Tag: Carcinoid Tumors

Clinical Utility of NETest®, a Liquid Biopsy Assay for Diagnosis, Monitoring Therapy and Prognosis, in Patients with Neuroendocrine Tumors

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SUMMARY: It is estimated that in the United States, more than 12,000 people are diagnosed with a Neuroendocrine tumor each year. NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and the most common sites of NETs are the lung, stomach, appendix, cecum, duodenum, pancreas, jejunum/ileum, colon, and rectum. NeuroEndocrine Tumors originating in the gastrointestinal tract and pancreas are also known as GastroEnteroPancreatic NETs (GEP-NETs). They constitute about 2% of all neoplasms and account for about 50-70% of all NETs. They are more frequent in gastric fundus/body, proximal duodenum, Vater’s papilla, pancreas, tip of the appendix, terminal ileum, and lower rectum. Majority of GEP-NETs are not symptomatic (nonfunctioning tumors), difficult to diagnose, and present with advanced disease at initial diagnosis. They often metastasize to the mesentery, peritoneum and liver. The functioning tumors however secrete biologically active substances that can lead to the development of characteristic clinical syndromes. NeuroEndocrine Tumors may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis.

Chromogranin A is a glycoprotein precursor to several functional peptides and is considered a standard biomarker for NETs. However, serum Chromogranin A levels can be elevated in several non-oncologic conditions such as atrophic gastritis, pancreatitis, chronic hepatitis, liver cirrhosis, irritable bowel, and inflammatory bowel diseases. The use of proton pump inhibitors can also result in elevated Chromogranin A levels. Diagnostic imaging as well as serum biomarkers lack the sensitivity and are unable to detect early changes in disease state. As such, the absence of a clinically useful blood biomarker remains an important unmet need.

The NETest® is a novel blood-based (liquid biopsy) molecular diagnostic test intended to aid in the identification of neuroendocrine tumor disease activity. The assay involves measurement of 51 neuroendocrine tumor gene transcripts, by Polymerase Chain Reaction (PCR). The gene expression signatures, which is the tumor activity score, stratifies patients into three groups: low score (40% or less), moderate/intermediate score (41-79%) and high score (80% or more). A higher score at the time of testing indicates a higher risk of tumor activity. Previously published prospective clinical studies have demonstrated the value of NETest® in predicting the effectiveness of surgery, in its ability to monitor tumor progression during SomatoStatin Analog (SSA) therapy, in its utility for watch‐and‐wait programs, as well as its ability in predicting response to Peptide Receptor RadioTherapy (PRRT) prior to treatment initiation.

The authors in this study examined the clinical utility of NETest® multigene assay in a real‐world setting, utilizing a registry of NETs in the USA. This registry was established to include clinical and biomarker data from patients enrolled by interested physicians who could then use it to answer specific clinical questions. NETest® registry patients were evaluated from large referral practices, and their subsequent clinical data, including decision‐making, were interfaced with NETest® data. This study addressed five important questions: 1) What is the diagnostic accuracy of the NETest®? 2) Does the NETest® score accurately reflect the disease status? 3) Does it have clinical utility in decision‐making? 4) Can it alter the frequency and type of imaging? 5) Does the NETest® have greater clinical utility than Chromogranin A?. The diagnostic accuracy and relationship to clinical disease status were evaluated in two patient cohorts (treated and watch‐and‐wait).

A total of 100 patients with pathological confirmation of a NET were enrolled over a 22 month period and NETest® was performed at enrollment. The primary site of the NET was gastroenteropancreatic (68%), lung 20%, and of unknown origin (12%). Stage IV disease was present in 96% of patients, 70% had undergone surgery before enrollment, 97% had well‐differentiated, low‐grade tumors and 56% were on drug therapy. The median age was 62 years and the median follow up was 6 months.

