New Standard of Care for Advanced Lung, GI NETs May Be Everolimus

James Yao, MD

James Yao, MD

Patients with advanced lung and gastrointestinal (GI) neuroendocrine tumors (NETs) had a 52% reduction in risk of progression or death with everolimus compared with placebo, according to findings from the pivotal RADIANT-4 study reported at the 2015 European Cancer Congress.

In the phase III study, the primary endpoint of progression-free survival (PFS), as assessed by central radiology review (modified RECIST 1.0), was a median 11.0 months with everolimus (95% CI, 9.23-13.31) compared with 3.9 months with placebo (95% CI, 3.58-7.43). A 52% reduction in the relative risk of disease progression or death was observed with everolimus versus placebo (HR, 0.48; 95% CI, 0.35-0.67;P<.001).

This &ldquo;robust benefit&rdquo; was confirmed in the investigator-assessed PFS, which was 14.0 months (95% CI, 11.24-17.71) compared with 5.5 months (95% CI, 3.71-7.39) with placebo (HR, 0.39; 95% CI, 0.28—0.54;&nbsp;P<.001), reported lead investigator James Yao, MD, chair of the Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, during the Congress&rsquo; Presidential Session. The randomized, placebo-controlled, double-blind, multicenter phase III RADIANT-4 trial of everolimus versus placebo was conducted in patients with advanced, lung and GI NETs.

&ldquo;We found a statistically significant 52% reduction in the risk of progression or death in favor of everolimus and also a clinically meaningful 2.8-fold improvement in PFS,&rdquo; said Yao. &ldquo;Although we knew from previous studies that everolimus could delay the growth of pancreatic NETs, this is the first time we have been able to conclusively show that it is effective in other NET sites. We hope our results will provide a new treatment option for lung and gastrointestinal NETs.&rdquo;

NETs originate in the neuroendocrine system where hormones governing different organs throughout the body are produced. Somatostatin analogs (SSAs) are widely used to block hormone production and slow tumor growth. However, in the case of nonfunctional NETs, either no hormone is secreted or one is secreted that does not cause symptoms.

The mTOR inhibitor everolimus was approved by the FDA for the treatment of advanced pancreatic NETs in 2011. However, advanced, nonfunctional NETs of lung/GI origin remains an area of significant unmet medical need, especially in the case of lung NETs where there is currently no approved standard treatment.

&ldquo;About 74% of NETs are nonfunctional, so unfortunately, late diagnosis is common and poses a major problem for these patients,&rdquo; Yao explained.

In RADIANT-4, 302 patients with progressive, well-differentiated, nonfunctional lung/GI NETs were stratified by tumor origin, WHO performance status (PS), and prior somatostatin analog treatment, then randomized 2:1 to receive best supportive care plus either everolimus at 10 mg per day (n = 205) or placebo (n = 97).

Patient median age was 63 years, 53% of patients were female, and 76% were Caucasian. Disease status was grade 1/grade 2 in 64% and 35% of patients, respectively, and WHO PS was 0 in 74% or 1 in 26% of patients. The most commonly reported tumor sites were the lung in 30%, and the ileum in 24% of patients. The two arms were well balanced regarding prior treatment; 53% versus 56% of patients in the everolimus and placebo groups, respectively had received prior somatostatin analog therapy; 26% versus 24% had received chemotherapy, and 22% versus 20% had undergone previous locoregional and radiotherapy.

Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. ORR by central review showed no complete response, but 4 (2%) of everolimus patients and one placebo patient showed partial response. DCR was 82% with everolimus versus 65% with placebo. Progressive disease was reported for 9% of everolimus patients compared with 27% of patients receiving placebo.

A preplanned interim OS analysis performed with 37% of the information fraction favored everolimus (HR, 0.64; 95% CI, 0.40-1.05;P= .037); however, OS difference did not achieve statistical significance.

&ldquo;We saw a trend towards an improved overall survival but this was an interim analysis, and it is too early to be able to be more definite about this at this time,&rdquo; Yao said, adding that he looked forward to presenting these results in 2016.

The most commonly reported adverse events (AEs) grades 1/2 included stomatitis, diarrhea, peripheral edema, fatigue, and rash. Grades 3/4 AEs of diarrhea (9% vs 2%) and anemia (5% vs 2%) were reported in patients receiving everolimus and placebo, respectively. Grades 3/4 abdominal pain was reported for 5% of each treatment arm, and stomatitis was reported by 7% of patients receiving everolimus.

The authors noted that treatment of patients with advanced, nonfunctional NETs of the lung or GI tract currently poses a challenge due to a lack of prospective data from large clinical trials.

Christoph C. Zielinski, MD, director of the Clinical Division of Oncology and coordinator of the Comprehensive Cancer Center at Medical University Vienna, was not involved in the study but confirmed that these results would change his own clinical practice and remarked, &ldquo;This is an example of the breakthrough in disease treatment that can follow after the genetic triggers of a disease are identified. Chemotherapy rarely produces this type of result.&rdquo;

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.