REVIEW
Current Clinical Trials of Targeted Agents for Well-Differentiated Neuroendocrine Tumors Nitya Raj, MD and Diane Reidy-Lagunes, MD, MS Abstract: Neuroendocrine tumors (NETs) are a group of tumors originating in various locations, including the gastrointestinal tract, lung, and pancreas. Clinical trial design and disease management of these tumors pose a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The recent completion of several phase II and III trials demonstrates that rigorous investigation of novel agents can lead to practice-changing outcomes. Furthermore, the molecular and genetic understanding of NETs has dramatically improved during the last few years; as a result, investigators have shifted clinical trial design to focus on targeted therapies. Most of these trials have targeted the somatostatin, vascular endothelial growth factor, and mammalian target of rapamycin pathways. This review will discuss the NET treatment landscape and trials of targeted agents currently offered. Key Words: neuroendocrine tumors, carcinoid, pancreatic neuroendocrine tumors, targeted agents, clinical trials (Pancreas 2014;43: 1185–1189)
W
ell-differentiated neuroendocrine tumors (NETs) are uncommon neoplasms arising from the diffuse neuroendocrine cell system. These tumors can be subdivided into carcinoid and pancreatic NETs (panNETs). Tumors that develop from the neuroendocrine tissues of the aerodigestive tract are called carcinoid tumors, whereas tumors of the endocrine tissues of the pancreas are known as panNETs. Although NETs are typically slow growing, overall survival (OS) after the development of metastatic disease is greatly shortened, and the majority of stage IV patients with liver metastases will succumb to their disease.1 Overall survival ranges from 2 to 5 years in several series and depends on the grade of tumor, disease burden, and age of diagnosis.1,2 Typical indications for therapy are pain/symptoms due to tumor bulk, symptoms from hormone secretion, or progression of disease and increased tumor burden under observation.3 In the presence of progressive metastatic disease, targeted and conventional therapies are available for panNETs, but options are much more limited for carcinoid tumors. With advances in the molecular and genetic understanding of NETs, most of the scientific effort has focused on the role of targeted agents for the management of both carcinoid and panNETs. Current trials are focusing on the somatostatin, vascular endothelial growth factor (VEGF), and mammalian target of rapamycin (mTOR) pathways. In this review, we will provide an overview of the rationale behind
From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. Received for publication May 28, 2014; accepted August 14, 2014. Reprints: Diane Reidy-Lagunes, MD, MS, Division of Solid Tumor Oncology, Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, and Weill College of Medicine, Cornell University, 300 East 66th St, 1039, New York, NY 10065 (e‐mail: [email protected]). Dr Reidy-Lagunes is on the advisory board for Novartis and Pfizer. In addition, Dr Reidy-Lagunes does both research and consulting for Novartis. For the remaining author, no conflicts of interest were declared. Copyright © 2014 by Lippincott Williams & Wilkins
Pancreas • Volume 43, Number 8, November 2014
the targeted agents used in NETs, as well as trials that are currently underway.
GENETICS Large studies validating NET molecular markers useful to predict response are unavailable. In a previous investigation, the exomic sequences of 10 nonfamilial panNETs were determined, and the most commonly mutated genes in 58 additional panNETs were then screened.4 Fourteen percent of the patients had mutations in genes from the mTOR pathway and mutations in the catalytic subunit of phosphatidylinositol 3-kinase (PI3K), along with 43% in DAXX and ATRX and 44% in MEN-1 genes. In patients who had all 3 mutations (MEN-1, DAXX, and ATRX), the median OS was 10 years. In contrast, 60% of the patients who lacked these mutations died within 5 years of diagnosis. After the completion of panNET whole exome sequencing, the first genomewide sequencing of 48 small bowel NETs was reported.5 As expected, a paucity of somatic mutations were identified; however, several recurrent mutated cancer-related pathways were found, including PI3K/Akt/mTOR signaling, the transforming growth factor β pathway, and the SRC oncogene. Such results suggest that sequencing-based analysis might help group small bowel NETs by therapeutic targets or dysregulated pathways.
Trial No current data allow us to tailor therapy based on tumor mutational status, although such clinical trials are ongoing. NCT01603004 is a study looking at 341 tumor-associated genes in 20 patients with metastatic panNET receiving either targeted (ie, sunitinib or everolimus) or conventional cytotoxic therapy to see if we can identify factors that may best predict therapy response and/or resistance.
SOMATOSTATIN ANALOGS Somatostatin and its synthetic analogs (eg, lanreotide, octreotide) act through a family of 5 G-protein couple receptors to exert many functions, including inhibition of endocrine and exocrine secretions and of tumoral cell growth. For this reason, somatostatin analog therapy is highly useful to treat hormonally related NET symptoms.6 In addition, it has been long assumed that somatostatin analogs have antiproliferative tumor effects. The first randomized data to support this hypothesis was provided by the PROMID study.7 In this trial, 85 patients with newly diagnosed asymptomatic midgut carcinoid tumors were randomly assigned to receive octreotide long acting release (LAR) 30 mg intramuscularly monthly or placebo. The median time to progression was 14.3 months in the octreotide arm compared with 6 months in the placebo group. As would be expected in such a small trial, there was no difference in OS. Building on the PROMID data, the CLARINET trial was a phase III trial with interim results recently reported.8 This study randomized patients with nonfunctioning advanced NETs (45% of which were panNETs) to lanreotide versus placebo. At 2 years after initiation of treatment, median progression-free survival (PFS) was not reached with lanreotide, compared with 18 months www.pancreasjournal.com
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with placebo. This study confirmed that lanreotide prolongs PFS for gastrointestinal NETs. Given the prolonged PFS in the placebo arm, serial monitoring at approximately 12-week intervals (with computed tomography triphasic or magnetic resonance imaging) to establish an individual's natural disease growth pattern should be considered. Upon progression, we favor initiation of somatostatin analog-based therapy.
