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) 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?

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.

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.

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)
  • 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.

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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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!



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Chemotherapy for Neuroendocrine Cancer

One of the great things about learning is that it never ends 🙂   I came across this piece of information about how chemotherapy was invented. I had no idea.  It began as a deadly cloud but it eventually ended up as a silver lining for certain cancer patients.  It all began with the development of mustard gas and I’m sure we’ve all seen the awful pictures of solders leading each other from the battlefield having been affected by this ‘deadly cloud‘.  Let’s hope we never have to witness that again.  This weapon was first used 100 years ago this week (note: blog published in Apr 2015) but out of the horror came a ‘silver lining‘ – the idea behind what is now called chemotherapy.

However, the development didn’t really begin until the second world war when two doctors from Yale University (Louis Goodman and Alfred Gilman), conducted animal and then human trials.  Then in 1948, UK scientist Professor Alexander Haddow published a ground breaking piece of research in the journal Nature, showing exactly which bits of the nitrogen mustard molecule were needed to kill cancer cells. Perhaps more importantly, he also found out how to make the chemical less toxic, but with more potent cancer-killing activity. So mustard gas went from the very real battleground of the WWI trenches into the frontline of cancer treatment where it still is today.

You can read more about this on the Cancer Research UK Science Blog

Chemotherapy and Neuroendocrine Cancer

One of the unusual aspects of Neuroendocrine Cancer is that chemotherapy is not normally considered as a ‘standard’ treatment unlike many other cancers. The exception is high grade (Grade 3) where it is often a first and/or second line therapy.  Poorly differentiated Neuroendocrine disease is normally labelled as Neuroendocrine Carcinoma (NEC) but worth pointing out there is now a Grade 3 well differentiated classification known as a ‘Grade 3 NET’ rather than Grade 3 NEC. Depending on Ki67 score, there could be differing treatment options for Grade 3 NET and Grade 3 NEC.  Read more in my article Staging and Grading.

The type of chemo or the combination of different treatments will often depend on the tumour type and anatomical location involved but may include (but not limited to): Capecitabine (Xeloda), Temozolomide (Temodal), Fluorouracil (5-FU), Oxaliplatin (Eloxatin) Cisplatin, Etoposide (Etopophos, Vepesid), Carboplatin, Streptozotocin (Zanosar). Some of these may be given as a combination treatment, e.g. CAPecitabine and TEMozolomide (CAPTEM). many as a combo treatment.  There is a useful article explaining the role of Ki-67 in determining optimal chemotherapy in high grade neuroendocrine tumors.

Horses for Courses – Chemo is sometimes used for well differentiated lower grade NETs. 

Cytotoxic chemotherapy is often inadequate for treatment of Grade 1 and 2 (well differentiated) Neuroendocrine tumours which have a low proliferation index. Chemotherapy does not appear to like their slow cytokinetic growth. However,  it tends to work better on certain parts of the anatomy than others, e.g. pancreatic NETs and Lung NETs.  Of interest is a statistic from NET Research Foundation indicating that 23% of patients who were to be prescribed chemo had their treatment changed to a non-chemo option following a Ga68 PET scan.  Read more here.

For second line therapy (including for well differentiated NETs where other conventional treatments are not working), chemo may be given.  These include (but not limited to) Capecitabine, Temozolomide, Bevacizumab, Xelox, Folfox.  There are other specialist chemos for Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN).

Capecitabine plus Temozolomide (CAPTEM for short) is fast becoming the standarad chemotherapy treatment when it is required with certain lower grade NETs.  Dr Robert Fine says the results of the CAPTEM trial showed “tremendous responses in every neuroendocrine tumor”. The treatment elicited a response rate of 45% and a stable disease rate of 52% including those with certain types of NETs and pituitary tumours – types of neuroendocrine tumour that are notoriously ‘chemoresistant’.  You can read more about this here (click here) and you can also listen to Dr Fine enthusiastically talking about this on a short You Tube video clip – (click here).  Clearly it is not going to work for all.

Other CAPTEM Resources:

  • There’s a very interesting report on the use of CAPTEM in NETs – (click here)
  • CAPTEM Trial Document – (click here)

PRRT and Chemo Combo Treatment

In Australia, they’re also using a combo treatment of chemo (CAPTEM) and PRRT – I blogged about this click here.

“Chinese Dumplings”

There’s also a useful surgical technique which includes the use of intra-operative chemo, known as “Chinese Dumplings” – I wrote about this click here.

Chemo Embolisation

My Oncologist did mention Chemotherapy on my initial meeting, that was a shock and realisation I had something serious.  However, that never transpired but I was once scheduled to have a chemo-embolisation (or TACE, Trans-arterial Chemo Embolisation). Clearly TACE is more targeted than conventional and generally systemic chemotherapy techniques. Perhaps that my Oncologist actually meant.  The chemo-embolisation never transpired either (long story).

Chemotherapy vs Targeted Biological Agents and Somatostatin Analogues

I often see people describing Somatostatin Analogues (Lanreotide/Octreotide), Afinitor (Everolimus) and Sutent (Sunitinib) as chemo but that’s isn’t technically correct, and I’ve yet to find a NET Specialist or a NET Specialist Organisation who classifies these drugs as chemo.  See my article “Chemo or not Chemo” (click here).

Future of Chemo?

A lot is written about how much longer chemo will be around.  It gets a bad press – I suspect mainly due to the side effects.  There are suggestions that it will eventually be replaced by Immunotherapy and other treatments downstream.  However, immunotherapy is really still in its infancy and there remains a lack of long term data on success rates and side effects.  I suspect chemo will be around for a while longer, particularly for cancers where it has a track record of curing according to ASCO.  Very recently (June 2018), cancer experts said that chemo will be around for a long time yet – read more here

None of the content of this post should be interpreted as advice or a  recommendation for chemotherapy. If in doubt about suitability for any form of chemo, or the type you have been prescribed, patients should seek the advice of their treating doctor or NET specialist.

Thanks for reading

Ronny

I’m also active on Facebook.  Like my page for even more news.  I’m also building up this site here: Ronny Allan

Disclaimer

My Diagnosis and Treatment History

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

patients included
Please Share this post for Neuroendocrine Cancer awareness and to help another patient