Two different targeted therapies improve the survival of patients with advanced forms of a rare type of pancreatic cancer, according to results from two phase III clinical trials. The therapies, sunitinib (Sutent®) and everolimus (Afinitor®), each increased the length of time patients with pancreatic neuroendocrine tumors (PNET) survived overall and without their disease progressing.
In 2011, based on the initial findings from these trials, the Food and Drug Administration (FDA) approved both everolimus and sunitinib for the initial treatment of patients with advanced PNET.
Pancreatic neuroendocrine tumors account for less than 2% of new pancreatic cancer cases. In pancreatic adenocarcinoma, which accounts for the vast majority of pancreatic cancer cases, tumors arise from epithelial cells that line pancreatic ducts. In patients with PNET, however, the disease arises from hormone-releasing cells in the pancreas, called islet cells.
Patients with PNET generally have better prognoses than patients with pancreatic adenocarcinoma. Even in patients who have advanced PNET, the disease can be quite stable for several years without treatment, explained Luis Diaz, M.D., of the Johns Hopkins University Cancer Center, whose research and clinical work focuses on pancreatic and other gastrointestinal cancers.
But once the disease begins to progress, Dr. Diaz continued, other therapies, including chemotherapy and streptozocin—which was the only drug approved for the treatment of PNET until the FDA approved everolimus and sunitinib—have limited efficacy and can be highly toxic.
First Treatments Shown to Improve Outcomes in PNET
The 171-patient trial that tested daily sunitinib—funded by the drug’s manufacturer, Pfizer—was stopped early by the study’s independent data and safety monitoring committee. The decision was based on the results of an interim analysis that showed a clear improvement in progression-free survival in patients receiving sunitinib and an increased risk of death and serious adverse events in the placebo group.
Median progression-free survival was 11.4 months among patients who received sunitinib, compared with 5.5 months among patients who received the placebo. Patients who received sunitinib also had a nearly 60% improvement in overall survival.
The everolimus trial—funded in part by the drug’s manufacturer, Novartis—enrolled 410 patients. Median progression-free survival in the trial, called RADIANT-3, was 11.0 months among patients who received everolimus daily compared with 4.6 months among patients who received a placebo. More than 70% of patients in the RADIANT-3 placebo arm eventually crossed over and received everolimus.
Updated results from the RADIANT-3 trial, published September 12, 2016, in the Journal of Clinical Oncology (JCO), showed that patients initially treated with everolimus had a higher median overall survival than patients initially treated with a placebo: 44 months versus 37.3 months.
The improvement in overall survival was not statistically significant, reported James Yao, M.D., of the University of Texas MD Anderson Cancer Center, and his colleagues. But the lack of statistical significance was likely due to the fact that the majority of patients in the trial’s placebo arm crossed over to begin receiving everolimus, they explained, diluting estimates of the drug’s effect on overall survival.
In both trials, the drugs were associated with an increased risk of side effects, including serious events such as anemia and neutropenia, which in many patients prompted dose reductions or a temporary halt in treatment. However, the adverse events were manageable, the research teams that led the trials reported, and were consistent with what has been seen with these drugs in the treatment of other cancers.
Changing Clinical Practice, But More Research Needed
Both drugs have had a substantial impact on patient care, Dr. Yao and his colleagues wrote in JCO. Their availability “has changed the treatment paradigm of [PNET] and has likely improved survival in this patient population,” they concluded.
But important questions remain about the optimal use of sunitinib and everolimus in patients with PNET, James Howe, M.D., co-director of the Neuroendocrine Cancer Clinic at the University of Iowa Carver College of Medicine, and his colleagues recently wrote.
“Further studies defining when to use these agents and factors associated with limitations in their utility are needed,” they noted.
Both sunitinib and everolimus target proteins in signaling pathways in cancer cells that studies have shown can fuel PNET progression and resistance to available treatments. Research that continues to identify ways to “specifically target the genetic alterations driving PNET initiation and metastasis” will be critical, Dr. Howe and his colleagues noted.
With more than 90 open clinical studies involving patients with PNET in the United States alone, they concluded, “each will add another piece to the PNET puzzle.”