Effective treatments for slow-growing neuroendocrine tumors (NETs) in the lungs and gastrointestinal tract have been limited. Results from the RAD001 in Advanced Neuroendocrine Tumors Fourth Trial (RADIANT-4) show that everolimus (Afinitor) statistically significantly improved progression-free survival (PFS) in adults with progressive, nonfunctional NETs in the lungs and gut, giving these patients their first U.S. Food and Drug Administration–approved treatment option ( Lancet 2016;387:968–77; doi:10.1016/S0140-6736(15)00817-X).
NETS originate throughout the body, but they are found mostly in the gastrointestinal (GI) tract, lungs, or pancreas. They are defined as functional when symptoms of oversecretion of hormones are apparent or nonfunctional when tumor growth causes the symptoms. Seventy-four percent of NETs are nonfunctional.
James C. Yao, M.D., professor in the Department of Gastrointestinal Medical Oncology at the University of Texas M. D. Anderson Cancer Center in Houston and others enrolled 302 patients with NETs of the GI tract and lungs from 97 centers in 25 countries. They were randomized to either 10mg of everolimus daily or placebo, both with supportive care. The primary endpoint was PFS as assessed by centralized review of radiographs.
PFS Increased by 50%
“[PFS] is essentially time to tumor growth,” Yao said. “While everyone in cancer research wants to increase overall survival, these are very slow-growing cancers with long natural histories, so overall survival would require enrollments of thousands of patients. This is a difficult goal in relatively rare cancers like these.”
Median PFS was 11 months among those in the treatment group, compared with 3.9 months in the placebo group. The medication was associated with a 52% reduction in the estimated risk of disease progression or death. With a median follow-up of 21 months, the median duration of treatment was nearly doubled in the treatment group compared with those getting a placebo.
The most common serious side effects included mouth sores, infections, diarrhea, fatigue, and rash. Those effects are consistent with the known safety profile of everolimus.
PFS increases were seen across many subgroups. Patients with lung tumors experienced a 50% improvement in lung tumor patients, and GI NETS saw a benefit of 44%. Tumors of unknown origin also saw 40% PFS increase with the medication.
“NETs in the past have been very rare diseases, but they have been on the rise recently in population-based registries,” Yao said. “Roughly half of these arise in the GI tract and until now there were no approved medications for those arising from the lung.”
Richard R. P. Warner, M.D.
FDA Approval for NET Treatment
As a result of the RADIANT-4 study, the FDA earlier this year approved everolimus to treat adult patients with progressive nonfunctional NETs that originated in the lungs or GI tract. The drug was previously approved to treat advanced, metastatic, or inoperable progressive NETs of pancreatic origin and as a third-line therapy for advanced renal cell carcinoma.
Yao stressed, however, that everolimus only slows the progression of tumor. Nearly all advanced NETs remain incurable.
“We can now offer approved therapies for areas, such as the lungs, for which there had previously been none available,” Yao said. “For NETs of the [GI] tract, the only approved therapy for control of cancer growth, lanreotide, has only demonstrated efficacy in indolent or stable tumors. Now there is a proven and efficacious treatment for progressing tumors, and that is an important clinical issue.”
Most chemotherapies are based on the concept that cancer cells are dividing quickly. That means better chances that the drugs will damage the cell’s DNA or interfere with cell division.
NETs Are Hard To Treat
NETs, however, tend to be hard to treat because they are slow growing. Because of this, the goal of therapy most often is to stop growth and keep the tumor size steady.
“Sometimes in cancer treatment you take what you can get, and not growing is a very good thing,” said Sandy Kotiah, M.D., director of the Neuroendocrine Tumor Center at Mercy Medical Center in Baltimore. “Even when you have something incurable and you are going to live for years, you want to know that when the first-line treatment stops working, there is something else around that can keep you alive longer.”
The results of the RADIANT-4 trial do that, extending the efficacy of everolimus to NETs of the GI tract and the lungs.
Longer Life May Mean Better Treatments
Richard R. P. Warner. M.D., director of the Center for Carcinoid and Neuroendocrine Tumors at the Icahn School of Medicine at Mount Sinai in New York, said that is an important step forward. With the speed at which new treatments are being approved, adding years to a person’s life alone could possibly increase his or her chances of being treatable with even newer modalities.
“Some treatments for cancers may not add much to a patient’s life and really don’t have a long-term impact,” Warner said. “Everolimus added years and not just a few weeks. With new drugs and technologies being rolled out at an increasing rate, adding extra years gives a person time for new modalities to be approved and applied to those who before might not have survived long enough to take advantage of these advances.”
Yao said that he agrees with that assessment, noting that the same can be said for NETs and their treatment.
“This is a very exciting time for NETs because we are starting to move from an era of few treatments mostly based on expert opinion to one where we have multiple options built on evidenced-based medicine and large, randomized trials,” he said. “With everolimus, we are reducing tumor growth by more than 50%, and that is a really exciting place to be.”