Trial NETTER-1 is the first randomized controlled phase III trial with PRRT. The study compares treatment with 177Lu-octreotate to octreotide 60-mg LAR in patients with advanced, inoperable, progressive, somatostatin receptor–positive, midgut low-grade carcinoid tumors.
MOLECULAR PATHWAYS Trial Based on the previously mentioned data, an ongoing randomized phase II study (SUNLAND) is being conducted of sunitinib versus placebo in combination with lanreotide in patients with progressive advanced or metastatic midgut carcinoid tumors.
Peptide Receptor Radiation Therapy The recognition that NETs highly express somatostatin receptors is the molecular basis for the successful use of tumor targeting with radiolabeled somatostatin analogs. After promising initial results, peptide receptor radiation therapy (PRRT) was clinically applied. Several radioisotopes linked to a somatostatin analog have been used and include indium-111 (111In), yttrium-90 (90Y), and lutetium-177 (177Lu). Building on several single-institution series demonstrating improved response and symptom control, the European multicenter trial known as MAURITIUS was conducted.9,10 The MAURITIUS trial included 154 patients; stable tumor disease was observed in 41% of the patients, and regression of disease was observed in 14% of the patients.11 177 Lu-octreotate has also been investigated. In a study of 504 patients with metastatic NET receiving 177Lu-octreotate, efficacy analysis was performed in 310 patients, and complete remission occurred in 2% of the patients, whereas partial remission occurred in 28% of the patients.12 Median time to progression was 40 months, although only 43% of the patients had documented disease progression before therapy initiation. These studies demonstrate that PRRT is a promising active treatment in NETs. However, the degree of activity and toxicity patients can expect from this treatment has not been adequately defined.
Angiogenesis and VEGF Well-differentiated NETs express higher levels of HIF-1α, VEGF, and microvessel density compared with poorly differentiated NETs.13,14 The highly vascular nature of well-differentiated NETs led to initial interest in angiogenesis inhibitors as a treatment modality. Such an approach seems to be more beneficial in panNETs as opposed to carcinoid. Nevertheless, several proposed trials are looking at VEGF inhibition for both carcinoid and panNETs. This section will review the published data on VEGF inhibition in both carcinoid and panNETs.
Drugs Targeting Angiogenesis Sunitinib Sunitinib is an orally active small multitargeted tyrosine kinase inhibitor that blocks the VEGF receptor as well as plateletderived growth factor receptor β, KIT, and RET (Fig. 1). In a phase II study, 107 patients with advanced NET received 50-mg sunitinib for 4 weeks followed by a 2-week break.15 Of the patients with panNET, 16.7% achieved a confirmed partial response, compared with 2.4% of the patients with carcinoid tumors, illustrating the differences in benefit between carcinoids and panNETs. Of note, in this study, 24.3% of the patients had grade 3 fatigue. Given the apparent lack of efficacy in carcinoid tumors, a phase III, double-blind, placebo-controlled trial of sunitinib was compared with placebo in patients with advanced, welldifferentiated panNET.16 Patients with progressive disease were randomly assigned to receive either 37.5 mg daily of sunitinib or a placebo. The dose reduction (37.5 mg instead of 50 mg) was due to the increased rate of grade 3 fatigue in the previously discussed phase II study. The primary end point was PFS. This
FIGURE 1. VEGF signal inhibition.
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study was initially designed to enroll 340 patients but was discontinued prematurely by the independent data monitoring committee after an early, unplanned analysis of 171 patients that indicated an increased number of deaths and serious adverse events in the placebo arm. Patients in the sunitinib group had a significantly longer median PFS of 11.4 months compared with 5.5 months for the placebo group. Based on these results, sunitinib was approved by the Food and Drug Administration for the treatment of patients with unresectable or metastatic progressive welldifferentiated panNET.
Clinical Trials in Neuroendocrine Tumors
Pazopanib Pazopanib is a small-molecule oral tyrosine kinase inhibitor. Like sunitinib, pazopanib is thought to be effective largely through the inhibition of VEGF and platelet-derived growth factor receptor β (Fig. 1). In a phase II clinical study of 52 patients, pazopanib plus octreotide LAR achieved a 17% RR in patients with low-grade panNET; there were 5 partial responses; however, all were in the panNET group, and no response was observed in the carcinoid group.22 Median PFS times were 11.7 and 12.7 months for panNET and carcinoid tumors, respectively.
Trial Given that the phase III study of sunitinib was discontinued prematurely, the Food and Drug Administration asked the company sponsor to continue enrollment of sunitinib in a phase IV study, which is ongoing.
Trial Although no responses were seen in carcinoid tumors, given the prolonged PFS, a randomized phase II trial (NCT01841736) of pazopanib versus placebo in 150 patients with metastatic carcinoid is ongoing.
