Suggestion of Survival Benefit Persists with mTOR Inhibitor in Subset of NETs

James C. Yao, MD

James C. Yao, MD

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

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. However, the difference did not meet the statistical threshold for significance.

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, reported at the 2016 ASCO Annual Meeting in Chicago.

“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,” Dr. Yao, chair of the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, 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, including 66 of 205 (32%) from the everolimus group and 35 of 97 (36%) in the placebo group.

RADIANT-4 evaluated the effect of everolimus versus placebo in patients with advanced NETs originating in lung or gastrointestinal tissue. Investigators randomized 312 patients 2:1 to everolimus or placebo. The trial had a primary endpoint of PFS, and the primary data analysis showed more than a twofold increase in PFS among patients randomized to everolimus (11.0 versus 3.9 months,P<0.00001).

Overall survival (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 survival hazard (P= 0.037). However, the difference did not meet the prespecified statistical parameters for significance (P= 0.0002).

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 (P= 0.071 as compared with the prespecified significance value ofP= 0.0020).

The estimated 30-month survival rate 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 (AEs).

&ldquo;The tails of the overall survival curves should be interpreted with caution due to the low number of patients at risk,&rdquo; the investigators noted.

AEs in the everolimus arm have been consistent with previous experience. The most frequent AEs (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).

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 34, 2016 (suppl; abstr 4090).