Combination and Sequential Treatment for pNETs

One question that remains unanswered is whether the available treatments for pancreatic neuroendocrine tumors (pNETs) are more effective in combination or in sequence. Sequential therapies are reasonable in patients who expect to live a long time and are less accepting of the additive side effects associated with combinations, states Pamela L. Kunz, MD.

Studies assessing the use of combination therapies have shown positive results as well as additive toxicities, says Kunz. One randomized study comparing everolimus, an mTOR inhibitor, to everolimus with the antiangiogenic agent bevacizumab demonstrated a higher response rate and higher progression-free survival in the combination arm, suggesting that combinations are more active. However, eighty-one percent of patients had grade 3 to 4 toxicities, says Diane Reidy-Lagunes, MD. Combination therapies may yield better responses, but more research is needed to better understand the risk/benefit ratio of these approaches, notes Lagunes.

NETs are not classically considered to be immune sensitive due to the low number of mutations, says Kunz, but using combination immunotherapies may help overcome this challenge. A study evaluating the combination of ipilimumab and an anti-PD-L1 inhibitor hopes to uncover whether there is an application for immunotherapies in NETs.

Various treatments are under investigation to address adverse events associated with NETs. Serotonin is the primary hormone responsible for carcinoid syndrome, notes Kunz. Telotristat etiprate is an oral agent that inhibits tryptophan hydroxylase, or TPH, the rate-limiting enzyme involved in the synthesis of serotonin. In a phase III study this therapy effectively lowered carcinoid syndrome-related bowel movements.