Steve Carrell

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

&ldquo;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.

In the phase III TELESTAR study, telotristat etiprate decreased mean daily bowel movements by 35% in participants who received 500 mg of the drug three times a day and 29% in 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 (

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 currently treated with somatostatin analogs (SSAs) and, although these therapies are initially effective, responses may become diminished over time, Kulke et al wrote in a research report.1 He said new therapies are needed for these patients.

The TELESTAR study enrolled 135 patients with well-differentiated metastatic neuroendocrine tumors and a documented history of carcinoid syndrome experiencing &ge;4 bowel movements per day.2 To be eligible, patients had to be receiving stable-dose SSA therapy.

The coprimary endpoints were the change in the number of daily bowel movements and the incidence of treatment-emergent adverse events (AEs) 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 50% of days in 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, according to Kulke.

Especially from a patient's perspective, reducing daily bouts of diarrhea from 6 to 4 is a significant improvement, said Kjell &Ouml;berg, 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. According to Kulke, the decreases are consistent with the drug's suggested mechanism of action, which is inhibition of intratumoral TPH.

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

&Ouml;berg said both doses of the drug were well tolerated with no significant AEs. However, 17% of the high-dose group had depression. This issue needs further study, but physicians should evealuate patients for depression.

During his presentation, Kulke noted that telotristat etiprate, at both doses, had a safety profile similar to 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 AEs for patients in the placebo, 250-mg, and 500-mg groups was 26.7%, 33.3%, and 68.9%, respectively, according to Kulke. However, the rate of serious treatment-related AEs 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 of the groups.

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

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

Kulke MH, O&rsquo;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]. Endocr Relat Cancer.&nbsp;2014;21(5):705-714.

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

Articles

A novel serotonin synthesis inhibitor, telotristat etiprate, helped reduce daily bowel movements for patients with carcinoid syndrome no longer responding to standard-of-care treatments, an encouraging sign for an emerging class of drugs.


Carcinoid Syndrome Symptoms May Improve With Telotristat Etiprate

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;

<.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 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 (

= .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 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 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 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 [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.

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.

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

The future of somatostatin analogs for neuroendocrine tumors (NETs) includes potential advances on several fronts, according to a presentation at the NANETS' 2015 Neuroendocrine Tumor Symposium.

One advance involves higher doses of somatostatin analogs, for example, a stronger formulation of lanreotide, which is in a phase II trial with optimal dosing not yet determined. That study illustrates the growing sentiment that higher doses of several somatostatin analogs will likely work better without increasing dangerous toxicities, said Martyn Caplin, BSc, DM, FRCP, a professor, consultant gastroenterologist, and neuroendocrine tumor physician at the Royal Free Hospital, London.

Speaking on somatostatin analogs' future and some important past studies, Caplin detailed other advances on the horizon including:

The potential for blood measurement of neuroendocrine gene transcripts to predict progression. For example, Caplin cited a study by Irvin Medlin, MD. Medlin's poster at the 2015 ASCO Annual Meeting showed the sensitivity and specificity of a blood-based multianalyte NET gene transcript measurement for identifying small-intestinal and pancreatic NETs.

Continuing study of vitamin D to help treat and prevent several cancers, including stabilizing NETs. After several years of treatment for NETs, patients often show vitamin D deficiencies. CAPLIN urged physicians to test patients for vitamin D and correct any deficiencies.

Further research on peptide agonists that have some binding affinity for all five somatostatin receptors. Such drugs under continuing study include somatostatin 14, somatostatin 28, and KE 108.

The efficacy of somatostatin analogs and their limited side effects will increasingly move these agents into standard, first-line therapy for many NETs, Wouter de Herder, MD, PhD, told

in an interview. de Hanerder is an endocrine oncology professor and physician at Erasmus MC in Rotterdam.

Gallstones are no longer a significant issue with somatostatin analogs, according to de Herder, who moderated a symposium session on the future of somatostatin analog therapy. He pointed out that gallstones seldom occur and are usually asymptomatic. He also noted that analogs are now far better than old treatment regimens that led surgeons to remove the gallbladder and the NETs at the same time.

These agents are being studied in higher oral dosing and in sustained-release formulations. Since administering somatostatin analogs can be complex, de Herder added that he looks forward to having more liquid dosing to make injections easier and eventually lead to self-dosing.

The future also includes the need for wider dissemination of existing knowledge. "Several significant NET studies have produced results that are too little known or utilized except by NET specialists," Caplin told

. The general message of these studies is that somatostatin analogs are often well-tolerated, effective treatments for grades 1 and 2 NETs.

