The incidence of neuroendocrine tumors (NETs) has increased 5-fold over the past 30 years, making it the second most prevalent diagnosis in gastrointestinal (GI) malignancies, explains Emily K. Bergsland, MD, a professor of medicine at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.
“Resection of the disease continues to be a treatment for patients with well-differentiated gastroenteropancreatic (GEP)- NETs and is still conducted in more than 70% of patients with these tumors. However, the recurrence rate for patients who received a resection is 100% at 10 years, changing the treatment paradigm as this was previously considered a curative therapy,” said Bergsland in her presentation at the 2018 OncLive®
State of the Science SummitTM
on Gastrointestinal Cancers.
Available and emerging systemic therapies are being used to improve these outcomes in patients with NETs, she added. These include octreotrotide and lanreotide, as well as newly approved agents such as Lutathera (lutetium Lu 177 dotatate).
For patients with treatment-naïve midgut NETs, octreotide was investigated in the phase III PROMID study. Although it is not FDA approved for this indication, octreotide long-acting repeat- able (LAR) lengthened the time to progression compared with placebo in patients with functionally active and inactive meta- static midgut NETs.
In PROMID, patients were randomly assigned to either placebo or octreotide 30 mg intramuscularly in monthly intervals until tumor progression or death. The primary efficacy endpoint was time to tumor progression, which was a median of 14.3 and 6.0 months in the octreotide and placebo arms, respectively (HR, 0.34; 95% CI, 0.20-0.59; P
After 6 months of treatment, stable disease was observed in 66.7% and 37.2% of the octreotide and placebo arms, respectively. The HR for overall survival (OS) was 0.81 (95% CI, 0.30-2.18). Because of the low number of observed deaths—7 in the octreotide LAR arm and 9 in the placebo arm—the survival analysis was not confirmatory.
Lanreotide was approved by the FDA in 2011 for patients with advanced GEP-NETs based on the results from the phase III CLARINET study. Treatment with lanreotide reduced the risk of disease progression within 96 weeks after thefirst dose by 53% compared with placebo for patients with 1 or 2 GEP-NETs. Patient quality of life was found to be similar between the 2 arms.3
This study randomized 204 patients to lanreotide at 120 mg or placebo, administered monthly for 24 months. The primary endpoint of the study was progression-free survival (PFS) with secondary endpoints of OS and quality of life. In a final analysis of the trial, the median PFS was 38.5 months with lanreotide.
The FDA initially approved lanreotide in 2007 as a long-term treatment for patients with acromegaly. Traditionally, somatostatin analogs have been used for symptom control in patients with NETs.
Oral Targeted Agents
Both everolimus (Afinitor) and sunitinib (Sutent) have been utilized in progressive pancreatic NETs. In 2016, the FDA approved everolimus for the treatment of patients with progressive well-differentiated, nonfunctional, locally advanced or metastatic GI or lung NETs based on findings from the phase III RADIANT-4 trial.
“Both sunitinib and everolimus were FDA approved in 2011 for the use of pancreatic NETs. They both delayed progression by 6 months and have a low response rate; however, they have different [adverse] effect pro les,” said Bergsland.
Due to the similar efficacy results, the adverse event (AE) profile is often how physicians determine which treatment to give patients based on their comorbidities.
The most recent FDA approval is Lutathera (lutetium Lu 177 dotatate) for the treatment of patients with somatostatin receptor–positive GEP-NETs. This FDA approval is based on the phase III NETTER-1 trial, which randomized 229 patients with grade 1/2 metastatic midgut NETs, all of whom had progressed on standard-dose octreotide, to Lutathera or to high- dose octreotide LAR. There was a 79% reduction in the risk of progression or death with Lutathera compared with octreotide.4
In this study, 229 patients who had progressed on standard-dose octreotide were randomized to Lutathera or high-dose octreotide. The primary endpoint of the study was PFS with secondary endpoints including objective response rates (ORR), OS, and safety.
The median PFS was not reached in the Lutathera arm compared with 8.5 months in the octreotide arm (HR, 0.21; 95% CI, 0.13-0.32). The ORR was 13% versus 4% in the Lutathera and octreotide arms, respectively. At the interim analysis of OS, there was a 48% reduction in the risk of death with Lutathera compared with octreotide (HR, 0.52; 95% CI, 0.32- 0.84). All-grade AEs were experienced in 96% of patients in the Lutathera arm versus 86% in the octreotide group.
- DasariA,ShenC,HalpernD,etal.Trendsintheincidence,prevalence,andsurvival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335-1342. doi: 10.1001/jamaoncol.2017.0589.
- Rinke A, Müller HH, Schade-Brittinger C, et al; PROMID Study Group. Placebo con- trolled, double-blind, prospective, randomized study on the e ect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tu- mors: A report from the PROMID study group. J Clin Oncol. 2009;27(28): 4656-4663. doi: 10.1200/JCO.2009.22.8510.
- Wolin EM, Pavel M, Cwikla JB, et al. Final progression-free survival (PFS) analyses for lan- reotide autogel/depot 120 mg in metastatic enteropancreatic neuroendocrine tumors (NETs): The CLARINET extension study. J Clin Oncol. 2017;35 (suppl; abstr 4089).
- Strosberg JR, Wolin EM, Chasen B, et al. NETTER-1 phase III: e cacy and safety results in patients with midgut neuroendocrine tumors treated with 177Lu-DOTATATE. J Clin Oncol. 2016;34(suppl 15; abstr 4005).