The antiproliferative effect of pasireotide LAR alone and in combination with everolimus in patients with medullary thyroid cancer: a single-center, open-label, phase II, proof-of-concept study
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Medullary thyroid cancer (MTC) is a neuroendocrine tumour of the thyroid C cells. Pasireotide, a multi-receptor targeted somatostatin analogue, and everolimus, an inhibitor of mTOR, showed antitumour properties in neuroendocrine tumours. Aim of this study was to evaluate pasireotide alone and in combination with everolimus in patients with MTC.
Patients with progressive metastatic or persistent postoperative MTC received pasireotide LAR 60 mg/m for at least 6 months. Patients exhibiting progressive disease received everolimus 10 mg/d as combination therapy. Primary endpoint was progression free survival (PFS). Secondary endpoints included, overall survival, objective response rates, change in circulating markers, safety. Study registration no. NCT01625520.
Nineteen consecutive patients were enrolled. Median follow-up was 31 months. Median PFS with pasireotide was 36 months (95% CI: 19.5–52.5). Nine patients (47%) had tumour progression: seven of them started everolimus in combination with pasireotide, achieving a median PFS of 9.0 months (95% CI: 0–21.83). Five of them (71%) had further tumour progression, one objective response (14.3%), one stopped treatment because of pulmonary embolism. Pasireotide alone and with everolimus was safe and required withdrawal only in one case. Diarrhoea and hyperglycaemia were the most frequent adverse events with pasireotide (grade 3 in 5.3% each). Hyperglycaemia was the most frequent grade 3 toxicity with the combination therapy (28.6%).
Pasireotide therapy shows antiproliferative effects in persistent postoperative MTC suggesting further investigation on larger series of patients. In progressive MTC lesions, the combination pasireotide plus everolimus may be of benefit. Both schemes were safe and well tolerated.
KeywordsMedullary thyroid cancer Pasireotide Everolimus Neuroendocrine Tumours
A.F.: conceived the study design and wrote the article. R.M., G.P., M.D.P., M.G.C., P.F.: collected clinical and biochemical data. L.C., R.S., R.F.: analyzed the radiological tumour response and wrote the part related to imaging. G.V., L.P.: proof-read the manuscript. A.C.: supervised the project
Compliance with ethical standards
Conflict of interest
A. Faggiano and A. Colao Department received grant for research from Novartis. The remaining authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.S.A. Wells Jr., S.L. Asa, H. Dralle, R. Elisei, D.B. Evans, R.F. Gagel, N. Lee, A. Machens, J.F. Moley, F. Pacini, F. Raue, K. Frank-Raue, B. Robinson, M.S. Rosenthal, M. Santoro, M. Schlumberger, M. Shah, S.G. Waguespack; American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma., Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25, 567–610 (2015)CrossRefPubMedGoogle Scholar
- 3.K. Frank-Raue, F. Raue, R. Ziegler, Therapy of metastatic medullary thyroid gland carcinoma with the somatostatin analog octreotide. Med. Klin. 90, 63–66 (1995)Google Scholar
- 4.E. Modigliani, R. Cohen, S. Joannidis, C. Siame-Mourot, J.M. Guliana, G. Charpentier, D. Cassuto, M. Bentata Pessayre, A. Tabarin, P. Roger, P. Caron, P.J. Gullasseau, J.D. Lalau, J. Tournlafre, F. Bayard, P. Aulevre, A. James-Deldier, C. Catmettest, Results of long-term continuous subcutaneous octreotide administration in 14 patients with medullary thyroid carcinoma. Clin. Endocrinol. 36, 183–186 (1992)CrossRefGoogle Scholar
- 5.G. Vitale, P. Tagliaferri, M. Caraglia, E. Rampone, A. Ciccarelli, A.R. Bianco, A. Abbruzzese, G. Lupoli, Slow release lanreotide in combination with interferon-alpha2b in the treatment of symptomatic advanced medullary thyroid carcinoma. J. Clin. Endocrinol. Metab. 85, 983–988 (2000)PubMedGoogle Scholar
- 6.M.C. Zatelli, D. Piccin, F. Tagliati, A. Bottoni, A. Luchin, C. Vignali, A. Margutti, M. Bondanelli, G.C. Pansini, M.R. Pelizzo, M.D. Culler, E.C. Degli Uberti, Selective activation of somatostatin receptor subtypes differentially modulates secretion and viability in human medullary thyroid carcinoma primary cultures: potential clinical perspectives. J. Clin. Endocrinol. Metab. 91, 2218–2224 (2006)CrossRefPubMedGoogle Scholar
- 7.M. Cives, P.L. Kunz, B. Morse, D. Coppola, M.J. Schell, T. Campos, P.T. Nguyen, P. Nandoskar, V. Khandelwal, J.R. Strosberg, Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors. Endocr. Relat. Cancer 22, 1–9 (2015)CrossRefPubMedGoogle Scholar
