Everolimus (Afinitor) improved progression-free survival by 7.1 months compared with placebo in patients with lung/gastrointestinal (GI) neuroendocrine tumors (NETs), representing a 52% reduction in the risk of progression or death, 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 anti-tumor 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 was the first large, placebo controlled, phase III study of advanced, progressive, nonfunctional lung/GI NET, according to Yao. In the study, 302 patients with progressive, well-differentiated, nonfunctional lung/GI NETs were randomized 2:1 to receive 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 progression-free survival (PFS) of 11 months compared with 3.9 months for placebo (HR, 0.48; 95% CI, 0.35-0.67; 

 <.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; 

 <.00001). This benefit was consistent 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."

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, Yao said. 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 deaths with everolimus was seen; however, it did not reach statistical significance (

 = .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 were consistent with the known safety profile for everolimus. Drug-related adverse events were mostly grades 1 and 2 stomatitis, diarrhea, fatigue, infections, rash and peripheral edema. The most common grades 3 and 4 adverse events among everolimus-treated patients were stomatitis in 9%, diarrhea in 7%, and infections in 7%, Yao said. Grade 3 and 4 adverse events 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 adverse events. 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 that everolimus could produce significant results for patients with lung tumors. Öberg, an endocrine oncology researcher at Uppsala (Sweden) University, noted that an earlier European study supported RADIANT-4's lung-related results.

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 NETs, regardless of primary tumor origin. In fact, at this time, the manufacturer of everolimus, Novartis, has noted that worldwide regulatory submission is currently underway for the medication as a treatment for patients with advanced, progressive, nonfunctional GI and lung NET.

Others at the symposium also shared their support for everolimus in patients with GI/Lung NETs. In an interview with 

, 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 utilized, 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 told 

. "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, 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.

Articles

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

Everolimus Shows Robust Activity in Lung/GI NETs

Lutetium DOTATATE; Lutathera) demonstrated an unprecedented 79% reduction in the risk of progression or death compared with high-dose octreotide LAR (60 mg) in patients with progressive, metastatic midgut neuroendocrine tumors (NETs), according to results from NETTER-1 trial presented by Jonathan Strosberg, MD, at the 2015 NANETS Symposium.

"The findings were, in my opinion, extraordinarily impressive, the median progression-free survival improved by nearly 80%, which is fairly unprecedented in oncologic studies," said Strosberg, a medical oncologist and researcher at the Moffitt Cancer Center. "The finding is important because limited therapeutic options exist for such patients, who comprise 20% to 45% of neuroendocrine tumor cases."

The NETTER-1 trial is the first prospective, randomized, phase III study for patients with midgut NETs, specifically those in the ileum and cecum. Patients in the trial had progressed on prior therapy with octreotide at 30 mg and had inoperable, somatostatin receptor positive tumors.

Those randomized to the Lu-Dotatate arm received the therapy at 7.4 GBq in 4 doses over eight weeks in combination with 30 mg of octreotide LAR every 28 days. In the comparator arm, octreotide LAR was administered alone at 60 mg every four weeks. Patient in the Lu-Dotatate arm also received renal protection via amino acid solution infusion.

Interim results showed the median progression-free survival had not been reached for Lu-Dotatate compared with 8.4 months for octreotide (HR, 0.21; 95% CI, 0.13-0.34; 

 <.0001). Disease progression had occurred in 4% of patients in the Lu-Dotatate group and 24% of the octreotide group. 

"The median time to progression was 8.7 months with high-dose octreotide, which was the control arm, and was not yet reached in the Lutetium arm, with a median follow up of nearly a year and a half," Strosberg said. "It is looking like the ultimate outcome, median progression-free survival, will probably be around the 40-month range."

The objective response rate with Lu-Dotatate was 19% compared with 3%. One patient in the radiopharmaceutical arm achieved a complete response compared with none in the octreotide arm. Stable disease was almost the same for both groups.

For the secondary endpoint of overall survival, 13 patients had died in the Lu-Dotatate arm compared with 22 in the octreotide group. The 

 value for this trend toward improvement in overall survival was .018; however, the threshold for statistical significant at the preliminary analysis was less than .001, Strosberg said.

"As far as overall survival, which was the secondary endpoint, there was a very strong trend toward improvement in overall survival," he told 

. "The results are extremely encouraging for survival, not quite meeting the exacting threshold for preliminary survival."

Safety data from the NETTER-1 trial confirmed favorable results of the preceding phase I/II studies. Serious adverse events related to treatment were 9% for Lu-Dotatate and 1% for octreotide. Withdrawals due to adverse events were 5% for Lu-Dotatate and did not occur in patients treated with octreotide, Strosberg said.

The ongoing study includes an 18-month accrual period (completed) plus a 5-year follow-up, starting from the last patient’s randomization on February 2015. Patients remain under treatment until disease progression, unacceptable toxicity or inability/unwillingness to comply with study requirements. Main secondary endpoints are objective response rate, overall progression, time to progression, safety, tolerability and health-related quality of life, which will continue to be assessed. In a subset of patients, dosimetry, pharmacokinetics, and ECG evaluations are also performed.

The drug's maker, Advanced Accelerator Applications, says Lu-Dotatate is the most advanced candidate in development of peptide receptor radionuclide therapy (PRRTs), which target tumors with radiolabelled somatostatin analog peptides. In April 2015, the FDA granted a fast track designation to Lu-Dotatate for the treatment of inoperable progressive midgut NETs. This designation is meant to facilitate the development of novel therapies.