Bevacizumab Bevacizumab is a humanized monoclonal antibody that binds to circulating VEGF-A (Fig. 1) and was tested in phase II study of 44 patients with advanced carcinoid tumors.17 Patients were randomized to receive either bevacizumab or pegylated IFN-α2b. There was an 18% partial response rate (RR) in the bevacizumab group compared with 0% in the IFN-α2b group. At 18 weeks, 95% of the patients treated with bevacizumab remained free of progression compared with 68% of patients treated with IFN-α2b. It is noteworthy that 40% of the patients on the bevacizumab arm did not have documentation of disease progression at study entry.
Trial SWOG 0518 (NCT00569127), a phase III trial of bevacizumab plus octreotide LAR versus IFN plus octreotide LAR, has been completed, and results are expected within the next year. This pivotal trial is expected to help further understand the role of VEGF inhibitors in patients with carcinoid.
Role of VEGF Inhibitors to Overcome Resistance A large challenge in oncology is managing disease progression when tumors become resistant to available therapies. For those tumors that respond to VEGF inhibition, strategies to overcome resistance have been explored in animal models and clinical studies.23 Initial data indicate that resistance to VEGF inhibition is likely to be mediated by both tumor and nontumor (stromal) cell types (including proangiogenic monocytes).24 In xenograft models, the combination of bevacizumab and HIF-1 or Sp1 inhibitors may increase the therapeutic efficacy of antiangiogenic treatment.25 Cotargeting of VEGF and FGF signaling pathways also improves efficacy and overcomes adaptive resistance to VEGF inhibition in the RIP-Tag2 model of panNETs.26 Taken together, the data suggest that upfront or sequential use of multitargeted inhibitors may limit the secondary wave of angiogenesis and tumor growth that occurs as a consequence of hypoxia-induced upregulation of alternative proangiogenic growth factors in the face of VEGF inhibition.23
Bevacizumab Combinations Combinations of bevacizumab plus other agents have also been tested. Bevacizumab plus temozolomide was shown to be effective in patients with advanced NET, with 27 (79%) of 34 patients demonstrating partial response or stable disease; the authors did not comment on which type of patients with NETwere enrolled.18 More recently, activity has been demonstrated with the combination of fluorouracil, oxaliplatin, and bevacizumab. One study reported a 33% RR in 6 patients with progressive panNET who received short-term infusional 5-fluorouracil, leucovorin, oxaliplatin (ie, FOLFOX) and bevacizumab.19 A second study used capecitabine in combination with oxaliplatin (ie, CapeOx) plus bevacizumab and reported an RR of 23%.20 A phase II trial of the mTOR inhibitor temsirolimus and bevacizumab showed promising results in panNETs. In this study of 55 patients, confirmed RR was 37% (20/55). Of the 49 evaluable patients, 12-month PFS was 49%.21
Trial To continue the evaluation of combination mTOR/VEGF pathway inhibitors, CALGB 80701 (NCT01229943) is a randomized phase II of octreotide LAR, bevacizumab, and everolimus versus octreotide LAR and everolimus in 140 patients with metastatic panNETs. The trial has been completed, and data analysis is ongoing. © 2014 Lippincott Williams & Wilkins
Trial Among the genes directly regulated by HIF-1, c-Met is involved in the invasive and metastatic behavior of tumor cells after the exposure to hypoxia. Recent studies have shown that inhibition of c-Met can reduce the promoted invasive and metastatic capabilities after VEGF pathway inhibition.27 The studies suggest that inhibition of c-Met, together with VEGFtargeted therapy, may diminish resistance. Cabozantinib is a tyrosine kinase inhibitor that inhibits c-MET as well as VEGF-R2 (Fig. 1). NCT01466036 is an ongoing phase II trial of cabozantinib in advanced NETs. The planned primary end point is RR, with secondary end points of OS, PFS, and toxicity.
Other Potential VEGF Trials Ziv-aflibercept is a recombinant fusion protein that acts as a decoy receptor for VEGF-A and placental growth factor (PIGF). Decoy receptor binding prevents VEGF-A and PIGF from activating endothelial cell receptors, thereby suppressing neovascularization (Fig. 1). In colon cancer trials, ziv-aflibercept was found to be more toxic than bevacizumab; whether the same holds true in NETs is unknown.28 NCT01782443 is a phase II study designed to test the safety and efficacy of ziv-aflibercept in progressive carcinoid tumors. www.pancreasjournal.com
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mTOR Inhibition The mTOR is a serine-threonine kinase that has a central role in the regulation of cellular function and mediates downstream signaling from a number of pathways that are implicated in NET growth (Fig. 2). Given this knowledge, the role of mTOR inhibition in the treatment of NETs has been studied. Everolimus is an mTOR inhibitor showing promising phase II data in both carcinoid and panNETs.29,30 As a result, 2 phase III studies were initiated. RADIANT-3 was a randomized phase III double-blind placebo-controlled study of 410 patients with lowor intermediate-grade, progressive and advanced panNETs.31 They were randomized to receive everolimus plus best supportive care or placebo plus best supportive care. The results demonstrated significantly improved median PFS of 11.0 months with everolimus compared with 4.6 months with placebo. Response rate was 5% in the everolimus arm compared with 2% in the placebo arm. A subsequent phase III study, RADIANT-2, evaluated the efficacy of everolimus plus octreotide LAR versus placebo plus octreotide LAR in 429 patients with functional carcinoid tumors.32 The primary end point was PFS, and patients in the placebo arm were allowed to cross over to everolimus upon disease progression. By central review, median PFS was 16.4 months in the everolimus group versus 11.3 months in the placebo group but did not meet its statistical predefined end point. Therefore, the study is considered negative.
