Targeted Therapies May Be Effective Against Rare Pancreatic Cancer
Patients with advanced forms of a rare type of pancreatic cancer may have new, effective treatment options. According to results from two phase III clinical trials, the targeted therapies sunitinib (Sutent) and everolimus (Afinitor) increased the length of time patients with pancreatic neuroendocrine tumors (PNET) survived without the disease progressing. And, in the sunitinib trial, patients who received the drug also had better overall survival. The findings were published February 9 in the New England Journal of Medicine (NEJM).
Pancreatic neuroendocrine tumors account for less than 2 percent of new pancreatic cancer cases. Over the past 2 decades, no effective treatments for this cancer type have been identified, wrote Drs. Robert Jensen and Gianfranco Delle Fave in an accompanying editorial in NEJM, but the results from these trials “provide optimism” that this may no longer be the case.
Dr. Luis Diaz, of the Johns Hopkins University Kimmel Cancer Center, whose clinical work and research focuses on pancreatic and other gastrointestinal cancers, went even further, calling the results “pretty spectacular.” If the FDA approves these agents for patients with advanced PNET whose disease is progressing, he continued, they “should become the standard of care.”
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 when an interim analysis 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 percent improvement in overall survival at the time of the analysis.
The everolimus trial, called RADIANT-3 and funded in part by the drug’s manufacturer, Novartis, enrolled 410 patients. Median progression-free survival in the trial was 11 months among patients who received everolimus daily compared with 4.6 months among patients who received a placebo. Follow-up in the everolimus trial was not long enough to judge whether overall survival improved; however, 73 percent of patients in the placebo arm eventually crossed over—which was allowed in the design of both trials—and received everolimus. As a result, an overall survival benefit in favor of everolimus may never materialize, wrote the trial’s lead author, Dr. James C. Yao from the University of Texas M. D. Anderson Cancer Center, and his colleagues.
In pancreatic adenocarcinoma, which accounts for the vast majority of pancreatic cancer cases, tumors arise from epithelial cells that line pancreatic ducts. 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, Dr. Diaz explained. Once the disease begins to progress, however, commonly used treatments such as chemotherapy and streptozocin, which is the only FDA-approved drug for PNET, have limited efficacy and can be highly toxic, he said.
Sunitinib and everolimus have their own toxicities. 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 researchers reported, and were consistent with what has been seen with these drugs in the treatment of other cancers.
Both sunitinib and everolimus target proteins in intracellular signaling pathways that earlier studies have suggested can drive PNET progression and resistance to available treatments. For example, a study published in Science last month by researchers from Johns Hopkins, including Dr. Diaz, found mutations in genes in the mTOR signaling pathway, which is everolimus’ molecular target, in 14 percent of the PNET samples tested. Also, Dr. Yao and colleagues explained, patients with several genetic cancer syndromes in which the mTOR pathway is known to play an important role, including tuberous sclerosis and von Hippel-Lindau disease, often develop PNET.
In the Science study, patients with mutations in mTOR pathway genes—including PTEN, PI3K, and TSC2—had a worse prognosis than patients with other common mutations that they identified. In addition, Dr. Diaz noted, in several other cancer types, studies have shown that TSC2 mutations preferentially sensitize patients’ tumors to respond to mTOR inhibitors. Further studies are needed to correlate genetic alterations or mutations with response to the agents, he cautioned.
“But if you bundle our paper with the results from these two trials, they are synergistic and very complimentary with what we found,” Dr. Diaz said.
Additional biomarker studies may improve therapy choice and the selection of “rational combinations” of drugs in patients with both progressive and earlier disease, Dr. Yao said. Such biomarkers could include mutations in genes in the mTOR pathway for everolimus. They could also include findings from perfusion computed tomography (CT) scans, he continued. In a small study presented at the 2010 ASCO annual meeting, Dr. Yao explained, patients with NETs whose tumors had higher permeability on the CT scans—that is, greater flow of blood in and out of the tumor—had significantly better response to treatment with bevacizumab (which, like sunitinib, targets blood vessel formation) and everolimus than patients with low tumor permeability.
In the meantime, Drs. Jensen and Delle Fave wrote, in patients with advanced PNET there are still important questions left to answer. “Will patients have to continue taking these drugs for years since both drugs primarily stabilize, rather than cure, the disease?” they asked. “If patients no longer have a response to one drug, can they then be effectively treated with the other drug or with a combination of the two drugs?”
Several clinical trials testing everolimus in combination with other targeted therapies in patients with PNET are under way. Everolimus has been granted priority review by the FDA for the treatment of advanced PNET (as well as neuroendocrine tumors of the lung and gastrointestinal tract). Sunitinib is already approved in Europe to treat some patients with PNET, and according to a company spokesperson, Pfizer is working with the FDA to pursue a regulatory approval to use sunitinib in unresectable PNET.