The diagnostic accuracy of NETest® was more than 96% and the NETest® was concordant with image‐confirmed disease in 96% of patients. Scores were reproducible (97%) and concordant with clinical status (98%). Chromogranin A was ordered for 53 of the 100 patients, but was not elevated in 75% of these patients despite documented clinical evidence of disease. NETest® was positive in 100% of these patients (P=0.0004 for accuracy). NETest® scores were reproducible (97%) and concordant with clinical status (98%). Multivariate analyses identified the NETest® score as the only variable significantly related to Progression Free Survival (PFS). High NETest® score correlated with progressive disease (81%; median PFS, 6 months), and low NETest® score correlated with stable disease (87%; median PFS, Not Reached)-P<0.0001). The NETest® score was the only feature linked to PFS (odds ratio, 6.1; p < .0001). In the watch‐and‐wait group of patients, low NETest® scores were concordant with stable disease in 100% of patients, and high NETest® scores were associated with management changes in 83% of patients. In the treated group, all patients with low NETest® scores (100%) remained stable. A high NETest® score was linked to treatment intervention and disease stabilization (100%). Further, the utilization of NETest® was associated with reduced imaging (biannual to annual) in 36-38% of patients.

It was concluded that real‐time liquid biopsy assessment of Neuroendocrine tumors with NETest® has more than 96% diagnostic accuracy, and has clinical utility in monitoring disease status, as well as patient management. Assessment of NETest Clinical Utility in a U.S. Registry‐Based Study. Liu E, Paulson S, Gulati A, et al. The Oncologist 2019;24:783-790.

Immune Checkpoint Inhibitor Combination Efficacious in High-Grade Neuroendocrine Tumors

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SUMMARY: It is estimated that in the United States, more than 12,000 people are diagnosed with a Neuroendocrine tumor each year. NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and is most frequently diagnosed in the small intestine, appendix, rectum, lungs and bronchi. The most common type of malignant gastrointestinal NETs originate in the midgut (jejunoileum and the proximal colon) and often metastasize to the mesentery, peritoneum and liver. NETs may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2. Majority of the NETs are nonfunctioning and are diagnosed incidentally but are clinically symptomatic following spread to the liver. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Immune checkpoint blockade with monoclonal antibodies such as OPDIVO® and YERVOY® has revolutionized the treatment of multiple cancers. Previously published studies have demonstrated successful patient outcomes across various tumor types, when treated with a combination of CTLA-4 and PD-1 inhibitors. However, it has remained unclear whether these agents can benefit those with rare, metastatic solid tumors. The investigators therefore launched the DART trial to fulfill this unmet need.

SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) is the first NCI-funded prospective, open-label, rare tumor immunotherapy basket study. Basket trials involve single treatment and single biomarker, different histologies, placed in multiple groups or baskets. These trials are an efficient way for screening experimental therapeutics across multiple patient populations.

In this phase II trial which included 37 different types of rare tumors, patients received YERVOY® 1 mg/kg IV every 6 weeks along with OPDIVO® 240 mg IV every 2 weeks. The Primary endpoint was Overall Response Rate (ORR) and Secondary endpoints included Progression Free Survival (PFS), Overall Survival (OS), Stable disease more than 6 months, and toxicity. This publication included a cohort of 33 eligible patients with Neuroendocrine tumors. Pancreatic Neuroendocrine tumors are currently being evaluated in a separate cohort within the trial. More than half of the patients (58%) had high-grade disease, and the most common tumor sites were gastrointestinal-non pancreatic (45%) and lung (18%). Enrolled patients had received a median of 2 prior lines of therapy.

The Overall Response Rate was 24% with 3% Complete Responses and 21% Partial Responses. Patients with high-grade Neuroendocrine cancer had a 42% Response Rate, whereas the Response Rate was 0% in low/intermediate grade tumors (P=0.01), independent of primary site. The authors hypothesized that the high response rate among those with high-grade Neuroendocrine carcinomas may be related to a higher Tumor Mutational Burden, which is an indicator of better response to immunotherapy. The 6-month PFS was 30% and the median OS was 11 months (historically, it has been around 10% and 3 months respectively). The most common toxicities were fatigue (30% of patients) and nausea (27%) and the most common grade 3/4 immune-related Adverse Events were ALT elevation in 9% of patients.

It was concluded that YERVOY® plus OPDIVO® combination was well tolerated with a 42% ORR in patients with high-grade Neuroendocrine cancer, regardless of primary site. The authors based on this study pointed out that, clinical trials are feasible even in rare tumors. A Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort. Patel SP, Othus M, Chae YK, et al. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA.