Trial Given that the RADIANT-2 data favored the everolimus arm (albeit not statistically significant) with several study flaws, RADIANT-4 (NCT01524783) was initiated. This trial is a phase III study of everolimus versus placebo in the treatment of patients with advanced nonfunctioning NETs (ie, carcinoid tumors of gastrointestinal or lung origin). The study has completed accrual, and data analysis is ongoing.
Trial The COOPERATE-2 trial (NCT01374451) is a phase II trial evaluating the addition of pasireotide (a somatostatin analog) to everolimus in advanced NETs. This study has completed accrual.
Trial The efficacy of everolimus and other rapamycin analogs may be compromised by feedback loop mechanisms that include the concomitant activation of the PI3K and mitogen-activated protein kinase (MAPK) pathway. Strategies to counteract this feedback loop have included the development of ATP-competitive mTOR inhibitors, targeting both mTOR complexes. In vitro and in vivo data suggest that these new compounds have therapeutic benefit over rapamycin, but concerns exist about their potential toxicity. An alternative approach is the use of dual PI3K/mTOR inhibitors, for which several clinical trials are underway. BEZ 235 is a potent oral PI3K and mTOR inhibitor (Fig. 2). Accrual is ongoing for 2 trials using BEZ235. The first trial randomizes mTOR inhibitor–naive patients to BEZ235 versus everolimus. The second trial evaluates BEZ235 in patients that are refractory to mTOR inhibitor therapy. In both studies, up to 2 previous therapies are allowed. These trials will analyze the role of feedback loop mechanisms in mTOR inhibitor efficacy.
CONCLUSIONS/FUTURE DIRECTIONS Given the tumor heterogeneity and varying degrees of aggressiveness, management of well-differentiated NETs poses a significant challenge. After decades of treatment stagnation, a better understanding of tumor signaling mechanisms has led to the development of drugs targeting clinically significant pathways. The recent discovery of targeted therapy options for patients with NETs opens the landscape for future clinical trial design. The phase II and III trials discussed in this review have established the safety and efficacy of multiple agents targeting the somatostatin, VEGF, and mTOR pathways.
FIGURE 2. mTOR signal inhibition.
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Although the current ongoing trials of NETs address the efficacy of various targeted therapy options, they fail to offer insight into individualizing therapy and highlight a crucial challenge: how to select the optimal therapy for a single patient. We hope that tumor mutational analysis will identify biomarkers that may serve as a predictor of response and/or resistance, and such trials are ongoing. In addition, recent genomic discoveries suggest that alternative pathways, such as DAXX and ATRX in panNETs, may offer the potential for new alternative therapeutic advances for our patients. REFERENCES 1. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–3072. 2. Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis in patients with metastatic pancreatic endocrine carcinomas. Pancreas. 2009;38:255–258. 3. Reidy-Lagunes D, Thornton R. Pancreatic neuroendocrine and carcinoid tumors: what's new, what's old, and what's different? Curr Oncol Rep. 2012;14:249–256. 4. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–1203.
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15. Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403–3410. 16. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–513. 17. Yao JC, Phan A, Hoff PM, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol. 2008;26:1316–1323. 18. Kulke M, Stuart K, Earle C. A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors. J Clin Oncol. 2006;24:2963–2968. 19. Venook AP, Ko AH, Tempero MA, et al. Phase II trial of FOLFOX plus bevacizumab in advanced, progressive neuroendocrine tumors. J Clin Oncol (Meeting Abstracts). 2008;26(suppl 15):15545. 20. Kunz PL, Kuo T, Zahn JM, et al. A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors. J Clin Oncol (Meeting Abstracts). 2010;28(suppl 15):4104. 21. Hobday T, Qin R, Reidy D, et al. Multi-Center Phase II Trial of Temsirolimus (TEM) and Bevacizumab (BEV) in Pancreatic Neuroendocrine Tumor (PNET): results of a planned interim efficacy analysis. Pancreas. 2013;42:375–376.
5. Banck MS, Kanwar R, Kulkarni AA, et al. The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest. 2013;123:2502–2508.
22. Phan AT, Yao JC, Fogelman DR, et al. A prospective, multi-institutional phase II study of GW786034 (pozopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). J Clin Oncol (Meeting Abstracts). 2010;28(suppl 15):4001.
6. Kraenzlin ME, Ch'ng JL, Wood SM, et al. Long-term treatment of a VIPoma with somatostatin analogue resulting in remission of symptoms and possible shrinkage of metastases. Gastroenterology. 1985;88:185–187.
23. Casanovas O, Hicklin DJ, Bergers G, et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309.
7. Rinke A, Muller HH, Schade-Brittinger C, et al. 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: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656–4663.
24. Ferrara N. Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev. 2010;21:21–26.
8. Caplin ME, Pavel M, Ćwikła J, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. New Engl J Med. 2014;371: 224–233. 9. Waldherr C, Pless M, Maecke HR, et al. The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol. 2001;12:941–945. 10. Waldherr C, Pless M, Maecke HR, et al. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90)Y-DOTATOC. J Nucl Med. 2002;43:610–616. 11. Virgolini I, Britton K, Buscombe J, et al. In- and Y-DOTA-lanreotide: results and implications of the MAURITIUS trial. Semin Nucl Med. 2002;32:148–155. 12. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–2130. 13. Couvelard A, O'Toole D, Turley H, et al. Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression. Br J Cancer. 2005;92:94–101. 14. Terris B, Scoazec JY, Rubbia L, et al. Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology. 1998;32:133–138.
