Clinical Trial SPARTALIZUMAB – Immunotherapy for Neuroendocrine Neoplasms (PDR001)

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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.  It’s brand name is SPARTLIZUMAB.

How PDR001 works

PDR001 is a type of immunotherapy, meaning that it acts by activating the body’s own immune system to recognize and fight cancer cells. Normally, an immune system cell called T-cells recognizes and kills infected or abnormal cells, including those that are cancerous. To prevent T-cells from accidentally damaging healthy and essential tissues, however several immune system checkpoints exist to inhibit, or block, them from going about this work. One example is the programmed cell death 1 (PD-1) pathway. Healthy cells produce and display a protein called programmed cell death ligand-1 or ligand-2 (PD-L1 or PD-L2) on their surface. These proteins bind to and activate a receptor called PD-1 that is produced by T-cells. When activated, PD-1 sends a message to the T-cells that prevents them from attacking that particular cell. Cancer cells can hijack this system by producing PD-L1 or PD-L2, effectively hiding from T-cells and evade destruction.
PDR001 is an antibody, a protein designed to interact with and block a specific target. It acts by binding to PD-1, blocking it from interacting with both PD-L1 and PD-L2. This binding blocks the PD-1-mediated inactivation of the T-cells, so that they are able to recognize and target cancer cells. This should result in a reduction in tumor growth and size.

PDR001 in clinical trials

PDR001 has been investigated in multiple completed and ongoing clinical trials, both alone and in combination with a wide range of other agents.

Novartis presented results from an ongoing first-in-human Phase 1/2 clinical trial (NCT02404441) of PDR001 at the American Society of Clinical Oncology (ASCO) meeting in 2016. Preliminary trial results suggested that the drug is well-tolerated and safe, with a similar profile to other anti-PD-1 drugs currently being developed. The trial is still recruiting patients with various types of advanced cancer at 43 sites across North America, Europe, and Asia; more information is available by clicking on its identification number.

Novartis then initiated several dozen other Phase 1, 2 and 3 trials, all registered on clinicaltrials.gov, to continue investigating the safety and anti-tumor activity of PDR001 in a wide range of cancer types, and in combination with other investigational and approved therapies. For example, a Phase 3 trial (NCT02967692) is comparing the safety and efficacy of PDR001 to a placebo, in combination with Tafinlar (dabrafenib) and Mekinist (trametinib), as a treatment for advanced melanoma.

What about Neuroendocrine?

A phase 2, multi-center study assessed the efficacy and safety of PDR001 in patients with non-functional well and poorly-differentiated Neuroendocrine Neoplasms.  According to the clinical trial document, the types of NENs covered are:

  • Well-differentiated Non-functional NET of Thoracic Origin
  • Well-differentiated Non-functional NET of Gastrointestinal Origin
  • Well-differentiated Non-functional NET of Pancreatic Origin
  • Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma

The clinical trial indicates the trial is active but not recruiting but it would look like they have all the patients needed and are currently analysing the trial data so far awaiting the next phase perhaps.  In fact I have discovered two pieces of evidence from the trial sponsors:

pdr001 results conclusion
Annals of Oncology (2018) 29 (suppl_8): viii467-viii478. 10.1093/annonc/mdy293

In another analysis of the results:  “Patients with well-differentiated advanced NETs were eligible if they had progressed on prior therapy, including everolimus, while the GEP-NEC patients were eligible if they had progressed on one line of chemotherapy. All patients in the trial received spartalizumab via a 30-minute infusion once every 4 weeks until disease progression or unacceptable toxicity.

In the full well-differentiated cohort, there were 7 partial responses (7%), and 55% had stable disease, while 31% had progressive disease. The confirmed objective response rate was 7%, and the disease control rate was 63%. In the GEP-NEC cohort, the objective response rate was 5%, and the disease control rate was 19%.

The thoracic NETs patients fared best with spartalizumab, with limited responses seen in the pancreatic and GI NETs groups; responses seemed to be associated with PD-L1 expression. In the thoracic NETs cohort, two of five PD-L1–positive patients had a partial response. PD-L1 positivity was more common in the GEP-NEC cohort; among 14 PD-L1–positive patients in that group, the partial response rate was 43%.

The most common adverse events regardless of cause included abdominal and back pain, anemia, dyspnea, and hypertension.

Kjell Öberg, MD, PhD, of Uppsala University in Sweden, discussed the study for ESMO. “We have hope,” he said. “We see that maybe there are some tumor types that might respond to immunotherapy.” In general, NETs are considered an “immunological desert.” There is usually very low infiltration of immune cells in these tumors, and there are a low number of genetic mutation events.”

You can also listen to two very well known NET experts (Simron Singh and Jonathan Strosberg) talk about this trial and the drug ……. “the highest response rate was seen in atypical lung neuroendocrine tumors. It was approximately 20%, but in most cases was not durable”.  See the remainder of the discussion by clicking here.

Also watch Dr Lowell Anthony talking about this drug by clicking here.

You can read more about immunotherapy trials for Neuroendocrine Neoplasms by clicking here. This article includes some advice in interpreting the ‘hype’ that can surround immunotherapy which is still a developing approach to treating cancer.

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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Update: Management of Neuroendocrine Tumors

This is an excellent and positive video based overview of where we are with the Management of NETs.  This is a presentation from a NET Specialist (who some of you may know) presenting to a “GI Malignancies” conference.  This is therefore not only awareness of NETs, it’s also some good education for non NET GI experts who may only know the very basics. Useful for patients too!  I met Dr Strosberg in Barcelona (ENETS 2017) and thanked him for his presentational and scientific paper output which I often use in my articles.

