Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis

Nicola Fazio, Roberto Buzzoni, Gianfranco Delle Fave, Margot E Tesselaar, Edward Wolin, Eric Van Cutsem, Paola Tomassetti, Jonathan Strosberg, Maurizio Voi, Lida Bubuteishvili-Pacaud, Antonia Ridolfi, Fabian Herbst, Jiri Tomasek, Simron Singh, Marianne Pavel, Matthew H Kulke, Juan W Valle, James C Yao, Nicola Fazio, Roberto Buzzoni, Gianfranco Delle Fave, Margot E Tesselaar, Edward Wolin, Eric Van Cutsem, Paola Tomassetti, Jonathan Strosberg, Maurizio Voi, Lida Bubuteishvili-Pacaud, Antonia Ridolfi, Fabian Herbst, Jiri Tomasek, Simron Singh, Marianne Pavel, Matthew H Kulke, Juan W Valle, James C Yao

Abstract

In the phase III RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), non-functional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio, 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63; placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in the everolimus arm vs 3.6 (1.9-5.1) months in the placebo arm (hazard ratio, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced tumor shrinkage compared with placebo (13%). Most frequently reported (≥5% incidence) grade 3-4 drug-related adverse events (everolimus vs. placebo) included stomatitis (11% vs. 0%), hyperglycemia (10% vs. 0%), and any infections (8% vs. 0%). In patients with advanced, progressive, well-differentiated, non-functional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 cohort. These results support the use of everolimus in patients with advanced, non-functional lung NET. The trial is registered with ClinicalTrials.gov (no. NCT01524783).

Keywords: RADIANT-4; everolimus; lung carcinoid; neuroendocrine tumors; progression-free survival.

© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

Figure 1
Figure 1
Progression‐free survival in patients with lung neuroendocrine tumors. Hazard ratio (HR) values presented are based on unstratified Cox regression analysis. A, Central radiology review. B, Local investigator review. CI, confidence interval
Figure 2
Figure 2
Best percentage change from baseline in lung neuroendocrine tumor response. *Change in size of target lesion contradicted by lesion response of progressive disease. Patients for whom the best percentage change in target lesions was not available and patients for whom the best percentage change was contradicted by overall lesion = unknown were excluded from the analyses

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.
    1. Detterbeck FC. Clinical presentation and evaluation of neuroendocrine tumors of the lung. Thorac Surg Clin. 2014;24:267–276.
    1. Taal BG, Visser O. Epidemiology of neuroendocrine tumours. Neuroendocrinology. 2004;80(Suppl 1):3–7.
    1. Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010;134:1628–1638.
    1. Oberg K, Hellman P, Ferolla P, Papotti M, Group EGW. Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow‐up. Ann Oncol. 2012;23(Suppl 7):vii120–vii123.
    1. Granberg D. Neuroendocrine tumors of the lung In:Yalcin S, Öberg K, eds. Neuroendocrine Tumors: Diagnosis and Management. Berlin, Heidelberg:Springer‐Verlag;2015:143–164.
    1. Filosso PL, Ferolla P, Guerrera F, et al Multidisciplinary management of advanced lung neuroendocrine tumors. J Thorac Dis. 2015;7:S163–S171.
    1. Krug LM, Kris MG, Rosenzweig K, et al Cancer of the Lung: small cell and other neuroendocrine tumors of the lung In:DeVita VT, Lawrence TS, Rosenberg SA, Weinberg RA, Depinho RA, eds. Cancer Principles and Practice of Oncology. Alphen aan den Rijn:Wolters Kluwer, Lippincott Williams and Wilkins;2008:946–971.
    1. Pavel M, O'Toole D, Costa F, et al ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology. 2016;103:172–185.
    1. Filosso PL, Ruffini E, Oliaro A, Papalia E, Donati G, Rena O. Long‐term survival of atypical bronchial carcinoids with liver metastases, treated with octreotide. Eur J Cardiothorac Surg. 2002;21:913–917.
    1. Waldherr C, Pless M, Maecke HR, Haldemann A, Mueller‐Brand J. 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.
    1. Mariniello A, Bodei L, Tinelli C, et al Long‐term results of PRRT in advanced bronchopulmonary carcinoid. Eur J Nucl Med Mol Imaging. 2016;43:441–452.
    1. Kulke MH, Lenz HJ, Meropol NJ, et al Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403–3410.
    1. Grande E, Capdevila J, Castellano D, et al Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open‐label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). Ann Oncol. 2015;26:1987–1993.
    1. 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.
    1. Brizzi MP, Berruti A, Ferrero A, et al Continuous 5‐fluorouracil infusion plus long acting octreotide in advanced well‐differentiated neuroendocrine carcinomas. A phase II trial of the Piemonte oncology network. BMC Cancer. 2009;9:388.
    1. Bajetta E, Catena L, Procopio G, et al Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low‐grade and high‐grade neuroendocrine tumours? Cancer Chemother Pharmacol. 2007;59:637–642.
    1. Ekeblad S, Sundin A, Janson ET, et al Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007;13:2986–2991.
    1. Fazio N, Granberg D, Grossman A, et al Everolimus plus octreotide long‐acting repeatable in patients with advanced lung neuroendocrine tumors: analysis of the phase 3, randomized, placebo‐controlled RADIANT‐2 study. Chest. 2013;143:955–962.
    1. 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.
    1. Yao JC, Shah MH, Ito T, et al Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–523.
    1. Yao JC, Fazio N, Singh S, et al Everolimus for the treatment of advanced, non‐functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT‐4): a randomised, placebo‐controlled, phase 3 study. Lancet. 2016;387:968–977.
    1. Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707–712.
    1. Rindi G, Arnold R, Bosman FT, et al Nomenclature and classification of neuroendocrine neoplasm of the digestive system In:Bosman FT, Carniero F, Hruban RH, Theise ND, eds. WHO Classification of Tumours of the Digestive System, 4th edn Lyon:International Agency for Research on Cancer;2010:13–14.
    1. Hendifar AE, Marchevsky AM, Tuli R. Neuroendocrine tumors of the lung: current challenges and advances in the diagnosis and management of well‐differentiated disease. J Thorac Oncol. 2017;12:425–436.
    1. Pelosi GFA, Cossa M, et al What clinicians are asking pathologists when dealing with lung neuroendocrine neoplasms? Semin Diagn Pathol. 2015;32:469–479.
    1. Ferolla P, Brizzi MP, Meyer T, et al Efficacy and safety of pasireotide LAR or everolimus alone, or in combination in patients with advanced carcinoids (NET) of the lung/thymus: results from the randomized, phase 2 LUNA study. Ann Oncol. 2016;27:136–148.
    1. Yao JC, Fazio N, Singh S, et al Everolimus (EVE) in advanced, nonfunctional, well‐differentiated neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin: second interim overall survival (OS) results from the RADIANT‐4 study. J Clin Oncol. 2016;34:4090.

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