Improved Therapy Options for Patients with Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are thought to arise from cells throughout the diffuse endocrine system.^1,2 According to a report published in JAMA Oncology, the incidence and prevalence of NETS are steadily rising, though for reasons not well understood.¹ Estimates put the incidence of NETs at 6.98 cases per 100,000 people in 2004, suggesting the prevalence of individuals with NETs in the United States may exceed 170,000.^1,2

NETs can occur throughout the body, but primary sites include the gastrointestinal (GI) tract, pancreas, rectum, lungs, and appendix.³ The majority of NETs can be divided into two classes: carcinoid and pancreatic NETs.³ Approximately one-third of carcinoid tumors arise in the lungs or thymus, and two-thirds arise in the GI tract.^1,2

Patients with NETs may or may not have symptoms attributable to hormonal hypersecretion, including intermittent flushing and diarrhea in patients with GI NETs,⁴ and symptoms attributable to secretion of insulin, glucagon, gastrin, and other peptides in patients with pancreatic neuroendocrine tumors.⁵

TREATMENT STRATEGIES AND CHALLENGES 

In a global survey of 1928 patients with NETs conducted in 2014, patients reported a substantially negative impact of their NET diagnosis on their personal and work lives. Patients also reported delayed diagnosis and extensive NET-related health care resource use.⁶

Survival for all NETs has improved over time, especially for distant-stage GI NETs and pancreatic NETs in particular, reflecting improvement in therapies.¹ Tumor resection surgery is the only curative strategy; however, most NETs are diagnosed when the disease is advanced and metastatic and are not amenable to curative surgery, leading to the need for systemic therapies.⁷

Somatostatin analogs (SSAs) have been the mainstay of therapy for the control of symptoms associated with carcinoid syndrome. Patients who have metastatic NETs and carcinoid syndrome should be treated with octreotide long-acting release (LAR) or Somatuline Depot (lanreotide; Ipsen).^8,9 Somatuline Depot has a similar mechanism of action as LAR octreotide but is administered as a deep subcutaneous injection.¹⁰ The multinational phase 3 ELECT trial randomized 115 patients with carcinoid syndrome who were naïve or responsive to octreotide to receive 120 mg Somatuline Depot or placebo. Patients in the Somatuline Depot arm required less frequent rescue octreotide than those in the placebo arm (33.7% vs 48.5%; P = .017).¹¹ SSAs have also been shown to inhibit the growth of well-differentiated GI and pancreatic NETs.^12,13

THE COSTS OF CARE 

A 2017 report in American Drug & Health Benefits estimated the costs to payers associated with 30-mg octreotide LAR and 120-mg Somatuline Depot treatment among patients with metastatic GI NETs. Cost estimates during 1-, 3-, and 5-year horizons were $74,566, $180,082, and $262,344, respectively, for octreotide LAR and $84,856, $205,562, and $299,667, respectively, for Somatuline Depot. Thus, octreotide LAR was associated with lower costs by $10,290 (1 year), $25,480 (3 years), and $37,323 (5 years) compared with Somatuline Depot. Over a 5-year horizon, the costs of adverse events and administration accounted for 0.72% of the total cost for octreotide LAR and 0.51% of the total cost for Somatuline Depot. The authors acknowledge that their analysis relied on assumed equivalent efficacy between the drugs, although no head-to-head studies comparing the efficacy of octreotide LAR vs Somatuline Depot have been published.¹⁴

If carcinoid syndrome is poorly controlled, Xermelo (telotristat ethyl; Lexicon Pharmaceuticals) may be considered for persistent symptoms (eg, diarrhea). Xermelo is not indicated for the treatment of flushing, however.¹⁵ Xermelo was evaluated in the TELESTAR study, a multicenter, randomized, double-blind, placebo-controlled phase 3 trial of 135 patients with metastatic NETs and a documented history of carcinoid syndrome. Patients were randomized to receive placebo, Xermelo 250 mg, or Xermelo 500 mg 3 times per day orally for 12 weeks. At baseline, patients experienced an average of at least 4 bowel movements per day while receiving SSA therapy for at least 3 months prior to enrollment. From baseline to week 12, reductions in mean bowel movement frequency with Xermelo 250 mg or Xermelo 500 mg were -1.7, and -2.1, respectively, vs -0.9 with placebo. Additionally, both Xermelo doses significantly decreased mean urinary 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin, compared with placebo at week 12 (P < .001).¹⁵

