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).
Be cautious with 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 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) 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.
Worth also noting that NANETS 2018 reported limited use of Keytruda (see below) as a single agent to treat high grade Neuroendocrine Neoplasms.
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 (and late) 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:
- Hodgkin lymphoma in adults and children. It is used in patients whose disease is refractory (does not respond to treatment) or has relapsed after at least three other types of treatment.
- Melanoma that cannot be removed by surgery or that has metastasized (spread to other parts of the body).
- Non-small cell lung cancer that has metastasized. It is used:
- With pemetrexed and carboplatin as first-line treatment in patients with nonsquamous disease.
- As first-line treatment in patients whose cancer has the PD-L1 protein and does not have a mutation in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene.
- In patients whose cancer has the PD-L1 protein and got worse during or after treatment with platinum chemotherapy. Patients whose cancer has EGFR or ALK gene mutations should receive Pembrolizumab only if their disease got worse after treatment with an FDA-approved therapy for these mutations.
- in combination with Pemetrexed and Platinum as first-line treatment of patients with metastatic, non-squamous non-small cell lung cancer.
- Squamous cell carcinoma of the head and neck that has metastasized or recurred (come back) in patients whose disease got worse during or after treatment with platinum chemotherapy.
- Urothelial carcinoma (a type of bladder cancer) that is locally advanced or has metastasized. It is used in patients who cannot be treated with cisplatin or whose disease got worse during or after platinum chemotherapy.
- Microsatellite instability-high (MSI-H) cancer that is metastatic and cannot be removed by surgery. It is used in adults and children for:
- Solid tumors that have gotten worse after other treatment or that cannot be treated with other therapies.
- Colorectal cancer that has gotten worse after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
MSI-H cancer has certain genetic mutations and may not respond to some types of treatment.
- The most recent approval in May 2017 MSI-H disease is a very interesting development as it’s the US FDA’s very first approval on a tissue/site agnostic basis. You can read about this approval here. Cancers of the breast, prostate, thyroid, bladder, colon, rectum and endometrium are just some of the cancers that have been found to have these biomarkers and would be new possible targets for Keytruda. There’s a great article which explains this approval in an easy way – click here to read.
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. More Information.
I found the following trials for high-grade NEC:
- currently recruiting Pembrolizumab (Keytruda) for the Treatment of Recurrent High Grade Neuroendocrine Carcinoma (Pembro NEC)
- currently recruiting A Study of Pembrolizumab (Keytruda) in Patients With Neuroendocrine Tumors
- currently recruiting Pembrolizumab (Keytruda) – based Therapy in Previously Treated High Grade Neuroendocrine Carcinomas
- This trial is interesting. Nivolumab (Opdiva) and Ipilimumab (Yervoy) in Treating Patients With Rare Tumors 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.
- I also have some evidence of the use of Pembrolizumab (Keytruda) by an Australian high-grade thymus patient – I posted something here (Danielle Tindle)
- Merkel Cell Carcinoma – a type of Neuroendocrine skin carcinoma is benefiting from Immunotherapy. Worth noting that this type of Neuroendocrine Carcinoma already has an FDA approved immunotherapy drug (Avelumab (Bavencio)) with another pending (Keytruda)
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.
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
You can read an update of progress by clicking here. This study will assess the efficacy and safety of Pembrolizumab (Keytruda) administered to participants with incurable advanced biomarker-positive solid tumors that have not responded to current therapy or for which current therapy is not appropriate. This study may be a overarching document for a number of sub-trials which will individually recruit. Apologies for the use of the antiquated and misleading term ‘Carcinoid’ within the document.
Study for the Evaluation of Pembrorolizumab (MK-3475) in Patients with Rare Tumors (Experimental: Paraganglioma-Pheochromocytoma Group)
This study is recruiting at MD Andersen Houston Texas. Read more 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.
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