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Neuroendocrine Tumors: Combo Therapies Usually Beat Single Agents

Combination therapies for neuroendocrine tumors (NETs) generally provided superior disease control compared to single agents alone, although there were a few notable exceptions, according to a systematic review and network meta-analysis.

“To our knowledge, this represents the most comprehensive overview of the available safety and efficacy data for NET therapies,” Martin Walter, MD, of the University of Geneva in Switzerland, and colleagues, wrote in JAMA Oncology.

“This overview of what we believe to be the most pertinent and current evidence demonstrates a range of efficient therapies with different safety profiles that are available for patients with NETs and may facilitate informed clinical decision making, drafting of guidelines, and planning of further research,” Walter and colleagues added.

The analysis included 30 randomized controlled trials in which a total of 3,895 NET patients (48% female) were treated with 22 different therapeutic strategies.

Patients had been diagnosed primarily with gastrointestinal and pancreatic NETs. Disease control, progression-free survival (PFS), overall survival (OS), adverse events, and quality of life were assessed when the data were available. The network meta-analysis included 16 trials involving NETs of all kinds. For pancreatic NETs, the network meta-analysis identified seven treatments that appeared to offer the best outcomes for patients.

For example, good-quality evidence showed single-agent everolimus (Zortress) along with a combination of everolimus and a somatostatin analogue each led to superior PFS compared with placebo, with hazard ratios of 0.35 for both strategies (95% CI 0.28-0.45 and 95% CI 0.25-0.51, respectively).

Lower-grade evidence in pancreatic NET also supported improved PFS with interferon plus a somatostatin analogue (HR 0.31, 95% CI 0.13-0.71, vs placebo) and triple therapy with everolimus, bevacizumab (Avastin), and a somatostatin analogue (HR 0.44, 95% CI 0.26-0.75).

Quality of evidence was generally poorer in the studies of GI NET treatment, but “bevacizumab (Avastin) plus a somatostatin analogue resulted in the highest disease control rate,” Walter and colleagues wrote, “followed by 177Lu-dotatate plus a somatostatin analogue.” With PFS as the endpoint, the latter agent came out on top, albeit with the poorest quality of evidence.

“All therapies but interferon and everolimus (given as monotherapy) reduced the hazard for progression compared with placebo,” the researchers pointed out. Also, in each of the trials that reported both PFS and OS rates, “superiority of a therapy regarding progression-free survival was associated with superiority regarding overall survival,” as researchers emphasized. Quality of life indices and adverse events data revealed that there was a broad range of adverse events with NET therapies but that telotristat (Xermelo) was associated with the greatest improvement in quality of life, followed by the somatostatin analogues.

In contrast, it appeared that dactolisib had the worst adverse event profile of the therapies assessed while interferon plus a somatostatin analogue had the lowest. Limitations to the analysis included the fact that the authors could not obtain additional unpublished data so that they could not rule out publication bias for the studies analyzed. In an accompanying editorial, Jonathan Raphael Strosberg, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and colleagues, pointed out that Walter’s group had more challenges to overcome when interpreting the literature than for most other cancers.

“First and foremost, NETs are clinically and biologically heterogeneous tumors,” they observed. This made it difficult to compare outcomes among different trials, they added. Different trialists also used different response criteria to evaluate patient response to the various treatments tested, so comparing responses across trials was again difficult. The quality of the clinical trials also varied over time. For example, “early trials of interferon were substantially underpowered and nonblinded,” Strosberg and colleagues suggested — another limitation that would make interpretation of later trials more complicated than it might otherwise have been.

“Cross-trial comparisons are particularly poor for contrasting toxic effects,” the editorialists additionally noted. And then there was the issue of offering combination vs sequential therapy which cannot be easily assessed in a meta-analysis such as this one. To better understand the comparative merits of competing treatments, “we need to start comparing active treatments with each other in a randomized fashion,” Strosberg and colleagues suggested.

Several such trials are now ongoing where competing treatments will be compared head-to-head including the COMPETE study in which 177Lu-dotatate will be compared to everolimus (Zortress) in gastroenteropancreatic NETs. “Such trials may require larger patient numbers than placebo-controlled studies,” the editorialists acknowledged.

“But [they] are essential if we are to really understand which treatments are optimal for specific populations of NETs and in which sequence,” they concluded.

None of the study authors had any conflicts of interest to declare.

Strosberg declared that he has served as a consultant for Novartis and has received honoraria from Ipsen and Lexicon.