CHICAGO—The multi-targeted drug sorafenib extends progression-free survival (PFS) for patients with differentiated thyroid cancer that is resistant to standard radioiodine therapy (RAI), according to interim findings from a randomized, global, Phase III trial reported here at the American Society of Clinical Oncology Annual Meeting.
The DECISION trial, reported during the plenary session (Abstract 4) was the first Phase III trial to demonstrate efficacy of any agent for the treatment of progressive RAI-refractory differentiated thyroid cancer (DTC), said the lead author, Marcia S. Brose, MD, PhD, Assistant Professor of Otolaryngology and Head and Neck Surgery at Abramson Cancer Center and Perelman School of Medicine at the University of Pennsylvania.
“Sorafenib is a potential new treatment option for patients with locally advanced or metastatic RAI-refractory DTC. There is a significant medical need for patients with thyroid cancer.”
The Discussant for the study, Ezra Cohen, MD, Associate Professor of Medicine at the University of Chicago, started his remarks by congratulating the investigators for completing a trial “that many thought could never be done because this was thought of as a rare disease.”
“This is not a rare disease, though, he emphasized. “These patients exist, and there are patients dying from DTC. We now have a therapy to offer them.”
Differentiated thyroid cancer is the most common subtype of thyroid cancer, accounting for about 85 percent of the 60,000 thyroid cancer cases diagnosed each year in the United States. Although DTC generally has high cure rates following standard treatment of surgery and RAI, between five and 15 percent of patients develop resistance to radioiodine therapy, a situation that then reduces the survival rate to typically two and a half to three and a half years, Brose said.
The only approved treatment for those patients, doxorubicin (Adriamycin), is rarely used due to its low efficacy and high toxicity.
This is the first time that a kinase inhibitor has been assessed for this indication in a large clinical trial, she noted. In the study, sorafenib stalled disease progression by five months.
Now, if approved by the FDA, sorafenib would become the first new active drug for this form of thyroid cancer in 40 years. The drug is already approved by the FDA for the treatment of advanced kidney cancer and inoperable liver cancer.
“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 Brose. “For these patients, a longer PFS 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.”
Targets VEGF Receptors, PDGF Receptors, BRAF, RET, & c-KIT
Sorafenib, which targets VEGF receptors, PDGF receptors, BRAF, RET, and c-KIT, had previously shown activity as a monotherapy in a Phase II trial of patients with advanced refractory thyroid cancer.
In the Phase III study, 417 patients, median age of 63, with metastatic, RAI-resistant DTC were randomly assigned to receive either sorafenib at 400 mg twice daily (207 patients) or placebo (210 patients). Those who had undergone previous treatment with targeted therapy or chemotherapy were excluded.
Disease progression was assessed every eight weeks, and patients were allowed to cross over to the sorafenib arm upon disease progression.
Patient demographics were well-balanced, she noted: Virtually all patients had metastatic disease, two-thirds had papillary thyroid cancer, and about one-quarter had follicular thyroid cancer.
The study met its primary endpoint of progression-free survival. The median PFS in the sorafenib-treated patients (10.8 months) was significantly longer than that of the placebo group (5.8 months).
Brose noted that the short PFS in the placebo arm reflects the progressive nature of the disease: “Unlike RAI-sensitive disease, which can be indolent, this clearly represents patients with progressing disease.” Treatment benefits were seen in all pre-specified subgroups and across all regions (North America, Europe, and Asia) and age groups.
Tumor shrinkage of 30 percent or more was observed in 12.2 percent of the patients receiving sorafenib and in 0.5 percent of the placebo patients. An additional 42 percent of patients in the sorafenib arm had stable disease for at least six months, for a disease-control rate of 54 percent, compared with 34 percent for patients in the placebo arm.
“Tumor shrinkage with sorafenib in symptomatic patients was often sufficient to alleviate symptoms,” Brose said. No complete responses were seen, though, and the median duration of partial responses was 10.2 months.
Overall survival data were not yet mature at the time of the ASCO report. Brose noted that this secondary endpoint will likely be affected by the more than two-thirds of patients in the placebo arm who have crossed over to treatment. Additional survival analyses are planned.
EZRA COHEN, MD
The most frequent adverse events were hand and foot skin reactions, diarrhea, alopecia, rash, fatigue, and hypertension, which were typical of those seen in earlier sorafenib studies, she said, adding that many of the skin conditions could be easily managed.