LUTATHERA® (Lutetium Lu 177 dotatate)

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The FDA on January 26, 2018 approved LUTATHERA®, a radiolabeled Somatostatin analog, for the treatment of Somatostatin receptor-positive GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors, in adults. LUTATHERA® is a product of Advanced Accelerator Applications USA, Inc.

FDA Approves LUTATHERA® for the Treatment of Somatostatin Receptor-Positive GastroEnteroPancreatic Neuroendocrine Tumors

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SUMMARY: The FDA on January 26, 2018 approved LUTATHERA® (Lutetium Lu 177 dotatate), a radiolabeled Somatostatin analog, for the treatment of Somatostatin receptor-positive GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors, in adults. The most common type of malignant gastrointestinal NeuroEndocrine Tumors (NET) originate in the midgut (jejunoileum and the proximal colon) and often metastasize to the mesentery, peritoneum and liver. These patients frequently present with Carcinoid syndrome and are treated with Somatostatin analogue for control of tumor growth, as well as symptoms related to hormonal secretion. For patients who progress with functional neuroendocrine tumors, there are currently no standard second-line systemic treatment options available. A majority of advanced, well-differentiated neuroendocrine tumors express high levels of Somatostatin receptors and radiolabeled Somatostatin analogue therapy, also known as Peptide Receptor Radionuclide Therapy (PRRT) has been studied since the early 1990’s, with promising results. The radiolabeled Somatostatin analogues bind to the Somatostatin receptors expressed on the surface of the tumor cells and deliver targeted radiation, with a high therapeutic index, directly to the tumor cells.

LUTATHERA® is a radioconjugate consisting of the Somatostatin analog Octreotide conjugated with Lutetium-177 (177Lu), a beta and gamma-emitting radionuclide, using the chelator DOTA. In a study involving 310 patients with GastroEnteroPancreatic, NeuroEndocrine Tumors, treatment with LUTATHERA® resulted in an Objective Response Rate of 30%, and a median Progression Free Survival of 33 months.

The approval of LUTATHERA® was based on NETTER-1, a phase III, randomized, multicenter, open-label, active-controlled trial, which compared LUTATHERA® with high-dose Octreotide LAR (Long Acting), for patients with grade I or II metastatic midgut NeuroEndocrine Tumors. In this study, 229 patients (N=229) with progressive, well differentiated, locally advanced/inoperable or metastatic Somatostatin receptor-positive midgut Carcinoid tumors were randomized in a 1:1 ratio to receive either LUTATHERA® (7.4 GBq [200 mCi] every 8 weeks for up to 4 administrations along with Octreotide LAR 30 mg by IM injection every 4 weeks (N=116) or control group which received high dose Octreotide LAR 60 mg by IM injection every 4 weeks (N=113). LUTATHERA® was co-administered with an amino acid solution as a renal protectant, and in the US, patients received Aminosyn II 10%, a commercially available solution of amino acids. Well-differentiated tumors were defined as those with a Ki-67 by immunostaining of 20% or less. Tumors were assessed as low grade if they had a Ki-67 of 0-2%, intermediate grade if they had a Ki-67 of 3-20%, or high grade if they had a Ki-67 of greater than 20%, with a lower grade indicating a lower rate of cell proliferation. Baseline characteristics were well balanced between the two treatment groups. Enrolled patients had Somatostatin receptor-positive tumors and the primary site of the tumor was the ileum in 74% of the patients and the most common sites of metastasis were the liver (84%) and lymph nodes (66%). The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Objective Response Rates (ORR), Overall Survival (OS), and safety.

At the time of the primary analysis, it was noted that the median PFS was not reached for the LUTATHERA® group and was 8.5 months in the high-dose Octreotide LAR group (HR=0.21; P<0.001). This meant a 79% reduction in the risk of progression or death with LUTATHERA® compared with high dose Octreotide LAR. The estimated rate of PFS at month 20 was 65.2% in the LUTATHERA® group and 10.8% in the control group. The ORR with LUTATHERA® was 18% versus 3% with high dose Octreotide (P<0.001). The OS at the planned interim analysis showed a 60% reduction in the risk of death in favor of LUTATHERA® (HR=0.40; P=0.004). The most common grade 3/4 adverse reactions among patients receiving LUTATHERA® along with Octreotide LAR were nausea, vomiting, cytopenias, liver function abnormalities, hyperglycemia and hypokalemia.