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25. Rapisarda A, Hollingshead M, Uranchimeg B, et al. Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther. 2009;8:1867–1877. 26. Allen E, Walters IB, Hanahan D. Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clin Cancer Res. 2011;17:5299–5310. 27. Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2:270–287. 28. Gaya A, Tse V. A preclinical and clinical review of aflibercept for the management of cancer. Cancer Treat Rev. 2012;38:484–493. 29. Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008;26:4311–4318. 30. Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28:69–76. 31. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–523. 32. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378:2005–2012.
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Current Clinical Trials of Targeted Agents for Well-Differentiated Neuroendocrine Tumors Nitya Raj, MD and Diane Reidy-Lagunes, MD, MS Abstract: Neuroendocrine tumors (NETs) are a group of tumors originating in various locations, including the gastrointestinal tract, lung, and pancreas. Clinical trial design and disease management of these tumors pose a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The recent completion of several phase II and III trials demonstrates that rigorous investigation of novel agents can lead to practice-changing outcomes. Furthermore, the molecular and genetic understanding of NETs has dramatically improved during the last few years; as a result, investigators have shifted clinical trial design to focus on targeted therapies. Most of these trials have targeted the somatostatin, vascular endothelial growth factor, and mammalian target of rapamycin pathways. This review will discuss the NET treatment landscape and trials of targeted agents currently offered. Key Words: neuroendocrine tumors, carcinoid, pancreatic neuroendocrine tumors, targeted agents, clinical trials (Pancreas 2014;43: 1185–1189)
W
ell-differentiated neuroendocrine tumors (NETs) are uncommon neoplasms arising from the diffuse neuroendocrine cell system. These tumors can be subdivided into carcinoid and pancreatic NETs (panNETs). Tumors that develop from the neuroendocrine tissues of the aerodigestive tract are called carcinoid tumors, whereas tumors of the endocrine tissues of the pancreas are known as panNETs. Although NETs are typically slow growing, overall survival (OS) after the development of metastatic disease is greatly shortened, and the majority of stage IV patients with liver metastases will succumb to their disease.1 Overall survival ranges from 2 to 5 years in several series and depends on the grade of tumor, disease burden, and age of diagnosis.1,2 Typical indications for therapy are pain/symptoms due to tumor bulk, symptoms from hormone secretion, or progression of disease and increased tumor burden under observation.3 In the presence of progressive metastatic disease, targeted and conventional therapies are available for panNETs, but options are much more limited for carcinoid tumors. With advances in the molecular and genetic understanding of NETs, most of the scientific effort has focused on the role of targeted agents for the management of both carcinoid and panNETs. Current trials are focusing on the somatostatin, vascular endothelial growth factor (VEGF), and mammalian target of rapamycin (mTOR) pathways. In this review, we will provide an overview of the rationale behind
From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. Received for publication May 28, 2014; accepted August 14, 2014. Reprints: Diane Reidy-Lagunes, MD, MS, Division of Solid Tumor Oncology, Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, and Weill College of Medicine, Cornell University, 300 East 66th St, 1039, New York, NY 10065 (e‐mail: [email protected]). Dr Reidy-Lagunes is on the advisory board for Novartis and Pfizer. In addition, Dr Reidy-Lagunes does both research and consulting for Novartis. For the remaining author, no conflicts of interest were declared. Copyright © 2014 by Lippincott Williams & Wilkins
Pancreas • Volume 43, Number 8, November 2014
the targeted agents used in NETs, as well as trials that are currently underway.
GENETICS Large studies validating NET molecular markers useful to predict response are unavailable. In a previous investigation, the exomic sequences of 10 nonfamilial panNETs were determined, and the most commonly mutated genes in 58 additional panNETs were then screened.4 Fourteen percent of the patients had mutations in genes from the mTOR pathway and mutations in the catalytic subunit of phosphatidylinositol 3-kinase (PI3K), along with 43% in DAXX and ATRX and 44% in MEN-1 genes. In patients who had all 3 mutations (MEN-1, DAXX, and ATRX), the median OS was 10 years. In contrast, 60% of the patients who lacked these mutations died within 5 years of diagnosis. After the completion of panNET whole exome sequencing, the first genomewide sequencing of 48 small bowel NETs was reported.5 As expected, a paucity of somatic mutations were identified; however, several recurrent mutated cancer-related pathways were found, including PI3K/Akt/mTOR signaling, the transforming growth factor β pathway, and the SRC oncogene. Such results suggest that sequencing-based analysis might help group small bowel NETs by therapeutic targets or dysregulated pathways.
Trial No current data allow us to tailor therapy based on tumor mutational status, although such clinical trials are ongoing. NCT01603004 is a study looking at 341 tumor-associated genes in 20 patients with metastatic panNET receiving either targeted (ie, sunitinib or everolimus) or conventional cytotoxic therapy to see if we can identify factors that may best predict therapy response and/or resistance.
