Richard Pazdur, MD
The FDA has expanded the approval for sorafenib (Nexavar) to include the treatment of patients with radioactive iodine (RAI)-resistant metastatic differentiated thyroid cancer (DTC), based a substantial prolongation in progression-free survival (PFS) for patients in the DECISION trial.
In the phase III trial, treatment with sorafenib improved PFS by 41% compared with placebo, resulting in a median PFS of 10.8 months compared with 5.8 months, for sorafenib and placebo, respectively. Based on these data, the FDA granted a priority review to sorafenib in August, which resulted in the eventual approval. Following the FDA's decision, sorafenib has become the first agent specifically approved for RAI-resistant DTC.
“Differentiated thyroid cancer can be challenging to treat, especially when unresponsive to conventional therapies,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval demonstrates the FDA’s commitment to expediting the availability of treatment options for patients with difficult-to-treat diseases.”
In the DECISION trial, which was presented at the 2013 ASCO Annual Meeting, patients were randomized in a 1:1 ratio to receive oral sorafenib (n = 207) at 400 mg twice daily or placebo (n = 210). Patients in the trial had locally advanced or metastatic RAI-refractory DTC. In all, by independent assessment, 57% of patients had papillary histology, 25% had follicular, and 10% were poorly differentiated. Altogether, 96% of patients had metastatic disease that had spread primarily to the lungs (71% of patients).
Upon progression, patients in the placebo arm were allowed to crossover to receive open-label sorafenib. The primary endpoint of the study was PFS, although overall survival (OS) and response rates were also assessed. At the time of the analysis, the median OS had not been reached. Given the design of the trial, approximately 70% of patients in the placebo arm were allowed to crossover to receive sorafenib.
The median PFS was 10.8 months with sorafenib compared to 5.8 months with placebo (hazard ratio [HR] = 0.58; 95% CI, 0.45–0.75; P
<0.0001). Partial responses were observed in 12.2% of patients receiving sorafenib compared with 0.5% in the placebo arm (P
< 0.0001). Additionally, 42% of patients in the sorafenib arm had stable disease for ≥ 6 months compared to 33% with placebo.
Sorafenib is an angiogenesis inhibitor that works by blocking multiple kinases involved in cell proliferation and growth. Amongst other kinases, sorafenib inhibits VEGFR1-3, PDGFR-B, KIT, and RET. Inherent in this mechanism of action is a higher risk for hypertension, which occurred in 41% of patients receiving sorafenib compared with 12% for placebo.
Other all grade adverse events associated with sorafenib included palmar-plantar erythrodysesthesia syndrome (69% vs. 8%), diarrhea (68% vs. 15%), alopecia (67% vs. 8%), weight loss (49% vs. 14%), fatigue (41% vs. 20%), rash (35% vs. 7%), decreased appetite (30% vs. 5%), stomatitis (24% vs. 3%), and others. Grade 3/4 adverse reactions were 65% with sorafenib compared with 30% for placebo.
"The DECISION trial results show sorafenib's ability to extend progression-free survival compared to placebo in patients with this type of advanced thyroid cancer," said Marcia Brose, MD, PhD, assistant professor in the Department of Otorhinolarlyngology: Head and Neck Surgery and the division of Hematology/Oncology in the Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania. "Physicians now have an approved treatment option that may help improve care in this patient population."
A subanalysis of the DECISION trial that was presented at the European Cancer Congress found an association between RAS
mutations and clinical outcomes for patients with DTC, regardless of treatment type.
This analysis examined tumor samples from 256 patients, 126 in sorafenib arm and 130 in the placebo arm. Overall, it found patients in the placebo arm with RAS
mutations had a worse PFS than their wild-type counterparts (HR=1.78, P
=0.03). Additionally, patients with BRAF
mutations had a better PFS outcome than patients with wild-type BRAF (HR=0.53, P
=0.01). However, in the analysis, outcomes for patients treated with sorafenib were similar, independent of BRAF
Bayer HealthCare and Onyx Pharmaceuticals, Inc., an Amgen subsidiary, market sorafenib, which is also approved as a treatment for patients with unresectable hepatocellular carcinoma and patients with advanced renal cell carcinoma.