Dec 08, 2014
A phase II, multicenter study published in the Journal of Clinical Oncology (JCO) found that patients with pancreatic neuroendocrine tumors who were treated with combined mTOR inhibitor temsirolimus and VEGF-A monoclonal antibody bevacizumab showed a response rate (RR) of 41%, meaning that tumors shrank in 23 out of the 56 patients, although no tumors disappeared. The study, “Multi-Center Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumor,” published online, ahead of print, December 8, also reported that 79% of the patients showed progression-free survival (PFS) at six months post-treatment, with a median PFS of 13.2 months, and a median overall survival (OS) of 34 months.
Commenting on the study, first author, Timothy J. Hobday, MD, said that, “These results are particularly encouraging since enrolled patients had rapidly progressing disease over the past seven months, as defined by RECIST criteria. “The activity of temsirolimus and bevacizumab in this phase II trial met or exceeded our criteria for defining a promising regimen in the treatment of progressive metastatic PNET.” The researchers were especially surprised by the RR of 41% since response rates to single agent mTOR inhibitors or VEGF pathway inhibitors are generally less than 10%.
A rigorous study design
The PFS of 13.2 months reported in this study is numerically similar to the PFS reported in phase III trials of mTOR inhibitor everolimus (PFS of 11 months) and VEGF pathway tyrosine kinase inhibitor sunitinib (PFS of 11.4 months). However, Dr. Hobday noted, direct comparison to those previous studies is difficult since the current study employed more stringent entry criteria that might make its findings seem less robust. For example, while the previous studies enrolled a broad spectrum of patients with PNET, the current study limited enrollment to patients with more rapidly progressing disease. Sicker patients, will, in general, have a lower OR and PFS.
In addition, radiographic assessments were performed every eight weeks in the current study, as opposed to every 12 weeks in the previous studies
“This rigorous design might tend to bias results in a negative fashion compared to the everolimus and sunitinib trials because those trials enrolled healthier, more slowly progressing patients, who are generally going to do better,” said Dr. Hobday. “The more frequent disease assessment at eight weeks also will potentially detect progression earlier than a 12-week interval.”
Discontinuation of treatment due to toxicity
As part of the study design, patients with locally advanced or metastatic, well, or moderately differentiated PNET and progressive disease were scheduled to receive 25 mg of IV temsirolimus on the first, eighth, 15th, and 22nd days of a 28-day cycle, and 10 mg of IV bevacizumab on the first and 15th days. However, a high percentage of patients discontinued treatment or had their doses reduced due to toxicity or refusal: 82% of patients had dose reductions in temsirolimus, 25% had dose reductions in bevacizumab, and 30% discontinued treatment due to adverse events or refusal. The most common adverse events were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (12%).
Commenting on these numbers, Dr. Hobday said, “The fairly common difficulty with ongoing grade 2 and 3 toxicity required dose reductions in the majority of patients and resulted in the duration of the temsirolimus being 2.5 months shorter on average than the bevacizumab. The treatment worked fairly well, but the more you gave it to people, the tougher it became later on.”
Looking ahead, Dr. Hobday said that the high rate of toxicity, dose reduction, and discontinuation of treatment reported in the study must be taken into account in future studies, but nonetheless, these current findings form a strong basis for the continued evaluation of combination mTOR and VEGF pathways inhibitors.
Currently, Dr. Hobday and his co-authors are carrying out an additional trial of single agent bevacizumab for the same population, since currently there are no data evaluating the activity of this medication alone in PNET. In addition, the Alliance for Clinical Trials along with the North American GI intergroup is conducting a randomized phase II trial of everolimus alone compared to combination everolimus and bevacizumab.
Timothy J. Hobday, MD, is an Assistant Professor of Oncology at the Mayo Clinic, in Rochester, Minnesota. He has been an ASCO member since 2001.
Abstract of the original JCO article.
PDF of the original JCO article.
Hobday TJ, Qin R, Reidy-Lagunes D, et al. Multi-center phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumor. J Clin Oncol. Epub 2014 Dec 8.
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@ 2014 American Society of Clinical Oncology