Everolimus Reduces Risk of Progression and Death in Lung/GI NETs

Everolimus demonstrated a 52% reduction in the risk of progression or death in patients with lung/gastrointestinal neuroendocrine tumors, improving progression-free survival by 7.1 months compared with placebo.

James Yao, MD

Everolimus demonstrated a 52% reduction in the risk of progression or death in patients with lung/gastrointestinal (GI) neuroendocrine tumors (NETs), improving progression-free survival (PFS) by 7.1 months compared with placebo, according to findings from the RADIANT-4 trial presented by James Yao, MD, at the 2015 NANETS symposium.

“RADIANT-4 showed everolimus is the first targeted agent to show robust antitumor activity, with acceptable tolerability, against a broad spectrum of NETs, including those arising from the lung and GI tract," said Yao, professor of medical oncology at the University of Texas MD Anderson Cancer Center. “This is an area of a lot of unmet need. At this time, there is no drug that has ever demonstrated activity or been approved for lung neuroendocrine tumors, and that is roughly 25% to 30% of all neuroendocrine tumors out there. In progressive GI tumors, there are also limited options.”

The RADIANT-4 trial produced indisputable evidence of efficacy in the tumors studied and was the first large, placebo-controlled, phase III study of advanced, progressive, nonfunctional lung/GI NETs, according to Yao. In the study, 302 patients with progressive, well-differentiated, nonfunctional lung/GI NETs were randomized 2:1 to best supportive care plus either everolimus at 10 mg per day (n = 205) or placebo (n = 97). Tumors were located in the GI tract (n = 175), lung (n = 90), or were of unknown origin (n = 36).

By central review, everolimus demonstrated a median PFS of 11 months compared with 3.9 months for placebo (HR, 0.48; 95% CI, 0.35-0.67;P<.00001). By investigator assessment, the median PFS was 14 months with everolimus compared with 5.5 months for placebo (HR, 0.39; 95% CI, 0.28-0.54;P<.00001). This benefit showed consistency across subgroup analyses.

“The study results showed a significant improvement in progression-free survival,” Yao said. “The median PFS was improved in the central, blinded analysis by a 2.8-fold improvement, which really shows a significant benefit in this group.”

By primary tumor origin, there was a 50% improvement in PFS seen for those with lung tumors and a 44% benefit in those with GI NETs, which were located in the stomach, colon, rectum, appendix, cecum, ileum, duodenum, and jejunum. Those with tumors of unknown origin saw a 40% improvement in PFS with everolimus.

Tumor shrinkage of any degree occurred in 64% of the everolimus group and 26% of the placebo group, according to Yao. The objective response rate (ORR) for those in the everolimus group was 2% compared with 1% in the placebo arm. The disease control rate (stable disease plus ORR) was 82.4% with everolimus versus 64.9% with placebo.

Benefits appeared early and were durable at 18 months, which was an interim analysis of the study. At this point, a 36% reduction in death in patient using everolimus was seen; however, it did not reach statistical significance (P= .037). Death rates in the everolimus and placebo group were similar, although the everolimus group was treated longer, Yao said. He added that the next interim analysis would occur in 2016.

Adverse events (AEs) were consistent with the known safety profile for everolimus. Drug-related AEs were mostly grades 1 and 2 stomatitis, diarrhea, fatigue, infections, rash, and peripheral edema. The most common grades 3 and 4 AEs among patients treated with everolimus were stomatitis in 9%, diarrhea in 7%, and infections in 7%, Yao said. Grade 3 and 4 AEs were uncommon in the placebo arm.

Patients received everolimus for a median of 40.4 weeks. The main reasons for treatment discontinuations were disease progression and AEs. Disease progression occurred in 37% of patients treated with everolimus versus 72% of those in the placebo arm. Adverse events accounted for discontinuations in 29% and 7% of the groups, for everolimus and placebo, respectively, Yao said.

Speaking after Yao's presentation at the NANETS Symposium, Kjell Öberg, MD, PhD, said the RADIANT-4 trial was the first randomized study to show everolimus produced significant results with lung tumors, which occurred in 31% of patients in the trial treated with everolimus. Öberg, an endocrine oncology researcher at Uppsala (Sweden) University, said an earlier European study supported RADIANT-4’s lung-related results.

Given the intriguing benefit seen in the RADIANT-4 study, Öberg called for further analyses to explore individual subgroups by tumor location in patients with GI tumors. Emerging data indicate everolimus likely has different efficacy rates by location in various GI tumors, specifically higher efficacy in rectal tumors, according to Öberg. Additionally, he questioned the role of everolimus in treating neuroendocrine tumors in the small intestine, given results from RADIANT-2.

However, given the consistent results from all of the RADIANT studies (1, 2, 3, and 4), Öberg supported using everolimus in grades 1 and 2 disseminated and progressive neuroendocrine tumors, regardless of primary tumor origin. In fact, at this time, the manufacturer of everolimus, Novartis, has noted that worldwide regulatory submission is currently under way for the medication as a treatment for patients with advanced, progressive, nonfunctional GI and lung NETs.

Others at the symposium also shared their support for everolimus in patients with GI/Lung NETs. In an interview withTargeted Oncology, Jennifer Eads, MD, assistant professor of medicine, senior clinical instructor of medicine, Case Western University, labeled the advance as a much-needed medicine for a hard-to-treat population that would quickly be adopted if approved, given past experience with the mTOR inhibitor following its approval for pancreatic NETs in 2011.

“RADIANT-4 is a very positive study. We don't currently have really any medical therapies available beyond somatostatin analogs for patients with carcinoid—to have another option is great,” She toldTargeted Oncology. “The results were very positive, and we have a lot of experience with the drug having used it in pancreatic neuroendocrine tumors. We know what the experience will be like [when] giving it to patients and will feel very comfortable giving it.”

Yao JC, Fazio N, Singh S, et al. Safety and efficacy of everolimus in advanced nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) origin: findings of the randomized, placebo-controlled, double-blind, multicenter, phase 3 RADIANT-4 Study. Presented at: 2015 NANETS Symposium; October 15-17; Austin, TX. Abstract C51.