Everolimus in the treatment of neuroendocrine tumors of the respiratory and gastroenteropancreatic systems Nicola Flaum 1, Juan W Valle 1,2, Wasat Mansoor 1, Mairéad G McNamara 1,2 1 – Department of Medical Oncology, The Christie NHS Foundation Manchester, UK 2 – University of Manchester, Institute of Cancer Sciences, Manchester, UK Corresponding author Dr Mairéad G McNamara Department of Medical Oncology The Christie NHS Foundation of Manchester, Institute of Cancer Sciences Manchester M20 4BX UK Tel: 0161 446 8106 Fax: 0161 446 3468 Keywords: Neuroendocrine pancreatic, carcinoid, metastatic, targeted therapy, everolimus, mTOR inhibitor trial,
and low grade typical carcinoids, as well as from pre-invasive lesions diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH). In 1972, Arrigoni et al described aggressive lung NETs, which they termed ‘atypical’, leading to the categories of typical versus atypical NETs. This definition is still used to describe low grade and intermediate grade lung NETs respectively (8). The prognosis for metastatic NETs is 24-37 months (2). Over the last decade, treatment options have been evolving in an effort to improve patient outcomes including further exploration into targeted therapies such as everolimus, a mammalian target of rapamycin (mTOR) inhibitor. This review will aim to discuss the treatment options for neuroendocrine tumors of the respiratory and gastroenteropancreatic systems, particularly focusing on the therapeutic role of everolimus in this disease group. Treatment of GEP NETs: where does everolimus fit into current guidance The ESMO Clinical Practice Guidelines advise on diagnosis, treatment, and follow up of GEP NET tumors (9). Management of local or locoregional disease should be evaluated in a multidisciplinary team (MDT) setting including an experienced surgeon, and these patients should be considered as candidates for curative surgery. It is generally agreed that grade 3 pancreatic NET patients are not surgical candidates as these tumors are widely metastasized at diagnosis. Cytoreductive surgery may be considered for patients with a diagnosis of metastatic well-differentiated NET if the metastatic disease is localized or if >70% of tumor load is thought to be resectable, although in clinical practice and other studies, surgery is advised against if <90% of the tumor is thought resectable (10). Follow up of patients should include biochemical parameters and conventional imaging. options for management of non-resectable or symptomatic gastro-enteric NETs include somatostatin analogues (SSA), chemotherapy, interferon, peptide receptor radiotargeted therapy trial
Table 3 – Examples of reported phase I and II trials of everolimus in patients with gastroenteropancreatic and lung neuroendocrine tumors Authors Year Phase Primary tumor location Regimen Number of patients Response assessment PFS Median OS (months) Chan et al (35) 2013 I Carcinoid (small bowel, bronchus, unknown primary) or pancreatic Sorafenib + everolimus 21 1 PR, 13 SD, 3 PD. 62% disease shrinkage. 26% CGA decrease. 79% at 6 months - Chan et al (36) 2012 I Carcinoid bowel, bronchus, unknown primary) or pancreatic Pasireotide + everolimus 22 90% SD, 81% some degree of tumor shrinkage. 21% CGA decrease. 76% at 6 months 65% at 12 months - Chan et al (79) 2013 I/II 1/2 pancreatic Everolimus 5mg or 10mg + temozolomide 43 16 (40%) PR, 53% SD, 7% PD. 45% CGA decrease. 15.4 * Not reached Kulke et al (39) 2015 II Pancreatic Everolimus + octreotide vs everolimus + bevacizumab + octreotide 150 Response rate 31% vs 12% 16.7 vs 14 * OS 36.7 vs 35.0 Yao J et al (38) 2014 II Pancreatic Everolimus vs placebo 79 72% risk reduction 15.47 vs 4.29* Not reached Bajetta et al (37) 2014 II GEP + lung Everolimus + octreotide LAR first line 50 18% ORR * 2% CR, 16% PR, 74% SD, 6% PD Not reached by 277 days Not reached by 277 days Yao et al (61) 2010 II Pancreatic Everolimus in octreotide naïve pts (stratum 1) Everolimus + octreotide - pts on octreotide for 3/12 (stratum 2) 160 9.6% (Radiological assessment), 10.4% (Ix assessment )ORR* 4.4% (radiological assessment), 11.1 (investigator assessment ) ORR 9.7, 8.5 16.7, 15.2 OS – 24.9 24month survival 54.7%
Yao et al (18) RADIANT-I 2008 II GEP, thymus, lung, renal Everolimus 5mg or 10mg + octreotide LAR 60 ORR 20% 22% PR, 70% SD, 8% PD 60 weeks 1 yr – 83% 2 yr – 81% 3 yr – 78% *= primary endpoint PR = Partial response; SD = stable disease; PD = progressive disease; CGA = chromogranin A; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; pts = patients 4 – Examples of reported phase III trials involving everolimus in patients with lung, gastroenteropancreatic, and other neuroendocrine tumors Authors Year type Regimen Number of patients Objective response PFS (months) Yao et al (44) (RADIANT IV) 2015 Advanced nonfunctional lung and GI NETs Everolimus 1mg vs placebo 302 52% risk reduction for progression or death 11.0 vs 3.9 (central review 14.0 vs 5.5 (investigator review) Anthony et al (40) (RADIANT-II sub-analysis) 2015 Functional advanced NETs Everolimus 10mg + octreotide vs placebo + octreotide. Comparison of previous SSA exposure with none 429 (339 previous SSA exposure) No sig difference in PFS relating to SSA O+E+SSA 14.3 O+E 25.2 P+O+SSA 11.1 P+O 13.6 et al (80) (RADIANT-3 sub-group) 2015 Pancreatic Everolimus vs placebo comparing prior chemo with 410 (204 = 50% were chemo-naïve) ORR 4.8% vs 2% in prior chemo, 4.9% vs 2% in chemo-naïve Prior chemo 11 vs 3.2 Chemotherapy-naïve 11 vs 5.4 * Castellano et al (41) (RADIANT-II sub group analysis) 2013 Colorectal Everolimus + octreotide vs placebo + octreotide 39 66% risk reduction for progression 29.9 vs 6.6 * Fazio et al (42) (RADIANT-II 2013 Lung Everolimus + octreotide vs placebo + octreotide 44 28% risk reduction for progression 13.63 vs 5.59 *