	Strosberg J, Wolin E, Chasen B, et al. 177-Lu-Dotatate Significantly Improves Progression-Free Survival in Patients with Midgut Neuroendocrine Tumors: Results of the Phase III NETTER-1 Trial. Presented at: 2015 NANETS Symposium; October 15-17; Austin, TX. Abstract C39.

Lu-Dotatate demonstrated an unprecedented 79% reduction in the risk of progression or death compared with high-dose octreotide LAR in patients with progressive, metastatic midgut neuroendocrine tumors.

Lu-Dotatate Shows Unprecedented PFS in Midgut NETs

Telotristat etiprate, a novel serotonin synthesis inhibitor, helped reduce daily bowel movements for patients with carcinoid syndrome no longer responding to standard-of-care therapies, an encouraging signal for an emerging class of drugs, according to research presented at the 2015 North American Neuroendocrine Tumor Society (NANETS) Symposium.

In the phase III TELESTAR study, telotristat etiprate decreased mean daily bowel movements by 35% among participants who received 500 mg of the drug three times a day and 29% among those who took 250 mg three times a day, compared with 17% for individuals who received a placebo. The results, measured from baseline to 12 weeks, were statistically significant (

“These results clearly show telotristat etiprate represents a potentially promising new class of treatment for patients with carcinoid syndrome," said Matthew H. Kulke, MD, director of the Program in Neuroendocrine and Carcinoid Tumors at Dana-Farber Cancer Institute in Boston.

Telotristat etiprate is a small-molecule inhibitor of tryptophan hydroxylase (TPH), which is overexpressed in carcinoid tumor cells and is involved in serotonin biosynthesis. Blockade of TPH reduces peripheral serotonin production (5-HT), resulting in fewer serotonin-mediated gastrointestinal effects, such as diarrhea.

Patients who develop carcinoid syndromes are typically treated with somatostatin analogs (SSAs) and, although these therapies are initially effective, responses may become diminished over time, Kulke and colleagues wrote in a research report.

He said new therapies are needed for these patients.

The TELESTAR study accrued 135 patients with well-differentiated metastatic neuroendocrine tumors and a documented history of carcinoid syndrome experiencing ≥4 bowel movements per day.

 To be eligible, patients had to be receiving stable-dose SSA therapy.

The co-primary endpoints were the change in the number of daily bowel movements and the incidence of treatment-emergent adverse events from baseline to 12 weeks. Secondary measures included change in urinary 5-hydroxyindoleacetic acid (5-HIAA) levels, cutaneous flushing episodes, and abdominal pain from baseline to 12 weeks.

Patients were randomized to receive telotristat etiprate at either 250 mg or 500 mg three times a day or placebo, with 45 patients in each arm. Patients in all arms continued to receive SSA therapy throughout the study.

The durable response rate, defined as at least a 30% reduction in daily bowel movements over at least half the days of the study period, was 44% for the 250-mg group, 42% for the 500-mg group, and 20% for the placebo cohort.

Using the Hodges-Lehmann estimator of treatment difference, the results showed a strong statistically significant reduction versus placebo, of 0.81 bowel movements daily for the 250-mg group and 0.69 daily for the 500-mg group, Kulke said.

Especially from a patient's perspective, reducing daily bouts of diarrhea from 6 to 4 is a significant improvement, said Kjell Öberg, MD, PhD, a professor of endocrine oncology at Uppsala University Hospital in Sweden.

Telotristat etiprate also significantly reduced urinary 5-HIAA. The levels decreased almost 58% in the 500-mg group and 40% in the 250-mg group, but increased more than 11% in the placebo group. Kulke said the decreases are consistent with the drug's suggested mechanism of action, which is inhibition of intratumoral TPH.

Comparing the two doses, Öberg said both produced fewer bowel movements. However, the lower dose had a better durable response. "So why use the higher dose?" Öberg said.

Öberg said both doses of the drug were well tolerated with no significant side effects. However, 17% of the high-dose group had depression. This issue needs further study but physicians already should be on the lookout for depression.

During his presentation, Kulke noted that telotristat etiprate, at both doses, had a safety profile similar to that of the placebo. He added that the few occasions of nausea and depression were "areas of potential interest" that needed watching and further study.

The incidence of treatment-related adverse events for patients in the placebo, 250-mg, and 500-mg groups was 26.7%, 33.3%, and 68.9%, respectively, Kulke said. However, the rate of serious treatment-related adverse events were low in all arms: 2.2% in the placebo group, 0% in the 250-mg arm, and 4.4% in the 500-mg group. Discontinuations were very low and were similar in all three groups.

Secondary endpoints, which did not reach statistical significance, show reduced flushing in the few patients who had it. Abdominal pain also improved. Kulke said the study's size may have limited researchers' ability to detect such problems.

Other studies will address efficacy and safety issues the 12-week TELESTAR study was not able to cover due to its size and time limitations, Kulke said. Lexicon Pharmaceuticals, based in Texas, is developing the drug under a Fast Track designation from the FDA.

			Kulke MH, O’Dorisio T, Phan A, et al. Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide [published online July 10, 2014]. 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01677910.

Telotristat etiprate, a novel serotonin synthesis inhibitor, helped reduce daily bowel movements for patients with carcinoid syndrome no longer responding to standard-of-care therapies.

Steve Carrell

Articles

Everolimus Shows Robust Activity in Lung/GI NETs

Lu-Dotatate Shows Unprecedented PFS in Midgut NETs

Novel Drug Relieves Carcinoid Syndrome Symptoms