Novel treatment options show promise for neuroendocrine tumors

CHICAGO — Neuroendocrine tumors are a heterogeneous group of neoplasms with a complex interaction of pathways, and despite the evolution of several systemic therapies, much remains to be discovered, according to a speaker here.

Treatment of neuroendocrine tumors is complicated by several factors, Marianne Ellen Pavel, MD, chair of the division of endocrinology in the department of medicine at Fredrich-Alexander University of Erlangen-Nurnberg, Erlangen, Germany, said at the Endocrine Society Annual Meeting. Disease spread, Pavel said, is highly variable with neuroendocrine neoplasms, depending on the site of tumor origin and whether the tumor is functional (10% to 30% of tumors, such as insulinomas or gastrinomas) or nonfunctional (70% to 90% of tumors). Whether the tumor has a genetic background or whether it is well differentiated or poorly differentiated will also impact treatment and overall survival, Pavel said.

Treatment options

Treatment options available for neuroendocrine tumors include surgery, somatostatin analogues, interferon-alpha injection, molecular-targeted therapies, peptide-receptor radionuclide therapy (PRRT) and systemic chemotherapy, Pavel said. For intestinal neuroendocrine tumors, approved, evidence-based treatments include octreotide (Sandostatin, Novartis), lanreotide (Somatuline, Ipsen), peptide receptor radionuclide therapy (PRRT) and everolimus (Afinitor, Novartis). For pancreatic neuroendocrine tumors, lanreotide, PRRT, everolimus, sunitinib (Sutent, Pfizer) and streptozotocin are approved, whereas for pulmonary neuroendocrine tumors, only everolimus is approved, Pavel said.

“What are the limitations of all these available drugs? They don’t cure,” Pavel said. “We all have exceptional cases where [a patient has] been cured. These are the exceptions. We have to face some toxicity and [treatments] lack predictive markers. We have a limited response duration with targeted drugs, most not exceeding 1 year, and limited overall survival.”

“If you look at the overall survival data just published, it looks quite good for metastatic intestinal neuroendocrine tumors, but it’s quite poor for pancreatic or colorectal neuroendocrine neoplasms,” Pavel said. She added that the overall survival rate is markedly lower in poorly differentiated neuroendocrine neoplasms.

An ‘ unmet need’

More work remains to be done to identify the right drug combination or sequence to avoid unnecessary toxicity in individuals with neuroendocrine tumors, overcome resistance and improve outcomes, Pavel said.

“The highest unmet need is the poorly differentiated neuroendocrine neoplasms,” Pavel said. “This is why we need to consider adjuvant treatments.”

Adjuvant treatment remains an unmet need in patients with high risk of recurrence and high-grade neuroendocrine neoplasms, Pavel said.

“We don’t know which drugs to use, or how long they should be used, and there are few trials exploring this area,” Pavel said.

Combination therapy “looks attractive,” Pavel said; however, when with signaling pathways, there is not one key driver specific for all neuroendocrine tumor types. Several novel therapies are in development to target multiple pathways, including those targeting the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mTOR signaling pathway, novel tyrosine kinase inhibitors, CDK4/6 inhibitors and HDAC inhibitors, among others.

Research into sequential therapies is ongoing, but a clear picture on outcomes is still unknown, Pavel said. Ongoing trials with chemotherapy or PRRT therapies compared with targeted drugs, including the SEQTOR, COMPETE and OCCLURANDOM trials, will soon provide more insight, Pavel said.

There is also a potential role for immunotherapy in treating neuroendocrine tumors, Pavel said, but the research is preliminary and thus a statement cannot yet be made on its value.

“Immunotherapy took the expressway — there are a lot of trials going on in that field. Although, we don’t really understand what they mean for neuroendocrine neoplasms.

“What is of utmost importance is to improve our understanding of tumor biology and therapy selection. This doesn’t only include profiling epigenetic changes, it also includes functional imaging and clinical response. This will lead us to a more personalized therapy in the future,” Pavel said. – by Regina Schaffer

Reference:

Pavel ME. New Avenues in the Treatment of Neuroendocrine Tumors. Presented at: The Endocrine Society Annual Meeting; March 17-20, 2018; Chicago.

Disclosure : Pavel reports she has received honoraria from and served on advisory boards for Ipsen, Lexicon, Novartis and Pfizer.