SOMATOSTATIN ANALOGS Somatostatin and its synthetic analogs (eg, lanreotide, octreotide) act through a family of 5 G-protein couple receptors to exert many functions, including inhibition of endocrine and exocrine secretions and of tumoral cell growth. For this reason, somatostatin analog therapy is highly useful to treat hormonally related NET symptoms.6 In addition, it has been long assumed that somatostatin analogs have antiproliferative tumor effects. The first randomized data to support this hypothesis was provided by the PROMID study.7 In this trial, 85 patients with newly diagnosed asymptomatic midgut carcinoid tumors were randomly assigned to receive octreotide long acting release (LAR) 30 mg intramuscularly monthly or placebo. The median time to progression was 14.3 months in the octreotide arm compared with 6 months in the placebo group. As would be expected in such a small trial, there was no difference in OS. Building on the PROMID data, the CLARINET trial was a phase III trial with interim results recently reported.8 This study randomized patients with nonfunctioning advanced NETs (45% of which were panNETs) to lanreotide versus placebo. At 2 years after initiation of treatment, median progression-free survival (PFS) was not reached with lanreotide, compared with 18 months www.pancreasjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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with placebo. This study confirmed that lanreotide prolongs PFS for gastrointestinal NETs. Given the prolonged PFS in the placebo arm, serial monitoring at approximately 12-week intervals (with computed tomography triphasic or magnetic resonance imaging) to establish an individual's natural disease growth pattern should be considered. Upon progression, we favor initiation of somatostatin analog-based therapy.
Trial NETTER-1 is the first randomized controlled phase III trial with PRRT. The study compares treatment with 177Lu-octreotate to octreotide 60-mg LAR in patients with advanced, inoperable, progressive, somatostatin receptor–positive, midgut low-grade carcinoid tumors.
MOLECULAR PATHWAYS Trial Based on the previously mentioned data, an ongoing randomized phase II study (SUNLAND) is being conducted of sunitinib versus placebo in combination with lanreotide in patients with progressive advanced or metastatic midgut carcinoid tumors.
Peptide Receptor Radiation Therapy The recognition that NETs highly express somatostatin receptors is the molecular basis for the successful use of tumor targeting with radiolabeled somatostatin analogs. After promising initial results, peptide receptor radiation therapy (PRRT) was clinically applied. Several radioisotopes linked to a somatostatin analog have been used and include indium-111 (111In), yttrium-90 (90Y), and lutetium-177 (177Lu). Building on several single-institution series demonstrating improved response and symptom control, the European multicenter trial known as MAURITIUS was conducted.9,10 The MAURITIUS trial included 154 patients; stable tumor disease was observed in 41% of the patients, and regression of disease was observed in 14% of the patients.11 177 Lu-octreotate has also been investigated. In a study of 504 patients with metastatic NET receiving 177Lu-octreotate, efficacy analysis was performed in 310 patients, and complete remission occurred in 2% of the patients, whereas partial remission occurred in 28% of the patients.12 Median time to progression was 40 months, although only 43% of the patients had documented disease progression before therapy initiation. These studies demonstrate that PRRT is a promising active treatment in NETs. However, the degree of activity and toxicity patients can expect from this treatment has not been adequately defined.
Angiogenesis and VEGF Well-differentiated NETs express higher levels of HIF-1α, VEGF, and microvessel density compared with poorly differentiated NETs.13,14 The highly vascular nature of well-differentiated NETs led to initial interest in angiogenesis inhibitors as a treatment modality. Such an approach seems to be more beneficial in panNETs as opposed to carcinoid. Nevertheless, several proposed trials are looking at VEGF inhibition for both carcinoid and panNETs. This section will review the published data on VEGF inhibition in both carcinoid and panNETs.
Drugs Targeting Angiogenesis Sunitinib Sunitinib is an orally active small multitargeted tyrosine kinase inhibitor that blocks the VEGF receptor as well as plateletderived growth factor receptor β, KIT, and RET (Fig. 1). In a phase II study, 107 patients with advanced NET received 50-mg sunitinib for 4 weeks followed by a 2-week break.15 Of the patients with panNET, 16.7% achieved a confirmed partial response, compared with 2.4% of the patients with carcinoid tumors, illustrating the differences in benefit between carcinoids and panNETs. Of note, in this study, 24.3% of the patients had grade 3 fatigue. Given the apparent lack of efficacy in carcinoid tumors, a phase III, double-blind, placebo-controlled trial of sunitinib was compared with placebo in patients with advanced, welldifferentiated panNET.16 Patients with progressive disease were randomly assigned to receive either 37.5 mg daily of sunitinib or a placebo. The dose reduction (37.5 mg instead of 50 mg) was due to the increased rate of grade 3 fatigue in the previously discussed phase II study. The primary end point was PFS. This
FIGURE 1. VEGF signal inhibition.
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study was initially designed to enroll 340 patients but was discontinued prematurely by the independent data monitoring committee after an early, unplanned analysis of 171 patients that indicated an increased number of deaths and serious adverse events in the placebo arm. Patients in the sunitinib group had a significantly longer median PFS of 11.4 months compared with 5.5 months for the placebo group. Based on these results, sunitinib was approved by the Food and Drug Administration for the treatment of patients with unresectable or metastatic progressive welldifferentiated panNET.
Clinical Trials in Neuroendocrine Tumors
Pazopanib Pazopanib is a small-molecule oral tyrosine kinase inhibitor. Like sunitinib, pazopanib is thought to be effective largely through the inhibition of VEGF and platelet-derived growth factor receptor β (Fig. 1). In a phase II clinical study of 52 patients, pazopanib plus octreotide LAR achieved a 17% RR in patients with low-grade panNET; there were 5 partial responses; however, all were in the panNET group, and no response was observed in the carcinoid group.22 Median PFS times were 11.7 and 12.7 months for panNET and carcinoid tumors, respectively.
