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Lutathera – Another step in the Evolution of Cancer Therapy

There are over 200 different types of Cancer, the most common being skin cancer, breast cancer, ovarian cancer, prostate cancer and lymphoma. Symptoms of cancer and its signs depend on the type of cancer which can vary from patient to patient. The treatment protocol for cancer also depends on the type and stage of cancer and it includes chemotherapy, radiation therapy and/or surgery. The Gastroenteropancreatic neuroendocrine tumor also abbreviated as GEP-NET is a heterogeneous group of tumor that originates in the anatomic locations of the body with nearly 0.5% of malignancy. They form in the organs like stomach, intestine and pancreas which secrete important hormones. When the cells function abnormally, the tumor becomes malignant and starts invading other parts as well. At first GEP-NETs tends to be silent but as it grows it becomes extremely painful. According to some reports, it is estimated that approximately one out of 27,000 people is diagnosed with GEP-NETs every year. Therefore, its treatment is critical and after several years of research, scientists have finally prepared a radioactive drug called Lutathera which is very helpful against GEP-NETs. It is the first ever drug to be approved by the U.S Food Drug Administration (FDA) for the treatment of GEP-NET.


(Source: Pixabay)

Effected parts of body in Gastroenteropancreatic neuroendocrine tumor (GEP-NETs)

A Gastroenteropancreatic neuroendocrine tumor is formed in organs like pancreas and other gastrointestinal tract that includes stomach, small intestine, colon, rectum and appendix. The figure below represents the distribution of GEP-NETs in various parts of the human body.


Figure. 1 (Source: Cancer Research and Treatment)

Symptoms and Treatment options for Gastroenteropancreatic neuroendocrine tumors

The Gastroenteropancreatic neuroendocrine tumor (GEP-NET) is a rare group of cancer which has very limited treatment options and present many clinical challenges. At an early stage, there are no noticeable symptoms but when it becomes malignant, it causes a constellation of symptoms called carcinoid syndrome. These symptoms include:

  • Flushing (Redness of skin mostly face or cheeks)
  • Asthma or wheezing
  • Diarrhea
  • Congestive heart failure
  • Bronchospasm (Tightening of bronchi muscles)
  • Abdominal cramping
  • Peripheral edema (Accumulation of fluid in lower limbs)
  • Heart palpitations

Prior treatments included proper diagnosis and treatment often involved collaboration between specialist in multiple disciplines using specific biochemical radiology and surgical methods. The treatment of GEP-NETs is guided by the respectability of the tumor, its location and extent of metastases and presence of other clinical symptoms. The treatment of pancreatic NETs includes targeted agents like everolimus and sunitinib with an important role of chemotherapy. The expression of somatostatin receptors in neuroendocrine tumors has facilitated its diagnosis and surgical treatment.

How Radioactive drug Lutathera works?

A radioactive drug or radiopharmaceutical is a pharmaceutical agent that is used for treatment as well as for diagnostic purposes. These radioactive agents consist of drug components and a radioactive element that emits gamma radiation. Recently, the U.S Food Drug Administration approved LUTATHERA for the treatment of cancer affecting the pancreas and gastrointestinal tract.

Lutathera is the first radioactive drug or radiopharmaceutical which has been approved for the treatment of GEP-NETs. It is a type of somatostatin analog, also called lutetium Lu 177-dotatate. It works by binding to the cell which has somatostatin receptor which is generally present on the tumors. After it binds to the receptor, it enters into the tumor cell and allows the radiation to cause damage to the cell thereby removing the tumor.

Dosage of Lutathera

Lutathera is administered by health providers directly by infusing into the blood, the process known as intravenous or IV infusion. This process takes nearly 30 minutes and is repeated once every 8 weeks for a total of 4 doses.

Clinical trials for Lutathera

The radioactive drug or pharmaceutical Lutathera has been supported by two clinical studies:

  • The first clinical trial was conducted and studied on 229 patients who had advanced somatostatin receptor-positive GEP-NET. These patients received either octreotide alone or octreotide in combination with Lutathera. It was observed that patients who received Lutathera in combination with octreotide had longer progression-free survival as compared to those patients who received octreotide alone. The trial were conducted at different sites i.e. 41 sites in Belgium, Germany, France, Portugal, Italy, Spain, United Kingdom and the United States.
  • The figure below represents the male and female ratio that enrolled for this clinical trial to evaluate its safety and efficacy.