Dose modification due to adverse events was more common with sorafenib (about 78%) than with placebo (30%). About one in five patients discontinued sorafenib due to adverse events, compared with only about four percent of patients receiving placebo.
The most frequent serious adverse events were secondary malignancies, occurring in 4.3 percent of patients receiving the drug and 1.9 percent of those receiving placebo. One death in each arm of the study was associated with the study drug.
In conclusion, Brose said, “Sorafenib significantly improved median PFS by five months compared with placebo, and the safety results were consistent with the known safety profile of sorafenib.”
Further analysis of data are planned to look for biomarkers to identify the patients who are likely to relapse after surgery and RAI and who might respond well to sorafenib, and to identify those who may need additional therapy, she added.
Since the disease will eventually progress after sorafenib treatment in most patients, additional treatment options still need to be developed for use as second-line agents.
‘Attractive Option, Renewed Hope’
Also commenting at the news briefing, Gregory Masters, MD, an ASCO spokesperson for head and neck cancers and Director of the Medical Oncology Fellowship and an attending physician at the Helen F. Graham Cancer Center in Delaware, said, “This is a new treatment for a disease where we do not have good options once patients become refractory to standard surgery and RAI. Adriamycin is not a good option. Most of us do not feel comfortable offering it because of the toxicity. Now we have an attractive option that can prolong PFS that will become a standard of care.
“Few good options exist for patients with these more aggressive thyroid cancers, so these findings offer renewed hope and momentum for patients and researchers alike. Sorafenib provides meaningful activity for these patients, nearly doubling PFS.”
Future studies will help identify which patients can benefit most from this therapy, and assess how other targeted therapies may further improve the outcome for these patients, he said.
The moderator of an ASCO press conference, Jyoti Patel, MD, Associate Professor in Medicine-Hematology/Oncology at Northwestern University Feinberg School of Medicine, added her enthusiasm for sorafenib treatment in this group of patients. “This certainly is an exciting study that brings an oral targeted therapy agent to these patients that need symptomatic treatment,” she said.
'Remains Curable Malignancy'
In his Discussant remarks, which he titled “Patients Finally Have Options,” Cohen noted that thyroid cancer is increasing in incidence and mortality and is one of the fastest growing cancers in the United States, but the reasons remain unknown.
Still, “thyroid cancer remains a curable malignancy,” he said. “Most patients do well, and the great majority of especially young patients and those with a differentiated histology survive their disease,” although patients do become refractory to therapy.
The introduction of VEGF inhibitors, with their ability to inhibit the VEGF receptor, has led to response rates of 15 to 50 percent and a median PFS of about one year. “Clearly, the class is active in this disease,” Cohen said. “Biology shows this cancer harbors a high rate of BRAF, RAS, and PIK3CA mutations. DTCs are highly vascular cancers with a high expression of VEGF.”
Another multi-kinase inhibitor, lenavatinib, is being tested in a multicenter, randomized, double-blind, placebo-controlled Phase III trial, and the data from this study “will likely reinforce the data with sorafenib,” he said.
New Standard of Care?
Is sorafenib the new standard of care for patients with differentiated thyroid cancer? “Clearly, the drug extends PFS. The majority of adverse events are manageable and not life-threatening. The rate of grade 3/4 adverse events is low. But sorafenib does not induce complete response or cure the disease,” he said.
Not all RAI-refractory patients need treatment, he added. About 25 percent of the placebo patients did not have disease progression in the trial, and some thyroid cancer patients with PET-negative scans have a PFS of more than three years.
Cohen emphasized that a rise in thyroglobulin should not be used to initiate therapy.
Future clinical trials must address therapeutic options for sorafenib-refractory patients, he continued. One solution may be to pair sorafenib with another VEGF tyrosine kinase inhibitor. Also, a combination of cediranib and lenalidomide appears to be active in a Phase I trial and may prove to be effective in sorafenib-refractory patients. In addition, selumetinib may allow patients with RAI-refractory advanced thyroid cancer to once again take up RAI.
He said it is unlikely the DECISION trial will show an overall survival advantage because of the large number of placebo patients who crossed over to drug treatment.
“The critical issue is that not all patients with DTC need therapy. We need to individualize care. This is not a life-threatening toxicity that will impact quality of life. This is particularly important for patients who are asymptomatic.”