Phase II Study of BEZ235 versus Everolimus in Patients with Mammalian Target of Rapamycin Inhibitor-Naïve Advanced Pancreatic Neuroendocrine Tumors

Ramon Salazar, Rocio Garcia-Carbonero, Steven K. Libutti, Andrew E. Hendifar, Ana Custodio, Rosine Guimbaud, Catherine Lombard-Bohas, Sergio Ricci, Heinz-Josef Klümpen, Jaume Capdevila, Nicholas Reed, Annemiek Walenkamp, Enrique Grande, Sufiya Safina, Tim Meyer, Oliver Kong, Herve Salomon, Ranjana Tavorath, James C. Yao

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Lessons Learned: Treatment with BEZ235 has not been shown to demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile. The hypothesis of dual targeting of the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways in patients with advanced pancreatic neuroendocrine tumors may warrant further study using other agents. Background: This phase II study investigated whether targeting the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naïve to mTOR inhibitor therapy. Methods: Patients with advanced pNET were randomized (1:1) to oral BEZ235 400 mg twice daily or oral everolimus 10 mg once daily on a continuous dosing schedule. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety, overall response rate (ORR), overall survival (OS), and time to treatment failure. Results: Enrollment in this study was terminated early (62 enrolled of the 140 planned). The median PFS was 8.2 months (95% confidence interval [CI]: 5.3 to not evaluable [NE]) with BEZ235 versus 10.8 months (95% CI: 8.1–NE) with everolimus (hazard ratio 1.53; 95% CI: 0.72–3.25). The most commonly reported all-grade adverse events (>50% of patients regardless of study treatment relationship) with BEZ235 were diarrhea (90.3%), stomatitis (74.2%), and nausea (54.8%). Conclusion: BEZ235 treatment in mTOR inhibitor-naïve patients with advanced pNET did not demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.
Original languageEnglish
Pages (from-to)766-e90
JournalOncologist
Volume23
Issue number7
DOIs
Publication statusPublished - 2018
Externally publishedYes

Cite this

Salazar, R., Garcia-Carbonero, R., Libutti, S. K., Hendifar, A. E., Custodio, A., Guimbaud, R., ... Yao, J. C. (2018). Phase II Study of BEZ235 versus Everolimus in Patients with Mammalian Target of Rapamycin Inhibitor-Naïve Advanced Pancreatic Neuroendocrine Tumors. Oncologist, 23(7), 766-e90. https://doi.org/10.1634/theoncologist.2017-0144