The classification picture is good as it explains the different facets of NETs and how NETs are classified and categorised in a general way – not seen it done this way before.   Slightly out of date as it does not adequately convey the possibility of a well differentiated high grade recently classified by the World Health Organisation – read more here.

Amazingly it is delivered without using the word ‘carcinoid’ other than in reference to syndrome, indicating it can be done and is something also being reflected in all my posts to ensure they are up to date with the latest nomenclature.  It’s also a good example for GI doctors as this branch of medicine is often involved in NET diagnostics and surveillance.

Excellent update of all the trials which have introduced treatments in the last decade.

Screenshot 2017-12-12 16.34.54

Great update and worth the 30 minutes it takes to watch – you can view it CLICK HERE.

 

 

All graphics courtesy of www.oncologytube.com

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

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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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Recent Progress in NET Management – Positive presentation from Jonathan R Strosberg MD

jonathan-strosbergI recently wrote a blog called Neuroendocrine Cancer – Exciting Times Ahead! I wrote that on a day I was feeling particularly positive and at the time, I wanted to share that positivity with you. I genuinely believe there’s a lot of great things happening. Don’t get me wrong, there’s a lot still to be done, particularly in the area of diagnosis and quality of life after being diagnosed. However, this is a really great message from a well-known NET expert.

In an interview with OncLive, Jonathan R. Strosberg, MD, associate professor at the H. Lee Moffitt Cancer Center in Florida, discussed his presentation on NETs at a recent 2016 Symposium, and shed light on the progress that has been made in this treatment landscape.

OncLive: Please highlight some of the main points from your presentation.

Strosberg: The question I was asked to address is whether we’re making progress in the management of NETs, and I think the answer is unequivocally yes. Prior to 2009, there were no positive published phase III trials.

Since then, there have been 8 trials, 7 of which have reached their primary endpoints. So it’s been a decade of significant improvement. And even though none of these studies were powered to look at overall survival as an endpoint, we’re certainly seeing evidence of improvement in outcomes.

OncLive: What are some of the pivotal agents that you feel have impacted the paradigm in the past several years?

Strosberg: The first group is the somatostatin analogs. We use them to control hormonal symptoms like carcinoid syndrome, but with the CLARINET study, we now know that they substantially inhibit tumor growth.

The next significant drug we use in this disease is everolimus (Afinitor), an oral mTOR inhibitor, which is now approved in several indications based on positive phase III studies. The first was in pancreatic NETs and subsequently, based on the RADIANT-4 trial, it was also approved in lung and gastrointestinal NETs. So that was an important advance.

The next important category of treatment is radiolabeled somatostatin analogs, otherwise known as peptide receptor radiotherapy. The one that’s been tested in a phase III trial is lutetium dotatate, also known as Lutathera. It was tested in patients with progressive midgut NETs and showed a very substantial 79% improvement in progression-free survival, and a very strong trend toward improvement in overall survival, which we hope will be confirmed upon final analysis.

OncLive: Are we getting better at diagnosing and managing the treatment of NETs?

Strosberg: Certainly. I think pathologists are better at making the diagnosis of a NET, rather than just calling a cancer pancreatic cancer or colorectal cancer. They’re recognizing the neuroendocrine aspects of the disease, and doing the appropriate immunohistochemical staining.

We also have better diagnostic tools. We used to rely primarily on octreoscan, and in many cases we still do, but there is a new diagnostic scan called Gallium-68 dotatate scan, also known as Netspot, which has substantially improved sensitivity and specificity. It’s not yet widely available, but it is FDA approved and hopefully will enable better diagnosis as well as staging in the coming years.

And, with the increase in number of phase III studies, we’re developing evidence-based guidelines, which will hopefully lead to more standardization, although knowing how to sequence these new drugs is still quite challenging.

OncLive: With sequencing, what are the main questions that we’re still trying to answer?

Strosberg: If we take, for example, NETs of the midgut, beyond first-line somatostatin analogs, physicians and patients often face decisions regarding where to proceed next, and for some patients with liver-dominant disease, liver-directed therapies are still an option.

For others, everolimus is a systemic option, and then hopefully lutetium dotatate will be an option based on approval of the drug, which is currently pending. Knowing how to choose among those 3 options is going to be a challenge, and I think there will be debates. Hopefully, clinical trials that compare one agent to another can help doctors make that choice. It’s even more complicated for pancreatic NETs. Beyond somatostatin analogs, we have about 5 choices—we have everolimus, sunitinib (Sutent), cytotoxic chemotherapy, liver-directed therapy, and peptide receptor radiotherapy. It’s even more challenging in that area.

OncLive: Are there any other ongoing clinical trials with some of these agents that you’re particularly excited about?

Strosberg: There’s a trial that is slated to take place in Europe which will compare lutetium dotatate with everolimus in advanced pancreatic NETs, and I think that’s going to be a very important trial that will help us get some information on both sequencing of these drugs, as well as the efficacy of Lutathera in the pancreatic NET population, based on well-run prospective clinical trials. I’m particularly looking forward to that trial.

OncLive: Looking to the future, what are some of the immediate challenges you hope to tackle with NETs?

Strosberg: One area of particular need is poorly differentiated neuroendocrine carcinomas. That’s a field that’s traditionally been understudied. There have been very few prospective clinical trials looking at this particular population, and we’re hoping that will change in the near future. There are a number of trials taking place looking at immunotherapy drugs. If these agents work anywhere in the neuroendocrine sphere, they are more likely to work in poorly differentiated or high-grade tumors, in my opinion, given the mutational profile of these cancers. So that’s something I’m particularly looking forward to being able to offer these patients something other than the cisplatin/etoposide combination that goes back decades, and is of short-lasting duration.

See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-24/expert-discusses-recent-progress-in-net-management#sthash.ypkilX2A.dpuf

Thanks for reading

Ronny

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