Everolimus Survival Benefit Suggested in Updated NET Trial Results

James C. Yao, MD

Patients with nonfunctioning neuroendocrine tumors (NETs) of lung or gastrointestinal (GI) origin continued to live longer when treated with the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) than with placebo, ongoing follow-up in a randomized trial has shown.¹

As previously reported, the trial met the primary endpoint of progression-free survival (PFS), and a first interim survival analysis showed a trend in favor of the everolimus arm. Follow-up for survival will continue, James C. Yao, MD, a professor at The University of Texas MD Anderson Cancer Center, reported at the 2016 ASCO Annual Meeting.

“The findings from this second interim overall survival analysis continue to suggest a positive trend for survival benefit with everolimus, even though statistical significance was not achieved,” Yao and colleagues concluded in a poster presentation. “The estimated 2-year survival rate was 77% with everolimus versus 62% with placebo.”

A final survival analysis will be performed after approximately 191 deaths have occurred (approximately two-thirds of patients in the trial). The second interim analysis occurred after 101 deaths.

In February 2016, the FDA approved everolimus for the treatment for patients with progressive, well-differentiated, nonfunctional NETs of lung or GI origin that are locally advanced or metastatic based on PFS data from RADIANT-4.

In an interview with OncologyLive, Yao indicated that everolimus is the most versatile approved therapy for NETs. “For progressive neuroendocrine tumors, everolimus probably has the broadest evidence and broadest label in that it has demonstrated activity in neuroendocrine tumors of the lung, GI tract, and the pancreas,” he said.

Yao said he follows clinical trial and guideline evidence when recommending therapy for patients with advanced disease. “In patients with oncologic progression and carcinoid syndrome, the priority for me is in controlling the oncologic progression,” Yao said. “In many cases, the control of the oncologic aspect and controlling the tumor also help with disease progression and with the symptom issue.”

RADIANT-4 randomized 302 patients 2:1 to everolimus (10 mg/d) or placebo with participants in both arms also receiving best supportive care. The sites of primary NETs were GI (175 patients), lung (90), and tumors of unknown primary origin (36).² The average age was 65 years in the everolimus arm and 60 years in the placebo group.

The trial had a primary endpoint of PFS. The primary data analysis showed more than twofold increase in PFS among patients randomized to everolimus (11.0 months vs 3.9 months, P <.00001).

OS was a secondary endpoint, and follow-up has continued for evaluation of that outcome. The first interim analysis, performed after 70 deaths, suggested a survival advantage for everolimus: a 36% reduction in the hazard ratio (P = .037). However, the difference did not meet the prespecified statistical parameters for significance at first interim analysis (P = .0002).

The second planned interim analysis for survival occurred after a median follow-up of 33.4 months. At that point, the number of deaths that had occurred represented 53% of total deaths specified for the final OS analysis.

The 27% reduction in the survival hazard for the everolimus group continued to suggest an improvement in survival, although the difference proved not to be significant (HR, 0.73; 95% CI, 0.48-1.11; P = .07), as compared with the prespecified significance value of P = .0020).

The estimated 30-month survival was 67.4% with everolimus and 58.8% with placebo. By the second survival analysis, 176 (86%) patients in the everolimus arm and 91 (94%) of participants in the placebo arm had discontinued. The primary reason for discontinuation was disease progression (43% in the everolimus group and 77% in the placebo group). Additionally, 31% of patients in the everolimus arm and 7% in the placebo group discontinued because of adverse events.

“The tails of the overall survival curves should be interpreted with caution due to the low number of patients at risk,” the investigators noted. Adverse events in the everolimus arm have been consistent with previous experience. The most frequent adverse events (all grades) in the everolimus arm were stomatitis (63%); diarrhea and fatigue (31%); infection (29%); rash (27%); peripheral edema (26%); nausea (17%); anemia, asthenia, noninfectious pneumonitis, and decreased appetite (16% each); dysgeusia (15%); cough and pruritus (13% each); pyrexia (11%); and dyspnea and hyperglycemia (10% each).

In a prior research abstract, researchers reported the results of an efficacy and safety analysis of a subgroup of RADIANT-4 participants consisting of patients with GI NETs and NET of unknown primary origin.³ Investigators noted that GI NETs make up approximately 60% of NETs and that treatment options are limited for patients with nonfunctional, progressive disease.

In the subgroup analysis, everolimus improved median PFS versus placebo among patients with GI NETs (13.1 months vs 5.4 months, respectively) and unknown primary origin (13.6 months vs 7.5 months, respectively).

In a further breakdown, investigators analyzed PFS among the GI subgroup on the basis of whether patients had nonfunctional midgut NET (n = 115) or nonmidgut NET (n = 60).

In the midgut NET group, patients who received everolimus achieved a median PFS of nearly 17.3 months compared with approximately 10.9 months with placebo (HR, 0.71). For the nonmidgut group, the median PFS was 8.1 months versus 1.9 months with placebo.

References

1. Yao JC, Fazio N, Singh S, et al. Everolimus (EVE) in advanced, nonfunctional, well-differentiated neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin: second interim overall survival (OS) results from the RADIANT-4 study. J Clin Oncol. 2016;34(suppl; abstr 4090).
2. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968-977.
3. Singh S, Carnaghi C, Buzzoni R, et al. Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract and unknown primary: A subgroup analysis of the phase III RADIANT-4 trial. J Clin Oncol. 2016;34(suppl 4S; abstr 315).

A second planned interim analysis of the RADIANT-4 trial showed a 27% reduction in the estimated risk of death for patients who received everolimus compared with placebo. However, the difference did not meet the statistical threshold for overall survival (OS) significance.