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Published on: October 27, 2014
Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors
Timothy J Hobday1, Rui Qin2, Diane Reidy-Lagunes2
1Timothy 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.
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.
Insights
This study shows that combining temsirolimus (an mTOR inhibitor) and bevacizumab (a VEGF inhibitor) is an effective treatment for pancreatic neuroendocrine tumors (PNETs), demonstrating significant response rates and progression-free survival.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- Pancreatic neuroendocrine tumors (PNETs) have limited effective treatment options.
- Targeted therapies like mTOR inhibitors and VEGF inhibitors have shown promise individually.
- Preclinical data suggest combined mTOR and VEGF pathway inhibition may enhance antitumor effects.
Purpose of the Study:
- To evaluate the efficacy and safety of a combination therapy targeting both mTOR and VEGF pathways in patients with progressive PNETs.
- To assess the tumor response rate and 6-month progression-free survival (PFS) of this combination therapy.
Main Methods:
- A two-stage, single-arm, phase II clinical trial was conducted.
- Patients received temsirolimus (an mTOR inhibitor) and bevacizumab (a VEGF-A inhibitor) intravenously.
- Eligibility criteria included well or moderately differentiated PNETs with disease progression within 7 months.
Main Results:
- The confirmed response rate (RR) was 41% (23 of 56 patients).
- Six-month progression-free survival (PFS) was 79% (44 of 56 patients), with a median PFS of 13.2 months.
- Common grade 3-4 adverse events included hypertension, fatigue, lymphopenia, and hyperglycemia.
Conclusions:
- The combination of temsirolimus and bevacizumab demonstrated substantial activity and reasonable tolerability in progressive PNETs.
- The observed response rate and 6-month PFS exceed those of single targeted agents.
- Further investigation of combined mTOR and VEGF pathway inhibitors for PNETs is warranted.