A cost-effectiveness analysis of Xermelo as an add-on to SSA treatment published in Journal of Medical Economics calculated drug costs for adequately and not adequately controlled patients to be $4291.75 and $5890.57 for SSA, respectively, and $9456.07 and $5890.57 for SSA plus Xermelo, respectively. The base-case analysis demonstrated lifetime quality-adjusted life-years (QALYs) of 1.67 at a cost of $495,125 for the SSA cohort and 2.33 at a cost of $590,087 for SSA plus Xermelo, with an incremental QALY for SSA plus Xermelo of 0.66 for an additional $94,962. The incremental cost per QALY gained was $142,545. Thus, adding Xermelo to SSAs was considered to be a cost-effective strategy.¹⁶

Cytotoxic chemotherapy with alkylating agents is an option for patients with pancreatic NETs but has only modest benefits for patients with carcinoid tumors.¹⁷

Afinitor (everolimus; Novartis) is recommended as a treatment option for patients with progressive metastatic GI tract NETs and may be considered for patients with clinically significant progression of metastatic bronchopulmonary or thymic disease.¹⁷ Afinitor was well tolerated and showed antitumor activity with and without SSA treatment in the RADIANT-2 and RADIANT-4 clinical trials, respectively.^18,19

Afinitor is also recommended for patients with advanced pancreatic NETs. In RADIANT-3, a multicenter study enrolling 410 patients with advanced, progressive tumors, the median progression-free survival (PFS) for patients randomized to Afinitor was 11.0 months compared with 4.6 months for patients receiving placebo (P < .001).20 Afinitor can also be considered to stabilize glucose levels for patients with insulinomas.²¹

Sutent (sunitinib malate; Pfizer) is an additional option for patients with pancreatic NETs. Sutent was studied in a multicenter randomized study in which 340 patients were enrolled, but the study was discontinued after enrollment of 171 patients, before the predefined efficacy analysis. At discontinuation, patients who received Sutent had a median PFS duration of 11.4 months, compared with 5.5 months for patients receiving placebo (P > .001). The objective response rate to Sutent was 9.3%.²²

The Journal of Clinical Oncology published an analysis of the projected cost-effectiveness of Afinitor vs Sutent for the treatment of patients with advanced, progressive pancreatic NETs from a US payer perspective. Absent head-to-head trials, efficacy data were based on a weight-adjusted indirect comparison of the two agents using the respective phase 3 trial data. The estimated gain of Afinitor over Sutent was 0.448 life-years (0.304 QALYs) at an incremental cost of $12,673, resulting in an incremental cost-effectiveness ratio of $28,281 per life-year ($41,702 per QALY gained), which fell within the cost per QALY range for many other widely used oncology drugs.²³

TESTING NEW THERAPY 

Treatment with radiolabeled SSAs has been associated with tumor responses and encouraging survival rates in a number of studies.¹⁷ In 2018, the US Food and Drug Administration (FDA) approved peptide receptor radionuclide therapy (PRRT) for the treatment of gastroenteropancreatic (GEP) NETs. In this novel approach, radiopeptides bind to somatostatin receptors on the tumor’s surface and emits radiation, killing the cell. Patients undergo multiple sessions of PRRT a few months apart.²⁴

Lutathera (177Lu-dototate; Advanced Accelerator Applications) is the first radiopharmaceutical approved for use in PRRT for the treatment of GEP-NETs. The phase 3 NETTER-1 study randomized 229 patients with advanced midgut NETs to receive either Lutathera or high-dose octreotide. Lutathera was associated with a significant improvement in PFS (not reached vs 8.4 months; P < .001).25. In another study of Lutathera in 610 Dutch patients with metastatic GEP and bronchial NETs, PFS and overall survival (OS) for all patients were 29 months and 63 months, respectively. This study included 133 patients with pancreatic NETs, and this patient group had the longest OS (71 months), with 6 patients having a complete response.²⁶

Lutathera for patients with mid-gut tumors who have progressed on SSAs and who are positive for somatostatin receptors is the only NET treatment option designated as a category 1 recommendation by National Comprehensive Cancer Network (NCCN) clinical practice guidelines.¹⁷ Most patients with GEP-NETs have tumors that express somatostatin receptors. In 2016, FDA approved a diagnostic imaging method that uses the radiolabeled somatostatin analog gallium-68 to locate somatostatin receptor–positive tumors using positron emission tomography scans. This approach is much more sensitive than older methods used to detect somatostatin receptor–positive GEP-NETs and can determine whether the dotatate is likely to be taken up by the tumor, in order to identify patients who are candidates for treatment with Lutathera.¹⁷ 

References:

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