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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 regard to Neuroendocrine Cancer. It’s 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 something 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 have been disappointing results so far with single agent Keytruda.
Immunotherapy – Hype or Hope?
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. 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
For those considering a trial, I think it’s worth spending some time reading this article from Cancer.NET – Doctor Approved Patient Information from the American Society of Clinical Oncology – “What You Need to Know About Immunotherapy Side Effects“.
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.
Neuroendocrine Tumours – “an immunological desert”
Not my words, they’re those of a well known NET specialist. It’s true that while there have been some approvals in two Neuroendocrine Carcinomas (two of the more esoteric ones), there’s little evidence immunotherapy is effective in the majority of Neuroendocrine Carcinomas or the slower growing well differentiated NETs.
This study from Southampton UK Researchers discovered a “cold environment” in a form of cancer which hides it from the immune system. Neil Pearce, co-founder of PLANETS and a consultant hepatobiliary surgeon (my surgeon!), said: “This is extremely useful research which shows that NETs have some yet to be identified mechanism which currently prevents immune cells from recognising them. “It could be a discovery that leads us to trying to find ways to switch on the immune system in different ways to recognise tumour cells.”
Read more here
Approvals for Neuroendocrine Neoplasms?
This drug crops up everywhere and it has connections to many different cancers. Before I talk about this trial called PLANET (see well-differentiated tumours section below), 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 excellent 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.
In March 2023, the FDA has approved pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. Read more – click here.
In June 2020, the FDA has approved pembrolizumab (Keytruda) to treat adult and pediatric patients with unresectable or metastatic solid tumors that are tissue tumor mutational burden (TMB) –high (≥10 mutations/megabase) and have progressed following prior therapy and who have no satisfactory alternative treatment options. The approval is based in part on the phase 2 KEYNOTE-158 trial, in which a link was established between TMB-high status and improved overall response rate (ORR) with the PD-1 inhibitor in patients with various solid tumors. The multicenter, multicohort, nonrandomized, open-label KEYNOTE-158 trial accrued patients with anal, biliary, cervical, endometrial, salivary, thyroid, or vulvar carcinoma, mesothelioma, a neuroendocrine tumor, or small cell lung cancer. Patients had to have an ECOG performance status of 0 or 1 and have progressed on or be intolerant to at least 1 prior line of standard treatment. The investigators used the FoundationOne CDx™ assay to assess TMB in FFPE tumor samples, with 10 Mut/Mb used as the threshold for TMB-high status.
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.
In Dec 2018, US FDA approved pembrolizumab for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Click here.
In Aug 2018, the FDA granted Nivolumab (OPDIVO) accelerated approval for third-line treatment of metastatic small cell lung cancer (SCLC) (a type of Neuroendocrine Carcinoma). Read more – click here.
In March 2017, 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.
Clinical Trials for Neuroendocrine Carcinoma (poorly differentiated)
- Completed – Pembrolizumab (Keytruda) for the Treatment of Recurrent High Grade Neuroendocrine Carcinoma (Pembro NEC)
- Completed – A Study of Pembrolizumab (Keytruda) in Patients With Neuroendocrine Tumors
- Completed – Pembrolizumab (Keytruda) – based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas
- This trial is interesting. Nivolumab (Opdiva) and Ipilimumab (Yervoy) in Treating Patients With High Grade Neuroendocrine Carcinoma and other cancers. It’s a multiple cancer setup and includes several of the less common NET/NEC types including ‘Lung Carcinoid’, ‘Anal NEC’, ‘Gastric NEC’, ‘Pancreatic NEC’ ‘Esophageal NEC. 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. Active, not recruiting as completes October 2023. 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.
See clinical trial document NCT02834013
See announcement of trial data – click here
See also a French trial entitled “Nivolumab +/- Ipilimumab in Patients With Advanced, Refractory Pulmonary or Gastroenteropancreatic Poorly Differentiated Neuroendocrine Tumors (NECs) (NIPINEC)” Clinical Trial reference NCT03591731 – Active, not recruiting
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.
