Interim findings from a randomized, global, phase III study indicate that the multi-targeted drug sorafenib nearly doubled PFS for patients with differentiated thyroid cancer resistant to radioactive iodine therapy.
Marcia Brose, MD, PhD
Interim findings from a randomized, global, phase III study indicate that the multi-targeted drug sorafenib (Nexavar) nearly doubled progression-free survival (PFS) for patients with differentiated thyroid cancer (DTC) resistant to standard radioactive iodine therapy (RAI).
If approved, sorafenib would become the first new drug in 40 years for the treatment of this rare and aggressive form of thyroid cancer. The study was presented Sunday during a plenary session at the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO).
“After having no effective drugs for these patients for so many years, it is very exciting to find an oral drug that stops growth of the cancer for several months,” said lead author, Marcia Brose, MD, PhD, assistant professor of Otolaryngology and Head and Neck Surgery in the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “For these patients, a longer progression-free survival means more months without hospitalization and invasive procedures to control pain and other symptoms. This is the first time we have had a systemic treatment that can help.”
DTC is the most common subtype of thyroid cancer, accounting for about 85% of the 60,000 thyroid cancer cases diagnosed each year in the United States. Although DTC generally has high cure rates following standard treatment—surgery and RAI—roughly 5% to 15% of patients develop RAI resistance, which has an expected survival of 2 ½ to 3 ½ years, Brose said. The only approved treatment for those patients, doxorubicin, is rarely used due to its low efficacy and high toxicity. This is the first time a kinase inhibitor has been assessed for this indication in a large clinical trial.
Sorafenib inhibits multiple kinases, including Raf and VEGF receptor kinases 1-3, which control tumor cell division and angiogenesis. The drug is FDA-approved for treatment of advanced kidney cancer and inoperable liver cancer.
In the DECISION study, 417 patients whose metastatic, RAI-resistant DTC had progressed in the past 14 months were randomly assigned to receive 400 mg of sorafenib twice daily (n=207) or placebo (n=210). Nearly all patients had metastatic disease; the median age was 63 years. Seventy percent of those in the control arm crossed over to the sorafenib arm upon disease progression.
The trial’s primary endpoint was PFS. Secondary endpoints included overall survival, response rate, and safety.
Median PFS was 10.8 months in the sorafenib group vs 5.8 months in the placebo arm (hazard ratio [HR] 0.58; 95% CI, 0.45—0.75; P<.0001). Tumor shrinkage of 30% or more was observed in 12.2% and 0.5% of patients in the sorafenib and placebo arms, respectively (P<.0001). An additional 42% of patients in the sorafenib arm had stable disease for six months or longer, for a disease control rate of 54%, compared with a disease control rate of 34% in the placebo arm. Overall survival data are not yet mature.
The most common any-grade treatment-emergent adverse events in the sorafenib arm included hand-foot skin reaction, diarrhea, alopecia, rash/desquamation, fatigue, weight loss, and hypertension. One death in each arm was attributed to study drug.
Also experienced were anorexia, oral mucositis, pruritis, and nausea, according to a statement released by the drug’s manufacturers, Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, which cooperatively supported the study. Treatment-emergent adverse events led to discontinuation in 18.8% of patients who received sorafenib, compared to 3.8% of patients who received placebo.
Researchers are conducting further analysis of the trial to look for biomarkers to identify patients who are likely to relapse after surgery and RAI, and who might benefit from sorafenib earlier in the course of their disease, Brose said.
“Let’s not give them a drug that makes them feel bad when they’re going to do well [on standard treatment] anyway,” she said. “There will be a role for moving things earlier in treatment, but we first must identify patients who will do badly” with surgery and RAI.
Doxurubicin was the last drug approved for patients with RAI-resistant DTC, in 1974, but the chemotherapy is no longer used because it isn’t effective and makes the patients sick, Brose said. Instead, she said, such patients are treated palliatively as they progress.
Even if sorafenib is approved, additional treatment options will be needed as second-line agents and beyond, since, in most patients, the disease eventually progresses after sorafenib treatment. Answers to this problem will most likely lie in targeted therapies, Brose said. Since 70% of differentiated thyroid cancers express mutations and genetic changes associated with kinases, she said, “this entire class of kinase inhibitors has been what’s made the difference.”
Researchers are also considering MEK and mTOR inhibitors for this population, Brose said. Another possibility is treating BRAF mutations in papillary thyroid cancer with BRAF-targeted therapy used to treat melanoma.
The DECISION data will form the basis for a supplemental New Drug Application planned for mid-year 2013, with additional submissions to follow globally.
Brose MS, Nutting C, Jarzab B, et al. Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. J Clin Oncol. 2013;31(suppl; abstr 4).