Trial Given that the phase III study of sunitinib was discontinued prematurely, the Food and Drug Administration asked the company sponsor to continue enrollment of sunitinib in a phase IV study, which is ongoing.
Trial Although no responses were seen in carcinoid tumors, given the prolonged PFS, a randomized phase II trial (NCT01841736) of pazopanib versus placebo in 150 patients with metastatic carcinoid is ongoing.
Bevacizumab Bevacizumab is a humanized monoclonal antibody that binds to circulating VEGF-A (Fig. 1) and was tested in phase II study of 44 patients with advanced carcinoid tumors.17 Patients were randomized to receive either bevacizumab or pegylated IFN-α2b. There was an 18% partial response rate (RR) in the bevacizumab group compared with 0% in the IFN-α2b group. At 18 weeks, 95% of the patients treated with bevacizumab remained free of progression compared with 68% of patients treated with IFN-α2b. It is noteworthy that 40% of the patients on the bevacizumab arm did not have documentation of disease progression at study entry.
Trial SWOG 0518 (NCT00569127), a phase III trial of bevacizumab plus octreotide LAR versus IFN plus octreotide LAR, has been completed, and results are expected within the next year. This pivotal trial is expected to help further understand the role of VEGF inhibitors in patients with carcinoid.
Role of VEGF Inhibitors to Overcome Resistance A large challenge in oncology is managing disease progression when tumors become resistant to available therapies. For those tumors that respond to VEGF inhibition, strategies to overcome resistance have been explored in animal models and clinical studies.23 Initial data indicate that resistance to VEGF inhibition is likely to be mediated by both tumor and nontumor (stromal) cell types (including proangiogenic monocytes).24 In xenograft models, the combination of bevacizumab and HIF-1 or Sp1 inhibitors may increase the therapeutic efficacy of antiangiogenic treatment.25 Cotargeting of VEGF and FGF signaling pathways also improves efficacy and overcomes adaptive resistance to VEGF inhibition in the RIP-Tag2 model of panNETs.26 Taken together, the data suggest that upfront or sequential use of multitargeted inhibitors may limit the secondary wave of angiogenesis and tumor growth that occurs as a consequence of hypoxia-induced upregulation of alternative proangiogenic growth factors in the face of VEGF inhibition.23
Bevacizumab Combinations Combinations of bevacizumab plus other agents have also been tested. Bevacizumab plus temozolomide was shown to be effective in patients with advanced NET, with 27 (79%) of 34 patients demonstrating partial response or stable disease; the authors did not comment on which type of patients with NETwere enrolled.18 More recently, activity has been demonstrated with the combination of fluorouracil, oxaliplatin, and bevacizumab. One study reported a 33% RR in 6 patients with progressive panNET who received short-term infusional 5-fluorouracil, leucovorin, oxaliplatin (ie, FOLFOX) and bevacizumab.19 A second study used capecitabine in combination with oxaliplatin (ie, CapeOx) plus bevacizumab and reported an RR of 23%.20 A phase II trial of the mTOR inhibitor temsirolimus and bevacizumab showed promising results in panNETs. In this study of 55 patients, confirmed RR was 37% (20/55). Of the 49 evaluable patients, 12-month PFS was 49%.21
Trial To continue the evaluation of combination mTOR/VEGF pathway inhibitors, CALGB 80701 (NCT01229943) is a randomized phase II of octreotide LAR, bevacizumab, and everolimus versus octreotide LAR and everolimus in 140 patients with metastatic panNETs. The trial has been completed, and data analysis is ongoing. © 2014 Lippincott Williams & Wilkins
Trial Among the genes directly regulated by HIF-1, c-Met is involved in the invasive and metastatic behavior of tumor cells after the exposure to hypoxia. Recent studies have shown that inhibition of c-Met can reduce the promoted invasive and metastatic capabilities after VEGF pathway inhibition.27 The studies suggest that inhibition of c-Met, together with VEGFtargeted therapy, may diminish resistance. Cabozantinib is a tyrosine kinase inhibitor that inhibits c-MET as well as VEGF-R2 (Fig. 1). NCT01466036 is an ongoing phase II trial of cabozantinib in advanced NETs. The planned primary end point is RR, with secondary end points of OS, PFS, and toxicity.
Other Potential VEGF Trials Ziv-aflibercept is a recombinant fusion protein that acts as a decoy receptor for VEGF-A and placental growth factor (PIGF). Decoy receptor binding prevents VEGF-A and PIGF from activating endothelial cell receptors, thereby suppressing neovascularization (Fig. 1). In colon cancer trials, ziv-aflibercept was found to be more toxic than bevacizumab; whether the same holds true in NETs is unknown.28 NCT01782443 is a phase II study designed to test the safety and efficacy of ziv-aflibercept in progressive carcinoid tumors. www.pancreasjournal.com
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mTOR Inhibition The mTOR is a serine-threonine kinase that has a central role in the regulation of cellular function and mediates downstream signaling from a number of pathways that are implicated in NET growth (Fig. 2). Given this knowledge, the role of mTOR inhibition in the treatment of NETs has been studied. Everolimus is an mTOR inhibitor showing promising phase II data in both carcinoid and panNETs.29,30 As a result, 2 phase III studies were initiated. RADIANT-3 was a randomized phase III double-blind placebo-controlled study of 410 patients with lowor intermediate-grade, progressive and advanced panNETs.31 They were randomized to receive everolimus plus best supportive care or placebo plus best supportive care. The results demonstrated significantly improved median PFS of 11.0 months with everolimus compared with 4.6 months with placebo. Response rate was 5% in the everolimus arm compared with 2% in the placebo arm. A subsequent phase III study, RADIANT-2, evaluated the efficacy of everolimus plus octreotide LAR versus placebo plus octreotide LAR in 429 patients with functional carcinoid tumors.32 The primary end point was PFS, and patients in the placebo arm were allowed to cross over to everolimus upon disease progression. By central review, median PFS was 16.4 months in the everolimus group versus 11.3 months in the placebo group but did not meet its statistical predefined end point. Therefore, the study is considered negative.
