A Comprehensive Look at Updates, Developments in NETs

During a session at the North American Neuroendocrine Tumor Society annual meeting, held October 4-6 in Seattle, Washington, Thorvardur Halfdanarson, MD, associate professor of medicine and consultant in medical oncology, Mayo Clinic, outlined the biggest news and updates in the treatment of neuroendocrine tumors (NETs), including updated guidelines and treatment with peptide receptor radionuclide therapy (PRRT).

Halfdanarson began by highlighting updated guidelines to surveillance following completely resected gastroenteropancreatic (GEP) NETs. Previously published guidelines recommended closer follow-up for the first few years. But, NETs have different patterns and timeframes of recurrence than many other cancers, with later recurrences being common, said Halfdanarson. He gave the examples of small bowel NETs, which have a median time to recurrence of 8.7 years, and pancreatic NETs, which have a median time to recurrence of 7.2 years.

The updated guidelines¹, published this summer, suggest follow-up for at least 10 years for fully resected small-bowel and pancreatic neuroendocrine tumors and also identify clinical situations in which no follow up is required.

Another update coming out of pancreatic NETs regarded the phase 2 E2211 trial, which compared treatment with temozolomide to treatment with temozolomide plus capecitabine in patients with progressive, grade 1 (G1) or G2 metastatic pancreatic NETs. Results of the study showed that median progression-free survival (PFS) increased from 14.4 months to 22.2 months when capecitabine was added. However, Halfdanarson noted, adverse events doubled from 22% to 44%.

Other trials for pancreatic NETs include ECOF 2161, a phase 2 trial testing TORC1/TORC2 inhibitor sapanisertinib (TAK-228) in patients with low to intermediate grade pancreatic NETs refractory to mammalian target of rapamycin inhibition. The primary endpoint is overall response rate (ORR), and secondary endpoints include PFS and disease control rate.

Turning his attention to immunotherapy, Halfdanarson noted that there are several ongoing trials testing different compounds, including programmed cell death 1 protein and cytotoxic T lymphcycte antigen-4 inhibitors. While there has been encouraging activity with atezolizumab plus chemotherapy and ipilimumab and nivolumab in small cell lung cancer and Merkel cell cancer, he questioned whether the method of treatment would be effective in extrapulmonary small cell cancer, non-small cell poorly differentiated neuroendocrine carcinomas (NECs), or G2 and G3 well-differentiated NETs.

He cited a phase 2 study that assessed pembrolizumab monotherapy in 21 patients with previously treated high-grade NEC. The study resulted in limited activity, and Halfdanarson raised doubts of a bright future with single-agent pembrolizumab.

With a lot of talk surrounding PRRT, Halfdanarson highlighted improved global health status and physical functioning, as well as decreased fatigue and diarrhea with the therapy.

While no trials have yet addressed it, Halfdanarson raised the question of whether somatostatin analogs (SSAs) should be given as maintenance following PRRT. However, there was a retrospective study demonstrating increased PFS (48 months vs 27 months) when patients received SSA treatment following PRRT. “So, is a prospective randomized trial warranted?” he asked.

He also mentioned 3 new PRRT trials:

• The randomized phase 3 COMPETE trial assessing ¹⁷⁷Lu DOTATOC versus everolimus, where patients with well-differentiated GEPNETs are randomized 2:1 to receive either treatment. The primary endpoint is PFS and secondary endpoints include overall survival and ORR.
• A trial examining nivolumab plus PRRT in small-cell lung cancer and G2/G3 lung NETs.
• The open-label ¹⁷⁷Lu-OPS201 trial testing somatostatin receptor (SSTR) antagonist (JR-11), which has a higher SSTR affinity, in GEPNETs, lung NETs, and pheochromocytoma/paraganglioma tumors. The primary endpoint is safety and tolerability, and secondary endpoints include optimal radioactivity and peptide mass and efficacy.

Rounding up the session, Halfdanarson brought attention to uncertainty in first-line treatment for well-differentiated G3 neuroendocrine neoplasms (NENs). While standard of care in these NENs is platinum plus etopiside chemotherapy, there is buzz around whether newer targeted agents should be considered for first-line treatment.

However, Halfdanarson emphasized, not all G3 NENs are the same, with NENs including both G3 NETs and G3 NECs, as well as both small cell and non-small cell disease. He added that second-line therapy in these NENs has been disappointing, with median PFS in a cohort progressing on platinum plus etoposide being 2.3 months per 1 study. Currently, there are multiple ongoing immunotherapy trials in these NENs.

Reference:

1. Singh S, Moody L, Chan D, et al. Follow-up recommendations for completely resected gastroenteropancreatic neuroendocrine tumors [published online July 26, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.2428.