Timothy J Hobday1, Rui Qin2, Diane Reidy-Lagunes2, Malcolm J Moore2, Jonathan Strosberg2, Andreas Kaubisch2, Manisha Shah2, Hedy Lee Kindler2, Heinz-Josef Lenz2, Helen Chen2, Charles Erlichman2. 1. Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD. hobday.timothy@mayo.edu. 2. Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
Abstract
PURPOSE: There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway-targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. PATIENTS AND METHODS: We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. RESULTS: A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). CONCLUSION: The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.
PURPOSE: There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway-targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. PATIENTS AND METHODS: We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. RESULTS: A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). CONCLUSION: The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.
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