CHMP Recommends Approval of Everolimus for GI, Lung NETs

Alessandro Riva, MD

Everolimus (Afinitor) has received a positive recommendation from the EMA’s Committee for Medicinal Products for Human Use (CHMP) as a treatment for patients with progressive, unresectable or metastatic, well-differentiated nonfunctional gastrointestinal (GI) or lung neuroendocrine tumors (NETs).

The positive opinion suggests the mTOR inhibitor everolimus is likely to be approved in this setting when the European Commission issues its final decision.

CHMP based its recommendation on data from the phase III RADIANT-4 trial.¹ In the study, median progression-free survival (PFS) by central review was 11 months with everolimus versus 3.9 months with placebo, representing a 52% reduction in the risk of progression or death (HR, 0.48; 95% CI, 0.35-0.67; P <.00001). Median PFS by investigator assessment with everolimus was 14.0 months versus 5.5 months with placebo (HR, 0.39; 95% CI, 0.28-0.54; P <.001).

"This important milestone reinforces our long-standing commitment to the NET community by providing solutions to help improve outcomes for patients with these rare and difficult-to-treat cancers," Alessandro Riva, MD, global head, Novartis Oncology Development and Medical Affairs, the manufacturer of everolimus, said in a statement.

In the RADIANT-4 trial, 302 patients with progressive, well-differentiated, nonfunctional lung/GI NETs were randomized in a 2:1 ratio to receive best supportive care plus 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). The primary endpoint of the study was PFS. Secondary outcome measures included overall survival (OS), response, and safety.

A preplanned interim OS analysis performed after 37% of events showed an early 36% reduction in the risk of death with everolimus (HR, 0.64; 95% CI, 0.40-1.05); however, the OS difference had not yet achieved statistical significance (P = .037).

PFS benefits were consistent across subgroup analyses. 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 patients in the everolimus group and 26% of the placebo group. The objective response rate for those in the everolimus group was 2% compared with 1% in the placebo arm. The disease control rate was 82.4% with everolimus versus 64.9% with placebo.

Data from a subgroup analysis looking specifically at GI NETs further illuminated the benefit in this population.² In the GI subgroup, median PFS was 13.1 months with everolimus versus 5.4 months with placebo (HR, 0.56; 95% CI, 0.37-0.84). In the midgut subgroup, median PFS was 17.3 months with everolimus versus 10.9 months with placebo (HR, 0.71; 95% CI, 0.40-1.26). Among patients with non-midgut NETS, median PFS was 8.1 months versus 1.9 months, respectively (HR, 0.27; 95% CI, 0.15-0.51).

The most common treatment-related all-grade adverse events (AEs) across the trial were stomatitis (63%), diarrhea (31%), fatigue (31%), infections (29%), rash (27%) and peripheral edema (26%). The most frequently occurring grade 3/4 AEs included stomatitis (9% with everolimus vs 0 with placebo), diarrhea (7% vs 2.0%), and infections (7% vs 0).

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. AEs accounted for discontinuations in 29% and 7% for everolimus and placebo, respectively.

In the United States, everolimus was approved by the FDA for the treatment of GI and Lung NETs in February 2016.

References

1. Yao J, Fazio N, Singh S, et al. Everolimus in advanced nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) origin: efficacy and safety results from the placebo-controlled, double-blind, multicenter, Phase III RADIANT-4 study. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract LBA5.
2. 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).