It was concluded that treatment with LUTATHERA® resulted in significantly longer Progression Free Survival and a significantly higher Response Rate, when compared with high-dose Octreotide LAR, among patients with advanced midgut neuroendocrine tumors. Preliminary evidence suggests that there is an Overall Survival benefit as well. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. Strosberg J, El-Haddad G, Wolin E, et al. for the NETTER-1 Trial Investigators. N Engl J Med 2017; 376:125-135

FDA Approves XERMELO® for Carcinoid Syndrome Associated Diarrhea

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SUMMARY: The U.S. Food and Drug Administration on February 28, 2017 approved XERMELO® (Telotristat ethyl) tablets in combination with SomatoStatin Analog (SSA) therapy for the treatment of adults with Carcinoid syndrome diarrhea that SSA therapy alone has inadequately controlled. The hallmark of Carcinoid syndrome is excessive tumor derived serotonin secretion. Carcinoid syndrome is characterized by flushing, diarrhea, bronchial constriction, and the development of cardiac valvular fibrosis, which may lead to heart failure. Diarrhea in these patients can be debilitating with significant impact on quality of life. Serotonin is metabolized into 5-HydyroxyIndoleAcetic Acid (5-HIAA) which can be measured in the urine and is often used to follow response to treatment in patients with Carcinoid syndrome. Somatostatin analogs (SSAs) target somatostatin receptors and can regulate important cellular activity as well as help inhibit hypersecretion of hormones, including serotonin and growth hormone. This in turn can control severe diarrhea and flushing associated with metastatic Carcinoid tumors. SSAs are often used as initial treatment in this patient group, although patients may develop recurrent or progressive symptoms during the course of their disease. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis, converts tryptophan to 5-hydroxytryptophan, which is then converted to serotonin.

XERMELO® is a novel, oral, small-molecule TPH inhibitor, with a high molecular weight, that reduces peripheral serotonin production by inhibiting the enzyme TPH in metastatic carcinoid tumors. XERMELO® was shown in previously published studies, to reduce bowel movement (BM) frequency and decrease urinary 5-HIAA, in patients with Carcinoid syndrome, without causing CNS adverse effects.

TELESTAR is an international, multicenter, randomized, double-blind, placebo-controlled phase III trial in which the safety and efficacy of XERMELO® was evaluated in patients with Carcinoid syndrome not adequately controlled with SSA therapy. One hundred and thirty five (N=135) patients were randomly assigned in a 1:1:1 ratio to receive oral doses of XERMELO® 250 mg, XERMELO® 500 mg, or placebo respectively, three times a day for 12 weeks. Eligible patients experienced four or more BMs per day despite treatment with a stable dose of SomatoStatin Analog (SSA). All patients continued to receive their SSA therapy for the 12 week duration. Patients were allowed to receive rescue doses of short-acting Octreotide and antidiarrheal agents. Treatment groups were well balanced and the mean age was 64 years. The primary end point was mean reduction from baseline in daily Bowel Movements (BMs), averaged over 12 weeks. Secondary end points included change in the urinary 5-HIAA from baseline at week 12, the number of daily flushing episodes, and abdominal pain severity averaged over 12 weeks. In an open-label extension study, 115 patients subsequently continued to receive XERMELO® 500 mg three times a day.

It was noted that 33% of patients randomized to the XERMELO® group experienced an average reduction of two bowel movements per day compared to only 4% of patients randomized to the placebo group. At the week 12 analysis, both XERMELO® doses significantly reduced mean urinary 5-HydroxyIndole Acetic Acid compared to placebo (P<0.001). The most common adverse events in those receiving XERMELO® ,were nausea, headache, increased levels of the liver enzyme gamma-glutamyl transferase, peripheral edema and sometimes constipation. No new safety issues were noted, when patients were followed up during the open-label extension study and patients had sustained BM responses to treatment.

