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.  Its 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. 

What about Neuroendocrine?

A phase 2, a 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:

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.