Recently, two multi-institutional cooperative group trials looked at synergistic uses with common related therapies, moving toward the goal of uncovering new standards of care for this rare disease.

“Phase III Prospective Randomized Comparison of Depot Octreotide plus Interferon Alpha-2b versus Depot Octreotide plus Bevacizumab in Advanced, Poor Prognosis Carcinoid Patients” (SWOG SO518) was led by James C. Yao from MD Anderson Cancer Center.

Participants were advanced NET patients with poor prognosis, as defined by one or more of the following criteria: progressive disease (not by RECIST per se), G2 with 6+ lesions, colorectal or gastric primaries.

Patients were randomized to receive either bevacizumab plus octreotide LAR or interferon alpha-2b (IFN α-2b) plus octreotide LAR.

The primary endpoint was progression free survival (PFS). The study was negative and the endpoint was not met.

The results are as follows: PFS was 16.6 months for the bevacizumab arm versus 15.4 months for the IFN α-2b arm. Response rate was higher on the bevacizumab arm (12% versus 4% interferon arm). As would be expected, toxicity was higher on the interferon arm with an estimated 26% grade 3-4 fatigue. Based on these findings, the authors concluded that neither bevacizumab nor IFN α-2b arm should be used as a standard treatment. The study left unanswered questions since the comparator arm (IFN α-2b) is considered a NCCN category 3 recommendation in part for of its toxicity and the fact that it is not typically used in the US as standard practice.

The second study was entitled, “Randomized Phase II Study of Everolimus vs. Everolimus plus Bevacizumab in Patients with Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors” (CalGB 80701/Alliance) and was presented by Matthew H. Kulke from the Dana-Farber Cancer Institute.

In this phase II study, patients were randomized to receive everolimus and octreotide LAR or everolimus, bevacizumab, and octreotide LAR. Key inclusion criteria included advanced pancreatic NET with evidence of progression within 12 months and no prior treatment with everolimus or bevacizumab.

The primary endpoint was progression free survival (PFS) and the endpoint was met.

The results are as follows: PFS was 16.7 month on everolimus +bevacizumab arm versus 14 month for everolimus alone. Response rate (RR) was also higher on the combination arm with a 31% response to everolimus +bevacizumab versus 12% RR to everolimus alone. Toxicity, however, was significantly higher on the combination arm: 28% patients on the everolimus +bevacizumab combination came off therapy due to adverse events. There was 81% grade 3 or 4 adverse events on the combination arm versus 49% on the everolimus arm. Grade 3-4 toxicities in the combination arm included: hypertension 38%, infection 6%, diarrhea 11%, and 3% cardiac arrest of myocardial infarctions. The investigators commented that two targeted agents causing tumor shrinkage is a paradigm shift and is very promising data but should be validated. However, they also comment that with survival measured in years, timing and toxicity of therapy need to be contemplated seriously in patients with advanced disease. Future trials emphasizing patient selection, biomarkers, and refinement to improve tolerability will be critical.