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

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.

• Authors: 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
• Journal: The oncologist (Oncologist) Vol. 23 Issue 7 Pg. 766-e90 (07 2018) ISSN: 1549-490X [Electronic] England
• PMID: 29242283 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Chemical References

• Antineoplastic Agents
• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Quinolines
• Everolimus
• MTOR protein, human
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• TOR Serine-Threonine Kinases
• dactolisib

Topics

• Antineoplastic Agents (therapeutic use)
• Everolimus (therapeutic use)
• Female
• Humans
• Imidazoles (therapeutic use)
• Male
• Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors, metabolism)
• Mechanistic Target of Rapamycin Complex 2 (antagonists & inhibitors, metabolism)
• Middle Aged
• Neuroendocrine Tumors (drug therapy, metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Progression-Free Survival
• Quinolines (therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)