Updated 24th September 2025.
There’s a lot of Immunotherapy stuff out there! The picture regarding its use in Neuroendocrine Neoplasms is not clear and there is no general roadmap printed. I first heard of Immunotherapy for NETs following attendance 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).
If you fast forward to 2025, that prediction worked out and there is little evidence of use in well differentiated NETs.
However …….
However, since then the landscape of different ways of targetting immunotherapy has broadened. Initially, most of the scope involved the use of immune checkpoint inhibitors (see below) but now there are several forms of immunotherapy, some of which I have already written about seperately without consolidating in here until now.
Immune Checkpoint Inhibitors: The mainstream use of immunotherapy is based on this type of targetting. These drugs block proteins that keep the immune system in check, allowing T-cells to attack cancer more effectively. Most of the effort you will see below involves checkpont inhibitors, particularly PD-1, PD-L1, CTLA-4, LAG-3.
Monoclonal Antibodies (MABs): These are man-made antibodies that can identify and bind to specific cancer cells, flagging them for destruction by the immune system. It’s complicated but there are Immune-Targeting MABs and tumour targeting MABs. i.e. they can be a type of targeted cancer drug or immunotherapy ….. but they can work in both ways. e.g. Drugs such as pembrolizumab (targeting PD-1/PD-L1) can be used with a MAB called Avelumab. Monoclonal antibodies are often used in combination with other cancer treatments like chemotherapy, radiation, or other forms of immunotherapy – so these are very versatile drugs.
CAR T-cell Therapy: This involves genetically modifying a patient’s own T-cells to recognize and kill cancer cells. Read about CAR-T and NENs click here.
Cancer Vaccines: These are used to stimulate an immune response against cancer cells. Read one example of cancer vaccines and NENs click here
Cytokines: These are proteins that help regulate the immune system. They were once used many years ago on NETs but sparingly today due to the introduction of more targeted treatments such as somatostatin analogues and somatostatin receptor based treatments. Left here for completeness. One example in the annals of NET oncology is Interferon alpha (IFN-a).
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 (the more esoteric ones), there’s little evidence immunotherapy is effective in all 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
Immunotherapy is exciting, there is no foubt about that when you read about the lastest batch of drugs in clinical trials and the use of combo drugs. The new kids on the block for NENs, DLL-3 is being watched carefully. Their use with small cell lung cancer (technically a Neuroendocrine Carcinoma) has led to wider clinical trials for extra pulmonary NENs (epNENs) particularly those known to express DLL-3 in higher than average levels. See DLL-3 section below.
We also need to be aware of the risks of taking the brakes off the immune systems. 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 realtively 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 (a blue n blue scenario), causing unpredictable side effects that may be life-threatening EVEN if not treated early. Hopefully the newer types of immunotherapy are considereing safety now that more is known.
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.
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”
I found the following:
Click here or on the photo
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.
Read about this trial click here. “The potential for PD-L1 inhibition in the thoracic cohort warrants further investigation.”
“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
In 2025, the lines are becoming blurred! A couple of examples here.
DLL-3 – Why DLL3 Therapies can be considered Immunotherapy
DLL3-targeted agents like Tarlatamab are considered immunotherapy because they engage the immune system directly:
• BiTEs (Bispecific T-cell Engagers): These link DLL3 on tumor cells to CD3 on T cells, forcing T cells to recognize and kill DLL3-expressing cells. That’s a classic immune-mediated cytotoxic mechanism.
• CAR-T cells: These are genetically engineered T cells that recognize DLL3 and destroy tumor cells—again, a direct immune response.
Even though DLL3 is a molecular target (like mTOR or VEGFR), the mode of action is immunologic, not just inhibitory. That’s why it can be classified under immunotherapy.
What About ADCs Like Rova-T?
Antibody-drug conjugates (ADCs) blur the lines even more. For example ADCs and DLKL-3 drugs can be used as a mono treatment. e.g. Rova-T targets DLL3 but delivers a cytotoxic payload—so it’s more of a targeted cytotoxic therapy than immunotherapy per se. However, because it uses an antibody to recognize a tumor antigen, it’s often grouped under immune-targeted therapies, especially in regulatory and clinical trial contexts.
I wrote an entire blog about DLL-3 and how they are expressed, offering targets in NENs. Read that by clicking here or on the graphic below.
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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