It was concluded that for patients with Carcinoid syndrome not adequately controlled by SomatoStatin Analogs (SSAs), addition of XERMELO® to SSA treatment was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-HydroxyIndole Acetic Acid. Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome. Kulke MH, Hörsch D, Caplin ME, et al. DOI: http://dx.doi.org/10.1200/JCO.2016.69.2780

SOMATULINE® – Tumor Growth Rate (TGR) a Better Indicator of Therapeutic Activity than RECIST in NeuroEndocrine Tumors

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SUMMARY: NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and is most frequently diagnosed in the small intestine, appendix, rectum, lungs and bronchi. NETs may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2. Majority of the NETs are nonfunctioning and are diagnosed incidentally but are clinically symptomatic following spread to the liver. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis.

SOMATULINE® (Lanreotide) is a synthetic analogue of Somatostatin, a naturally occurring inhibitory hormone, which blocks the release of other hormones, including Insulin, Glucagon, Growth hormone, Thyroid Stimulating Hormone, etc. The approval of SOMATULINE® by the FDA for the treatment of patients with unresectable, well or moderately differentiated, locally advanced or metastatic GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs), was based on the demonstration of improved Progression Free Survival (PFS) in the CLARINET trial, a multicenter, international, randomized placebo-controlled study. This study enrolled 204 patients of whom 55% (113/204) had NeuroEndocrine Tumors arising outside the pancreas. Patients were randomized to receive either SOMATULINE® 120 mg or placebo, subcutaneously every 28 days. This trial demonstrated a significant prolongation of PFS for the SOMATULINE® group compared to the placebo group (HR 0.47; P<0.001).

The authors now report an exploratory analysis of Tumor Growth Rate (TGR) with SOMATULINE® in patients with NeuroEndocrine Tumors from the CLARINET study. TGR has been proposed as a novel measure of tumor response. Target lesions were assessed by central radiologic review based on RECIST criteria. TGR was defined as the percentage of variation of tumor volume per month. This was calculated from sum-of-longest-diameters (SLD) of original target lesions (excluding new ones) on 2 CT scans during defined periods, which was 12-24 weeks prior to randomization versus baseline (pretreatment) and baseline versus each visit or between consecutive visits. TGR pre- and post-treatment were compared between treatment groups.

It was noted that even though all patients were classified as stable based on RECIST, a significant proportion of patients treated with SOMATULINE® showed changes in the TGR, following 12 weeks of treatment. This benefit was not seen in those on placebo. The TGR benefit with SOMATULINE® was significant compared to placebo and was maintained at subsequent study visits.

The authors concluded that in patients with NeuroEndocrine Tumors, Tumor Growth Rate provides an early and more precise characterization of therapeutic activity than RECIST and requires validation in prospective studies. Exploratory analysis of tumor growth rate (TGR) with lanreotide depot/autogel (LAN) in patients (pts) with neuroendocrine tumors (NETs) from the CLARINET study. Caplin ME, Pavel ME, Ruszniewski P, et al. J Clin Oncol 34, 2016 (suppl; abstr 4096)

AFINITOR® (Everolimus)

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The FDA on February 26, 2016 approved AFINITOR® for the treatment of adult patients with progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. AFINITOR® is a product of Novartis Pharmaceuticals Corporation.

FDA Approves AFINITOR® for Advanced NeuroEndocrine Tumors of GI or Lung Origin

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SUMMARY: The FDA on February 26, 2016 approved AFINITOR® (Everolimus) for the treatment of adult patients with progressive, well-differentiated non-functional, NeuroEndocrine Tumors (NET) of GastroIntestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and is most frequently diagnosed in the small intestine, appendix, rectum, lungs and bronchi. NETs may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2.

Majority of the NETs are nonfunctioning and are diagnosed incidentally but are clinically symptomatic following spread to the liver. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis. Somatostatin analogues, such as long acting SANDOSTATIN® LAR Depot (Octreotide), has been shown in the PROMID study to control tumor growth, as well as improve symptoms, in patients with newly diagnosed, well-differentiated metastatic midgut NETs. Following progression on SANDOSTATIN®, these patients have limited treatment options. Everolimus (AFINITOR®), is a mTOR (mammalian Target Of Rapamycin) inhibitor, which has shown activity in advanced NETs, in phase II trials.