Trial Given that the RADIANT-2 data favored the everolimus arm (albeit not statistically significant) with several study flaws, RADIANT-4 (NCT01524783) was initiated. This trial is a phase III study of everolimus versus placebo in the treatment of patients with advanced nonfunctioning NETs (ie, carcinoid tumors of gastrointestinal or lung origin). The study has completed accrual, and data analysis is ongoing.
Trial The COOPERATE-2 trial (NCT01374451) is a phase II trial evaluating the addition of pasireotide (a somatostatin analog) to everolimus in advanced NETs. This study has completed accrual.
Trial The efficacy of everolimus and other rapamycin analogs may be compromised by feedback loop mechanisms that include the concomitant activation of the PI3K and mitogen-activated protein kinase (MAPK) pathway. Strategies to counteract this feedback loop have included the development of ATP-competitive mTOR inhibitors, targeting both mTOR complexes. In vitro and in vivo data suggest that these new compounds have therapeutic benefit over rapamycin, but concerns exist about their potential toxicity. An alternative approach is the use of dual PI3K/mTOR inhibitors, for which several clinical trials are underway. BEZ 235 is a potent oral PI3K and mTOR inhibitor (Fig. 2). Accrual is ongoing for 2 trials using BEZ235. The first trial randomizes mTOR inhibitor–naive patients to BEZ235 versus everolimus. The second trial evaluates BEZ235 in patients that are refractory to mTOR inhibitor therapy. In both studies, up to 2 previous therapies are allowed. These trials will analyze the role of feedback loop mechanisms in mTOR inhibitor efficacy.
CONCLUSIONS/FUTURE DIRECTIONS Given the tumor heterogeneity and varying degrees of aggressiveness, management of well-differentiated NETs poses a significant challenge. After decades of treatment stagnation, a better understanding of tumor signaling mechanisms has led to the development of drugs targeting clinically significant pathways. The recent discovery of targeted therapy options for patients with NETs opens the landscape for future clinical trial design. The phase II and III trials discussed in this review have established the safety and efficacy of multiple agents targeting the somatostatin, VEGF, and mTOR pathways.
FIGURE 2. mTOR signal inhibition.
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Although the current ongoing trials of NETs address the efficacy of various targeted therapy options, they fail to offer insight into individualizing therapy and highlight a crucial challenge: how to select the optimal therapy for a single patient. We hope that tumor mutational analysis will identify biomarkers that may serve as a predictor of response and/or resistance, and such trials are ongoing. In addition, recent genomic discoveries suggest that alternative pathways, such as DAXX and ATRX in panNETs, may offer the potential for new alternative therapeutic advances for our patients. REFERENCES 1. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–3072. 2. Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis in patients with metastatic pancreatic endocrine carcinomas. Pancreas. 2009;38:255–258. 3. Reidy-Lagunes D, Thornton R. Pancreatic neuroendocrine and carcinoid tumors: what's new, what's old, and what's different? Curr Oncol Rep. 2012;14:249–256. 4. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–1203.
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15. Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403–3410. 16. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–513. 17. Yao JC, Phan A, Hoff PM, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol. 2008;26:1316–1323. 18. Kulke M, Stuart K, Earle C. A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors. J Clin Oncol. 2006;24:2963–2968. 19. Venook AP, Ko AH, Tempero MA, et al. Phase II trial of FOLFOX plus bevacizumab in advanced, progressive neuroendocrine tumors. J Clin Oncol (Meeting Abstracts). 2008;26(suppl 15):15545. 20. Kunz PL, Kuo T, Zahn JM, et al. A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors. J Clin Oncol (Meeting Abstracts). 2010;28(suppl 15):4104. 21. Hobday T, Qin R, Reidy D, et al. Multi-Center Phase II Trial of Temsirolimus (TEM) and Bevacizumab (BEV) in Pancreatic Neuroendocrine Tumor (PNET): results of a planned interim efficacy analysis. Pancreas. 2013;42:375–376.
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22. Phan AT, Yao JC, Fogelman DR, et al. A prospective, multi-institutional phase II study of GW786034 (pozopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). J Clin Oncol (Meeting Abstracts). 2010;28(suppl 15):4001.
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25. Rapisarda A, Hollingshead M, Uranchimeg B, et al. Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther. 2009;8:1867–1877. 26. Allen E, Walters IB, Hanahan D. Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clin Cancer Res. 2011;17:5299–5310. 27. Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2:270–287. 28. Gaya A, Tse V. A preclinical and clinical review of aflibercept for the management of cancer. Cancer Treat Rev. 2012;38:484–493. 29. Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008;26:4311–4318. 30. Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28:69–76. 31. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–523. 32. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378:2005–2012.
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