The treatment of liver metastasis is a common approach following a metastatic diagnosis or discovery of liver metastasis downstream via re-staging. In addition to surgery, there are several liver directed therapies available via embolization techniques. This comes in several flavours:
1. Bland liver embolization – a minimally invasive technique which simply blocks the blood supply to the liver tumours in an attempt to reduce or kill those tumours. Sometimes called Hepatic Arterial Embolization or HAE.
2. Chemotherapy liver embolization – as above but adds in some cytotoxic chemo to the mix. Sometimes called Trans Arterial Chemo Embolization or TACE.
3. Radioembolization is a minimally invasive procedure that combines embolization and radiation therapy to treat liver cancer. Tiny glass or resin beads filled with the radioactive isotope yttrium Y-90 are placed inside the blood vessels that feed a tumour. Often known as Sirtex or SIR-Spheres.
Of course systemic treatment is body-wide and so includes the liver as a target. Systemic treatment includes (but is not limited to) Lu177 (PRRT), Chemotherapy, Targeted Therapies such as Everolimus (Afinitor) and Sunitinib (Sutent). Also included are somatostatin analogues such as Lanreotide and Octreotide.
Sometimes systemic treatment is not fully effective on all metastases and although PRRT response rates are good, often patients still live with the burden of remnant liver tumours once therapy is finished.
Doctors in the Netherlands are looking at a trial using Lu177 (PRRT) as a liver directed therapy. The trial is based at 3 sites in the Netherlands and is titled: Intra-arterial Lutetium-177-dotatate for Treatment of Patients With Neuro-endocrine Tumor Liver Metastases (LUTIA). You can read more about the trial by clicking here.
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.
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
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.
While it’s a long way off becoming reality, this is quite an exciting clinical trial. I have no idea if it will pick up Neuroendocrine disease but initially, patients with suspected oesophageal and stomach cancers will be asked to try the test. Later it will be extended to include prostate, kidney, bladder, liver and pancreatic cancers. It’s possible that Neuroendcorine tumours in these locations might be picked up or at least show up some abnormality that triggers further checks.
The fact that Cancer Research UK is involved gives me some confidence as they tend to back the strong horses.
I will keep this article live and track developments.