moderately (sic) differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). i.e. most of us. It is recruiting. You can read about the PLANET trial by clicking here. Make sure you fully check the inclusion and exclusion criteria. Please note the incorrect reference to ‘moderately differentiated’ – this is no longer used in the grading classification for Neuroendocrine Neoplasms.
Study of Pembrolizumab in Participants With Advanced Solid Tumors (MK-3475-028/KEYNOTE-28) – NCT03054806 and another called ‘A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects With Advanced Solid Tumors’ (KEYNOTE 158) NCT02628067
From Gastrointestinal Tumor symposium 2019. “Disappointing results for single agent pembrolizumab in Well Differentiated NET. Response Rate 3.7%. Not a viable option. Listen to Dr Jonathan Strosberg describe the poor results. Click here.
Study for the Evaluation of Pembrorolizumab (MK-3475) in Patients with Rare Tumors (Experimental: Paraganglioma-Pheochromocytoma Group)
It is not known if this part of the trial is affected by the results above in Keynote-28. This study is recruiting at MD Andersen Houston Texas. Read more here.
PDR001 (Spartalizamab) -a Novartis drug – read about this trial click here.
Atezolizumab and Bevacizumab in Solid Tumors
In 2016, US FDA approved Atezolizumab (TECENTRIQ) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC). Bevacizumab (also known as AVISTAN) is a well known drug already used to treat many cancers. Avastin is not actually Immunotherapy but is a tumor-starving (anti-angiogenic) therapy, i.e. its purpose is to prevent the growth of new blood vessels …. ergo this is a combo treatment using an Immunotherapy drug and an anti-angiogenic drug.
Well differentiated Neuroendocrine tumors, Grade 1 or grade 2 according to reviewing pathologist
Progressive disease over the preceding 12 months
Any number of prior therapies
Patients using a somatostatin analogue for symptom control must be on stable doses for 56 days prior to enrolment.
According to the trial documenation, there are two ‘baskets’ of types: Pancreatic NET (pNET) and “extrapancreatic” (i.e. beyond or not in the pancreas) including typical or atypical Lung NETs. Merkel Cell Carcinoma (a type of Neuroendocrine Carcinoma of the skin) is also included in the trial. You can read about this trial by clicking here. Make sure you fully check the inclusion and exclusion criteria. Again, within the trial documentation, please note the incorrect reference to ‘moderately differentiated’ – this is no longer used in the grading classification for Neuroendocrine Neoplasms.
By the way, what exactly does Immunotherapy do?
For those still wondering what cancer immunotherapy actually is, this is the most basic description I could find!
Immunotherapy – Hype or Hope?
I mentioned above that there was a lot of hype surrounding Keytruda and other immunotherapy treatments. You may therefore enjoy this CNN article about the hype and hope aspect, it was given considerable sharing at ASCO17 – read the article by clicking here
If you’re on an Immunotherapy trial not listed here, please let me now so I can update the post. Thanks in advance.
New treatments seem to be appearing every month and that is good news for patients. I have a personal connection to this one though. In 2014, Chris and I walked along Hadrian’s Wall, a 2,000-year-old World Heritage structure in Northern England. This was part therapy for me but also part fund-raising to help pay for this new treatment which launches today in Southampton General Hospital (UK) which was recently awarded the coveted title of European NET Centre of Excellence (along with Bournemouth and Portsmouth Hospitals). It is the first ever deployment of this type of treatment in UK and Chris and I were happy to shred the soles of our feet to support this worthy cause, particularly when the two guys behind the idea were my surgeon (Mr Neil Pearce) and my Interventional Radiologist (Dr Brian Stedman). Both of these brilliant and skilled people ‘worked on me’ for 12 months in 2010/2011 and I live to tell you this tale! Shortly after my surgery, they decided to set up PLANETS to focus on providing additional support for Neuroendocrine Cancer and other types such as Pancreatic and Liver in which they specialised.
Intra-Operative Radiotherapy (IORT) provided by Mobetron is a bit of a game changer for advanced cancers which are hard to treat and remove. This development is said to be at the cutting edge of modern radiation oncology. Despite the heading, this treatment can be used for many cancers including Neuroendocrine, Pancreatic, Colorectal and Bladder. It is a mobile version and can be moved to different operating theatres. There are plans to eventually extend the portfolio to include Head and Neck, Oesophageal, Lung, Breast and Cervical cancers. The technology can also be used on Brain tumours but there are currently no plans to offer this service.
The radiotherapy is applied during surgery which means the treatment can be delivered more directly without causing damage to surrounding tissue and organs. It’s worth adding at this stage that this type of radiotherapy is not the same as PRRT. Moreover, it is not designed to replace PRRT which remains an option for patients downstream if they still need it (in addition to other treatments such as Sirtex, liver emobolisatons). Clearly dosage calculations would be required for cumulative radiation exposure over short timescales. Worth noting that PRRT currently remains denied to patients in England.
The type of radiotherapy is more similar to conventional external beam systems and the key advantage is that it can be used for areas where tumours have just been removed or part removed or in locations which have a tendency to recur; and for inoperable tumours such as those surrounding vital structures. Examples include: bulky pancreatic tumours, inoperable mesenteric root lymph node deposits, difficult pelvic tumours, metastases around the bladder, rectum or uterus and ovaries. It follows that in addition to treating certain tumours earlier than would normally be possible, IORT may preclude the need for further treatment or at least extend the period post surgery where further treatment would be required.
Clearly there is a lot of excitement surrounding this first ever deployment of IORT which has raised the profile of Neuroendocrine Tumours in the UK national press – check out this article in the Daily Mail by clicking here. There is a useful animated video to watch by clicking here.
The official launch happened on Mon 13 Jun 2016 and Chris and I were very proud to attend.
Thanks for reading
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