This is an interesting trial sponsored by Novartis (of Octreotide and Lutathera 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 trialed on many cancers including Neuroendocrine Neoplasms both well and poorly differentiated. Click here: Clinical Trial SPARTALIZUMAB – Immunotherapy for Neuroendocrine Neoplasms (PDR001)
Trial Completed. “Single agent PD-1/PD-L1 inhibitors have not demonstrated clinical utility in an unselected NET population and should not be used outside of clinical trials. The potential for PD-L1 inhibition in the thoracic cohort warrants further investigation”
Clinical Trials for Neuroendocrine Tumours (well differentiated)
I found the following:
New blog post on 21 July 2022 – Atezolizumab and Bevacizumab in Solid Tumors
Click here or on the photo
Pembrolizumab (Keytruda) in combination with Lanreotide – trial complete June 7, 2022
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. You can read about the PLANET trial by clicking here or on the photo below. Trial complete Jun 2022, nothing concrete to report yet.
“Further studies to identify other approaches to increase the immunogenicity of well/moderately differentiated GEP-NETs are required,” concluded the investigators.
PDR001 (Spartalizamab) – a Novartis drug
Read about this trial click here. “The potential for PD-L1 inhibition in the thoracic cohort warrants further investigation.”
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 – 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
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.
If you’re on an Immunotherapy trial not listed here, please let me now so I can update the post. Thanks in advance.
General Clinical Trials Disclaimer
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided in the clinical trials document. It’s very important to check the trial inclusion and exclusion criteria before making any contact. If you need questions, the articles here is very useful Questions to Ask About Clinical Trials | Cancer.Net
The inclusion of any trial within this blog should not be taken as a recommendation by Ronny Allan.
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8 thoughts on “Immunotherapy: Studies with Neuroendocrine Neoplasms”
Thank you for all the work you have done to shed light on this disease. My husband was given immunotherapy for his stage 4 poorly differentiated neuroendochrine carcinoma. He was diagnosed at age 48 in February of 2016. He was given Optiva in early August of 2016. He died September 27th 2016. It felt to me like the cancer multiplied in size that August. We were also told that this was not hereditary but after looking an article on your site and looking at his family history, I am not sure what is true. I am terrified for my two sons who are now 12 and 15. My husbands dad died of renal cell carcinoma at age 54 and his dad died of cancer in the abdominal area when he was in his late 30s but we don’t know what kind. His great grand dad lived a long life, past age 80. I want to look into genetic testing when my boys get a little older. We are still dealing with this huge loss and I don’t want to scare my children but this is very scary.
I can imagine how scary that might be for you Shannon. If this really worries you then genetic testing is probably sensible. I hope it comes out negative, positive vibes for this outcome.
Hi Ronnie, Thanks for your work. I have NETS/primary in pancreas/whippled in Jan 2017. Grade 2. I see NET specialists at Iowa University. Minor spread to spine, liver. I took affinitor and monthly Lanreotide shots and growth is somewhat slowed but side effects took over and made this undesirable. They did genetic testing and I have Lynch Syndrome. Per my doctor this information collected makes me a good candidate for Ketruda. She also consulted with the Mayo Clinic. I just found out yesterday and will start as soon as insurance is set up, etc. Should not be a problem per my doctor. Trying to find more information on NETS and immunotherapy, where someone has actually completed some of the therapy.
Better question for in my group?
Great article. Thanks.
Excellent info again Ronny. Our own UK NPF needs to update their pages faster. You always beat them to it with great explanations!
So at this point should we be asking for some sort of test to find out if we have this Gene…
What specifically should we ask for?
I have no idea Donna, this is somethimg for your specialist. I’m also hoping the NET RF immunotherapy team would have seen this news and incorporated it into their own NET research. Personally I doubt if anyone has looked at Neuroendocrine yet.