- 8.L.K. Kvols, K.E. Oberg, T.M. O’Dorisio, P. Mohideen, W.W. de Herder, R. Arnold, K. Hu, Y. Zhang, G. Hughes, L. Anthony, B. Wiedenmann, Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study. Endocr. Relat. Cancer 19, 657–666 (2012)CrossRefPubMedGoogle Scholar
- 11.J.C. Yao, N. Fazio, S. Singh, R. Buzzoni, C. Carnaghi, E. Wolin, J. Tomasek, M. Raderer, H. Lahner, M. Voi, L.B. Pacaud, N. Rouyrre, C. Sachs, J.W. Valle, G.D. Fave, E. Van Cutsem, M. Tesselaar, Y. Shimada, D.Y. Oh, J. Strosberg, M.H. Kulke, M.E. Pavel; RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group., 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 387, 968–977 (2016)CrossRefPubMedGoogle Scholar
- 12.J.C. Yao, M.H. Shah, T. Ito, C.L. Bohas, E.M. Wolin, E. Van Cutsem, T.J. Hobday, T. Okusaka, J. Capdevila, E.G. de Vries, P. Tomassetti, M.E. Pavel, S. Hoosen, T. Haas, J. Lincy, D. Lebwohl, K. Öberg; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group., Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 514–523 (2011)CrossRefPubMedGoogle Scholar
- 14.A. Faggiano, V. Ramundo, A. Dicitore, S. Castiglioni, M.O. Borghi, R. Severino, P. Ferolla, L. Crino, A. Abbruzzese, P. Sperlongano, M. Caraglia, D. Ferone, L. Hofland, A. Colao, G. Vitale, Everolimus is an active agent in medullary thyroid cancer: a clinical and in vitro study. J. Cell. Mol. Med. 16, 1563–1572 (2012)CrossRefPubMedGoogle Scholar
- 15.T.C. Schneider, D. de Wit, T.P. Links, N.P. van Erp, J.J. van der Hoeven, H. Gelderblom, T. van Wezel, R. van Eijk, H. Morreau, H.J. Guchelaar, E. Kapiteijn, Beneficial effects of the mTOR inhibitor everolimus in patients with advanced medullary thyroid carcinoma: subgroup results of a phase II trial. Int. J. Endocrinol. 2015, 348124 (2015)CrossRefPubMedGoogle Scholar
- 16.E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij, New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009)CrossRefPubMedGoogle Scholar
- 17.E. Modigliani, R. Cohen, J.M. Campos, B. Conte-Devolx, B. Maes, A. Boneu, M. Schlumberger, J.C. Bigorgne, P. Dumontier, L. Leclerc, B. Corcuff, I. Guilhem, Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d’etude des tumeurs a calcitonine. Clin. Endocrinol. 48, 265–273 (1998)CrossRefGoogle Scholar
- 18.R. Elisei, M.J. Schlumberger, S.P. Muller, P. Schoffski, M.S. Brose, M.H. Shah, L. Licitra, B. Jarzab, V. Medvedev, M.C. Kreissl, B. Niederle, E.E. Cohen, L.J. Wirth, H. Ali, C. Hessel, Y. Yaron, D. Ball, B. Nelkin, S.I. Sherman, Cabozantinib in progressive medullary thyroid cancer. J. Clin. Oncol. 31, 3639–3646 (2013)CrossRefPubMedGoogle Scholar
- 19.S.A. Wells Jr., B.G. Robinson, R.F. Gagel, H. Dralle, J.A. Fagin, M. Santoro, E. Baudin, R. Elisei, B. Jarzab, J.R. Vasselli, J. Read, P. Langmuir, A.J. Ryan, M.J. Schlumberger, Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J. Clin. Oncol. 30, 134–141 (2012)CrossRefPubMedGoogle Scholar
- 20.M.E. Caplin, M. Pavel, J.B. Ćwikła, A.T. Phan, M. Raderer, E. Sedláčková, G. Cadiot, E.M. Wolin, J. Capdevila, L. Wall, G. Rindi, A. Langley, S. Martinez, J. Blumberg, P. Ruszniewski; CLARINET Investigators., Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N. Engl. J. Med. 371, 1556–1557 (2014)CrossRefPubMedGoogle Scholar
- 21.A. Rinke, H.H. Muller, C. Schade-Brittinger, K.J. Klose, P. Barth, M. Wied, C. Mayer, B. Aminossadati, U.F. Pape, M. Blaker, J. Harder, C. Arnold, T. Gress, R. Arnold; PROMID Study Group., 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. 27, 4656–4663 (2009)CrossRefPubMedGoogle Scholar
- 22.S. Grozinsky-Glasberg, H. Rubinfeld, Y. Nordenberg, A. Gorshtein, M. Praiss, E. Kendler, R. Feinmesser, A.B. Grossman, I. Shimon, The rapamycin-derivative RAD001 (everolimus) inhibits cell viability and interacts with the Akt-mTOR-p70S6K pathway in human medullary thyroid carcinoma cells. Mol. Cell. Endocrinol. 315, 87–94 (2010)CrossRefPubMedGoogle Scholar
- 23.S. Grozinsky-Glasberg, G. Franchi, M. Teng, C.A. Leontiou, A. Ribeiro de Oliveira Jr., P. Dalino, N. Salahuddin, M. Korbonits, A.B. Grossman, Octreotide and the mTOR inhibitor RAD001 (everolimus) block proliferation and interact with the Akt-mTOR-p70S6K pathway in a neuro-endocrine tumour cell Line. Neuroendocrinology 87, 168–181 (2008)CrossRefPubMedGoogle Scholar
- 24.K.C. Bible, V.J. Suman, J.R. Molina, R.C. Smallridge, W.J. Maples, M.E. Menefee, J. Rubin, N. Karlin, K. Sideras, J.C. Morris 3rd, B. McIver, I. Hay, V. Fatourechi, J.K. Burton, K.P. Webster, C. Bieber, A.M. Traynor, P.J. Flynn, B. Cher Goh, C.R. Isham, P. Harris, C. Erlichman; Endocrine Malignancies Disease Oriented Group, Mayo Clinic Cancer Center, and the Mayo Phase 2 Consortium., A multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H. J. Clin. Endocrinol. Metab. 99, 1687–1693 (2014)CrossRefPubMedGoogle Scholar