NET research review paper published.

Oncology, one of the big names in cancer research publications, published a new review article on the state of NET Research July 12.

A link to the full text of the article is also available on the Medical Reading page. What follows is my summary of the article’s contents aimed at a “civilian” audience.

The article by Boris G. Naraev, Jonathan R. Strosberg, and Thorvardur R. Halfdanarson examines a number of research studies that show a number of new therapies on the horizon for treatment of both pNETs and Carcinoid tumors. Some of these grow out of an improving understanding of how cancer in general–and NETs in specific work.

On such pathway is the mammalian target of rapamycin (mTOR) receptor. Everolimus targets this particular pathway. It has already been approved by the FDA for use in pancreatic NETs and is currently being studied for carcinoid tumors, in particular in combination with octreotide LAR (somastatin), the current go-to drug for most NETs. The results of that Phase III trial were a 16.4 month progression free median survival rate as opposed to 11.3 months for octreotide and a placebo. It improved median progression free survival in  pNET patients by 6.4 months.

Everolimus is also under study with other drug combinations, particularly for pNET.

VEGF Pathway Drugs

VEGF helps regulate the formation and growth of new blood vessels. Tumors hijack it to grow themselves a blood supply. Prevent that from happening and you can stop a tumor cold–at least theoretically. There are three different VEGF receptors. The important one in tumor formation appears to be VEGFR-2. Two different approaches can be used to control it: blockers, such as bevacizumab and tyrosine kinase inhibitors (TKIs). Among these are sunitinib, pazobanib, and sorafenib. Trials are underway on all four drugs.

A Phase II trial of 44 patients looked at bevcizumab in combination with octreotide. That combination seems to be promising, according to the review, but the trial is not yet complete. Twenty-seven of the 44 patients in the study were still alive after three years.

A number of other trials are ongoing with a variety of other drugs.

The most important for patients, however, is a large Phase III trial of bevcizumab and octreotide LAR. The Southwest Oncology Group trial has an estimated enrollment of 400 patients. That trial may still be accepting patients. Check www.clinicaltrials.gov under NCT00569127 or SWOG S0518).

Sunitinib

Sunitinib targets multiple TKIs. It is more effective against pNETs than against carcinoids, according to the review. It may also be useful in combination with hepatic artery embolization for pNETs that have metastasized to the liver. A Phase III showed it more than doubled median progression free survival versus a placebo (11. 4 months versus 5.5 months). The FDA approved the drug for pNET in May 2011.

Pazopanib and Sorafenib

Pazopanib plus octreotide LAR had a 17 percent response rate in a Phase II trial among pNET patients but no effect was seen in patients with carcinoid tumors. About 10 percent of both NET and pNEt patients responded to sorafenib as a single agent in a Phase II trial. However, 43 percent experienced significant toxic effects. A Phase II study of sorafenib with beacizumab was more promising.

Somastatin Receptors

Somastatin is involved in a number of things involving the way the body works. It has also long been the key to how we treat neuroendocrine tumors. This is because about 80 percent of NETs and carcinoid tumors have one or more of five possible somsatin receptors: SST1, SST2, SST3, SST4, and SST5.

Octreotide, the drug Jane was on, binds very well to SST2 and somewhat to SST5. It does a good job for many patients in controlling the diarrhea and flushing that go along with carcinoid syndrome.

It has now, however, been shown to slow the progression of the disease–14,6 months versus 6 months on a placebo.

Laneotride does the same job octreotide does but has a much longer half-life.

Pasireotide

When octreotide LAR fails, pasireotide is effective for 27 percent of those patients. It binds as effectively to SST2 as octreotide but binds 40 times more effectively to SST5, 30 times more effectively to SST1 and five times as effectively to SST3. It has to be injected twice a day, however.

A study (Phase III) comparing the LAR forms of the two drugs has been terminated.

PRRT

Studies of Peptide Receptor Radionuclide Therapy in Europe have resulted in considerable buzz in the United States. But even in Europe, where the treatment has become common, response rates vary from four percent to 35 percent. However, those who do respond to the treatment do have improved survival. Currently, two different sources of radiation are being used: lutetium-177 and yttrium 90. Indium-111 was in use at one point but is now rarely used. No trials comparing the use of the other two have been done. The technique has not been FDA approved in the US.

There was a study being planned in the US, but the paper makes no mention of it.

Other Therapies

The paper looks at a number of other drugs and pathways, including an epidermal growth factor receptor phase II trial of gefitinib, the IGF-1R pathway and AMG479 and cixutumumab, the histone deacetylase pathway, protein degradation pathways, immunomodulating therapy using thalidomide, and c-kit and PDFGR pathways, but all those techniques are in Phase I or II trials with very few patients involved at this point.