Figure. 2
  • The next figure summarizes the percentage of patients enrolled in clinical trial 1 by race.
Figure. 3
  • The second clinical trial was conducted on 1,214 patients with somatostatin receptor-positive tumors including GEP-NETs. They received Lutathera at a single site in Netherlands. Complete or partial tumor shrinkage was reported in 16 percent of a subset of 360 patients with GEP-NETs who were evaluated for response by the FDA.

Side effects of Lutathera

The common side effects of Lutathera include:

  • Lymphopenia (Low levels of white blood cells)
  • High level of enzymes in certain organs
  • Vomiting
  • Nausea
  • Hyperglycemia (High level of blood sugar)
  • Hypokalemia (Low level of potassium)

Serious side effects include:

  • Myelosuppression (Low level of blood sugar)
  • Development of blood or bone marrow cancer
  • Kidney damage
  • Hormonal imbalance
  • Can harm fetus during pregnancy

Patent information for Lutathera

The FDA reviewed the New drug application (NDA) for Lutathera to decide whether the drug was safe and effective in its proposed use(s), whether the benefits of the drug outweighed the risks, whether the drug’s proposed labeling (package insert) was appropriate, and whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity. After the review, the FDA granted the approval to sell or market Lutathera for the treatment of gastroenteropancreatic neuroendocrine tumors to Advanced Accelerator Applications USA, Inc. which is a subsidiary of the Novartis group. As this drug was approved in January 2018, therefore there are only 9 patent applications (as of October 17, 2018) filed by different companies/institutes. The 2 most notable ones have been briefly described below:-

  • US20180185524 titled “Method of Treatment of Neuroendocrine Tumors That Over-Express Somatostatin Receptors”, granted to Advanced Accelerator Applications, discloses a method for the treatment of cancer that over express somatostatin receptors. This method includes treating a patient using a combination of a Peptide Receptor Radionucliotide Therapy (PRRT) and an immune-oncology therapy, which produces a therapeutic effect on said cancer. In this patent, PRRT is described as a radioactive drug that is Lutathera.
  • US20180221499A1  titled “SSTR-targeted conjugates and particles and formulations thereof”, granted to Tarveda Therapeutics Inc., discloses a method for reducing proliferation, increasing apoptosis or increasing cell cycle arrest of cells by administering conjugate to the cells where conjugate is an active agent which is coupled to somatostatin receptor targeting moiety. The active agent, as described in this patent is mertansine and an additional active agent i.e. Lutathera can also be used.

Various applications for a radioactive drug (Lutathera) has been filed and approved worldwide.

Application Number Publication Date Drug Substance Claimed Application Use Applicant
US20160271279A1 September 22, 2016 Yes Pharmaceutical Composition North-West University
US20170087260A1 March 30, 2017 Production of radiopharmaceuticals Scherrer Institute Paul
WO2017127710A1 July 27, 2017 Treatment of Neuroendocrine Tumors Chiasma Inc.
WO2017210246A2 December 07, 2017 Yes Pharmaceutical composition Tarveda Therapeutics Inc.
SG11201710255A1 January 01, 2018 Treatment of Neuroendocrine Tumors Advanced Accelerator Applications
WO2018081521A1 May 03, 2018 No Pharmaceutical composition Tarveda Therapeutics Inc.
US20180185524A1 July 05, 2018 Treatment of Neuroendocrine Tumors Advanced Accelerator Applications
EP3378068A1 September 26, 2018 Administering Radio-pharmaceutical drug Assist Publique Hopitaux De Paris
US20180221499A1 August 09, 2018 Yes Pharmaceutical composition Tarveda Therapeutics Inc.

The chart below (Figure. 4) shows the patent application profile of Lutathera for the several assignees.

Figure. 4

Conclusion

The Gastroenteropancreatic neuroendocrine tumor (GEP-NET) being a silent disease at its initial stage makes it difficult to diagnose until it becomes a malignant tumor. Earlier patients with GEP-NET had very limited treatment options as they would get to know about it only after the tumor would become malignant and start invading other parts of the body. The FDA has recently approved Lutathera (Lu 177-dotatate) which proved to be very advantageous for the treatment of GEP-NETs in several clinical trials. According to clinical trials performed on various patients, besides treatment of the cancer, the Lutathera drug is also helpful in the diagnosis of the disease before it invades other parts of the organ. This is just one small step towards our long running fight against cancer. Several companies have been researching to find drugs or compounds that may be helpful for the treatment and cure of cancer. Only due to these efforts, the human race has now reached a stage where we can now defeat Cancer and it is no more a fatal disease. We hope to be able to totally eradicate it from our planet, but if that is even possible, only time will tell.

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