Immunotherapy: Studies with Neuroendocrine Neoplasms

CAR T-cell therapy, SEM

Headline in April 2019:

Update from 2019 AACR Annual Meeting

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 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 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:

    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?

Approvals:

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.

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).

Clinical Trials:

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 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.

    See clinical trial document NCT02834013
    See announcement of trial data – click here

  • 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)
  • PDR001 (Spartalizamab) – click here.

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.

SPARTALIZUMAB (PDR001)

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 optionListen 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.

Criteria:

  • 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.

Thanks for reading

Ronny

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8 thoughts on “Immunotherapy: Studies with Neuroendocrine Neoplasms”

  1. 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.

    1. 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.

  2. 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.

    1. 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.

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