The FDA approved AFINITOR® in 2011, for the treatment for patients with progressive, metastatic pancreatic NETs. This approval was based on the phase III RADIANT-3 study, in which the primary end point of Progression Free Survival (PFS) was met, with a PFS of 11 months in the AFINITOR® group and 4.6 months in the placebo group (HR=0.35; P<0.001).

RADIANT-4 is a randomized, double blind phase III trial, in which 302 patients with unresectable, locally advanced or metastatic, well differentiated (low or intermediate grade), non-functional (no current or prior history of carcinoid symptoms), NeuroEndocrine Tumors (NETs) of gastrointestinal or lung origin, were randomly assigned in a 2:1 ratio, to receive AFINITOR® (Everolimus) 10 mg orally once daily plus best supportive care (N=205) or placebo plus BSC (N=97). Tumor locations were, GI tract (N=175), Lung (N=90) and Unknown origin (N=36). The median age was 63 years. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), response, and safety.

The median PFS were 11 months and 3.9 months in the AFINITOR® and placebo groups, respectively (HR=0.48; P<0.001), with a 52% reduction in the risk of progression in the AFINITOR® group. In a subgroup analysis which specifically looked at GI NETs, the median PFS was 13.1 months with AFINITOR® versus 5.4 months with placebo (HR=0.56), with a 44% risk reduction in favor of AFINITOR®. In patients with NETs of unknown primary, the median PFS was 13.6 months with AFINITOR® versus 7.5 months with placebo. (HR=0.60), with a 40% risk reduction in favor of AFINITOR®. The most common adverse reactions (incidence greater than or equal to 30%) were stomatitis, infections, diarrhea, peripheral edema, fatigue and rash.

The authors following this subgroup analysis concluded that, there was a 40-44% risk-reduction in favor of AFINITOR®, compared to placebo, for patients with metastatic GI NeuroEndocrine Tumors, as well as NeuroEndocrine Tumors from an unknown primary, thus providing a new treatment option for this patient group. Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract and unknown primary: A subgroup analysis of the phase III RADIANT-4 trial. Singh S, Carnaghi C, Buzzoni R, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 315)

SOMATULINE® Depot Injection (Lanreotide)

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The FDA on December 16, 2014 approved SOMATULINE® Depot Injection for the treatment of patients with unresectable, well or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. SOMATULINE® Depot Injection was previously approved for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. SOMATULINE® Depot Injection is a product of Ipsen Pharma.

Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID) Results on long-term survival

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SUMMARY: The role of Somatostatin analogs such as SANDOSTATIN® (Octreotide) for symptom control in patients with gastrointestinal and pancreatic NeuroEndocrine Tumors (NETs) is well established. SANDOSTATIN® also demonstrated antiproliferative activity in controlling tumor growth of well-differentiated metastatic midgut NETs (Carcinoid), by lengthening the Time to Tumor Progression (TTP), when compared with placebo (PROMID Study). Whether SANDOSTATIN® prolongs Overall Survival (OS) remained unclear. The study investigators now reported the long term follow up data from the same PROMID trial. Between 2001 and 2008, 85 patients were randomly assigned to receive either SANDOSTATIN® LAR (N=42) or Placebo (N=43). On disease progression, patients in the placebo group were allowed to crossover and receive SANDOSTATIN® LAR. Outcomes in patients with Hepatic tumor Load (HL – percentage of liver replaced by malignancy) at study entry of 10% or less, was compared to those whose HL was more than 10%. The median OS by January 2013 in the Placebo arm was 84 months whereas the median OS in the SANDOSTATIN® LAR group was not reached, suggesting that the OS in this group will exceed 84 months and therefore a longer follow up would be needed. Patients with HL 10% or less benefited the most whereas those with high HL did not have OS benefit with SANDOSTATIN® LAR. The authors concluded that SANDOSTATIN® LAR prolongs TTP as well as OS in patients with metastatic midgut NETs, carrying a Hepatic Load of 10% or less. Arnold R, Wittenberg M, Rinke A, et al. J Clin Oncol 31, 2013 (suppl; abstr 4030)