Data confirm feasibility of conducting studies in rare tumors

There is strong rationale for both the octreotide LAR and everolimus studies in NET”, said Dr. Siu, associate professor of medicine at the University of Toronto and Princess Margaret Hospital. “And I applaud both sets of authors for conducting trials in rare tumors.”

PROMID, the only double-blind placebo-controlled trial to evaluate biologic therapy in NET, contained a homogeneous population by histology and proliferative index, included patients with both functional (i.e., carcinoid syndrome) and nonfunctional tumors, and involved a central independent radiology assessment. But the study’s main strength, she said, is that the primary endpoint was reached with significant results at the interim analysis. “The time-to-progression was double over the control arm,” she noted.

But patient accrual was less than projected, accrual duration was long to enable sufficient events to be observed on follow-up, and disease progression was not mandated as an entry criterion, which could have led to bias between the arms and obscured the role of therapy in nonprogressing patients, she added. The lacking data on adherence, crossover, and use of subsequent therapies will ideally be provided in the final manuscript, she said.

This is a very important study, giving us randomized evidence that confirms the antiproliferative effect of somatostatin analogs in midgut NET, Dr. Siu concluded. “We can accept this as a therapeutic means of delaying disease progression in patients with midgut (or unknown primary) NET, and perhaps after cytoreduction of bulky metastases,” she said. Dr. Yao’s single-arm phase II study of mTOR inhibition validates a concept that has been shown in preclinical models, Dr. Siu continued. Again, the population was homogeneous, and central independent radiology review was mandated. The study provided informative pharmacokinetic data showing a lack of interaction between everolimus and octreotide.

For such a rare tumor, the sample size was quite large (> 150 patients), she observed, but she questioned the need for this size cohort in a single-arm phase II study.

“Couldn’t we have done a randomized phase II study with a placebo control with similar patient numbers?” she suggested. Additionally, there were missed opportunities to explore and identify potential predictive biomarkers that could be validated in future trials.

“Regardless, we will have the opportunity to learn more about everolimus as a potential treatment in a phase III trial,” she added. Currently, RADIANT-3 is enrolling 392 patients to be treated with everolimus or placebo.

The two studies confirmed the feasibility of studying these rare tumors, she emphasized. Future studies of this “difficult and complex disease” should include the appropriate\ selection of endpoints, patients, study design, and standardization of criteria that are germaine to this topic, she said.