One significant study was the open-label extension (OLE) of CLARINET, which studied the somatostatin analog, lanreotide 120 mg. Reinforcing CLARINET's results, the OLE

study further illustrated lanreotide's antitumor effects because patients who had progressed on placebo gained an additional PFS of 14 months after switching to lanreotide, according to Caplin.

The original phase III CLARINET study, published in the

the first randomized placebo-controlled trial investigating PFS with a somatostatin analog in a population that included patients with pancreatic NETs and with grade G2 tumors. The original study produced significantly prolonged PFS compared with placebo in patients with metastatic gastroenteropancreatic (GEP) NETs. Treatment with lanreotide improved PFS by 53% compared with placebo for patients with grade 1 or 2 GEP NETs.

several other speakers at the symposium had to add, "except for pancreatic tumors" when they discussed the many NETs still needing better treatment.

Caplin summarized another significant study, pasireotide LAR versus octreotide LAR in patients with metastatic NETs. The 2013 multicenter, randomized, blinded, phase III study by Wolin et al showed pasireotide produced PFS lasting 5 months longer than octreotide, with no differences in symptom response rates. The drugs had similar safety profiles, except for more hyperglycemia with pasireotide

The last significant study Caplin summarized was the PROMID study of somatostatin analog, octreotide LAR in patients with well-differentiated, metastatic midgut NETs. The phase III study in 2009 showed the median PFS with octreotide was 14.3 months versus 6 months with placebo. After 6 months of treatment, 67% of patients had stable disease with octreotide versus 37% with placebo.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;

Somatostatin Analogs Show Cumulative Benefit in NET Trials

Results from NETTER-1 trial showed an unprecedented 79% reduction in the risk of progression or death with the radiopharmaceutical Lu-Dotatate (

Lutetium DOTATATE; Lutathera) compared with high-dose octreotide LAR (60 mg) in patients with progressive, metastatic midgut neuroendocrine tumors (NETs).

&ldquo;The findings were, in my opinion, extraordinarily impressive, the median progression-free survival improved by nearly 80%, which is fairly unprecedented in oncologic studies,&rdquo; said presenter and medical oncologist Jonathan Strosberg, MD, Moffitt Cancer Center, at the 2015 NANETS Symposium. &ldquo;The finding is important because limited therapeutic options exist for such patients, who comprise 20% to 45% of neuroendocrine tumor cases.&rdquo;

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 8 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 4 weeks. Patient in the Lu-Dotatate arm also received renal protection via amino acid solution infusion.

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

<.0001). 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. Disease progression had occurred in 4% of patients in the Lu-Dotatate group and 24% of the octreotide group. Stable disease was almost the same for both groups.

&ldquo;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,&rdquo; Strosberg said. "It is looking like the ultimate outcome, median progression-free survival, will probably be around the 40-month range."

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

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

&ldquo;As far as OS, which was the secondary endpoint, there was a very strong trend toward improvement in OS,&rdquo; he told

. &ldquo;The results are extremely encouraging for survival, not quite meeting the exacting threshold for preliminary survival.&rdquo;

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

The ongoing study includes an 18-month accrual period (completed) plus a 5-year follow-up starting from the last patient&rsquo;s randomization date, which was in February 2015. Every 12 weeks, evaluators use the RECIST 1.1 criteria to assess tumor response in both arms. Patients remain under treatment until disease progression, unacceptable toxicity or inability/unwillingness to comply with study requirements.

The first patient was enrolled in July 2012. The analysis of primary endpoint started after 74 evaluable and centrally confirmed events. 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&rsquo;s maker, Advanced Accelerator Applications, called Lu-Dotatate the most advanced candidate in development of peptide receptor radionuclide therapy (PRRTs), which target tumors with radiolabeled somatostatin analogue peptides. In April 2015, the FDA granted a fast track designation to Lutathera for the treatment of inoperable progressive midgut NETs. This designation is meant to facilitate the development of novel therapies.

A diagnostic for identifying patients who are likely to respond to Lutathera, SomaKit-TATE, was granted a priority review designation in early September 2015. The kit is designed to facilitate 68Ga-DOTATATE for injection, which can be used to detect somatostatin receptor-positive NETs by PET scan.

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.

Results from NETTER-1 trial showed an unprecedented 79% reduction in the risk of progression or death with the radiopharmaceutical Lu-Dotatate compared with high-dose octreotide LAR (60 mg) in patients with progressive, metastatic midgut neuroendocrine tumors (NETs).

Steve Carrell | Authors

Articles

Carcinoid Syndrome Symptoms May Improve With Telotristat Etiprate

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

Somatostatin Analogs Show Cumulative Benefit in NET Trials

Unprecedented PFS in Midgut NETs Shown With Lu-Dotatate