CHICAGO—The addition of the mammalian target of rapamycin (mTOR) inhibitor everolimus to the oral kinase inhibitor sorafenib leads to good activity in medullary and Hürthle cell thyroid cancers, according to results of a study reported here at the American Society of Clinical Oncology Annual Meeting (Abstract 6024).
There is good preclinical evidence to suggest that a combination of everolimus and sorafenib would have synergistic activity in thyroid cancer, said Eric J. Sherman, MD, Assistant Attending in Solid Tumors at Memorial Sloan-Kettering Cancer Center.
He noted that unpublished work shows that mTORC1 is required for the growth-promoting effects of the oncoproteins RET/PTC, RAS, and BRAF in rat thyroid PCCL3 cells. Further work shows synergy of the mTORC inhibitors with RET kinase inhibitors in medullary thyroid cancer cell lines.
Sorafenib is active against multiple targets, including RAF, RET, vascular endothelial growth factor (VEGF) receptor 1, and VEGF receptor 2, and is approved for the treatment of radioactive iodine (RAI)-refractory and medullary thyroid cancer. “Sorafenib does a good job in treating thyroid cancer, and adding an mTOR inhibitor makes for good synergy,” he said in an interview.
In medullary thyroid cancer, there is good preclinical data that everolimus reduces RET completely. In Hürthle cell thyroid cancer, “genetic analysis of mutations is similar to what we see in temsirolimus-sensitive genes.”
Sherman reported on a Phase II single-institution study whose primary objective was response rate. Included were 41 patients, median age of 61, who had progressive, RAI-refractory/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-anaplastic thyroid cancer.
Sorafenib was given at 400 mg orally twice a day and everolimus at 5 mg orally once daily. Of the 41 enrolled patients, 36 were eligible for response. Seventeen patients are still actively on study. A mutational analysis of tissues is ongoing, he said.
“Medullary thyroid cancer patients showed little response to sorafenib alone. Adding in the mTOR inhibitor, we got a response rate of about 40 percent and progression-free survival [PFS] of 6.8 months. PFS lasts a long time for some—more than 30 months. Everolimus hits RET, so it makes sense.”
For patients with Hürthle cell thyroid cancer, there was zero response, with a PFS of 4.5 months with sorafenib alone. The two-drug therapy led to a 67 percent response and PFS of 12 months. Another one-third of patients now have stable disease.
“Five patients are still on active combination therapy for more than one year, with good responses,” Sherman said. These responses are so much better than what we normally see,” so patient selection could play a role in the results.
Grade 4 adverse events at least possibly related to drugs included alanine aminotransferase increase, hyperglycemia, and pancreatitis in one patient each.
He said his group now plans to conduct a randomized trial in Hürthle cell thyroid cancer comparing sorafenib with sorafenib plus everolimus. “For medullary thyroid cancer, we need to find the right combination of drugs. We might add in another RET inhibitor—either vandetanib or cabozantinib—with an mTOR inhibitor,” Sherman said.
The Discussant for the study, Vassiliki Papdimitrakopoulou, MD, Professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center, explained that preclinical evidence shows that mTORC1 is required for the growth-promoting effects of RET papillary thyroid cancer, and that mTOR inhibitors plus RET kinase inhibitors have activity in medullary thyroid cancer cell lines: “This trial demonstrates an interesting subset of Hürthle-cell thyroid cancer patients who have a dramatic response to the addition of everolimus.”
There has been a rising incidence of thyroid cancers, with a 2.4-fold increase between 1973 and 2002, she noted.
“Differentiated thyroid cancers comprise more than 90 percent of all thyroid cancers. The majority are cured with standard therapy with surgery, RAI, and thyroxine suppression. Recurrent disease occurs in 10 to 15 percent of patients, primarily in the neck or distant metastases in the lungs or bones. Patients who become RAI refractory have a loss of differentiation or an inability to trap RAI,” and chemotherapy with doxorubicin, platinum, and taxanes has produced only modest response rates.
Potential targets for differentiated thyroid cancer therapy include BRAF V600E and RAS mutations for papillary thyroid cancer and PPAR rearrangements, RAS mutations, and PI3KCA mutations in follicular thyroid cancer. “There has been an explosion of clinical studies in the last five years with multi-targeted tyrosine kinase inhibitors,” she said, noting that inhibitors of angiogenesis, such as VEGF, appear to have the most activity seen in clinical trials of multi-kinase inhibitors targeting VEGF receptors. Response rates range from five to 50 percent, with progression-free survival times of 32 weeks to 18 months.
Everolimus as a Single Agent for RAI-refractory Disease
Another presentation at the meeting examined the activity of everolimus as a single-agent therapy in patients with RAI-refractory thyroid cancer (Abstract 6023).
This open-label, Phase II study, reported by Jochen Lorch, MD, Assistant Professor of Medicine at Harvard Medical School, included 33 patients with metastatic, incurable RAI-refractory thyroid cancer who had shown radiographic progression within six months prior to enrollment. The patients received everolimus at 10 mg orally once a day. Responses were monitored by computed tomography scans every two months, and the primary endpoint was progression-free survival. Sequential biopsies were obtained in selected patients.
Included were 11 patients with Hürthle cell thyroid cancer, 10 with medullary thyroid cancer, and five with anaplastic thyroid cancer. PFS among the differentiated thyroid cancer patients was 16 months. Eighteen patients had stable disease for six months and 10 had stable disease for 12 months. Eleven patients remain on study.
The median overall survival has not been reached, but the one-year survival rate was 76 percent, Lorch reported. One patient achieved a partial response. Three patients with differentiated thyroid cancer underwent sequential biopsies, which revealed activation of autophagy while markers for apoptosis were not detected.
Of the 10 patients with medullary thyroid cancer, one had a partial response and nine had stable disease for at least six months (up to 33 months). Among the five anaplastic thyroid cancer patients, one patient achieved a complete response that lasted for more than 18 months and another patient has had ongoing disease stability for 10 months, Lorch said.
The most common treatment-related adverse events were as anticipated, he said: fatigue, stomatitis, and infections. Grade 3 events included infection, weight loss, leukopenia, thrombocytopenia, fatigue, hypophosphatemia, stomatitis, pneumonitis, and thrombosis. One patient had grade 4 hypercholesterolemia and another patient had grade 4 leukopenia.
In conclusion, Lorch said, “Everolimus has significant anti-tumor activity in patients with advanced thyroid cancer. Activation of autophagy could account for the high rate of disease stability.”
He noted that the study included patients with a poor prognosis and very aggressive disease that had progressed within six months. Sequencing may identify the mechanistic basis and predictive markers for treatment response, he said.
“TKIs work to some degree, but patients eventually become refractory and need more options. This study shows that everolimus is a very active drug and is proof of principle that the mTOR pathway is a significant, valuable target in this disease.”
The real surprise, though, he said, was the response in anaplastic thyroid cancer patients: “If these patients have the mutation, they will respond to this drug. Any patients with anaplastic thyroid cancer who are not responding to TKI, or have side effects such as bleeding that preclude taking a TKI, may be better off treated with everolimus.”
He said his group plans to conduct a randomized trial comparing everolimus and sorafenib in anaplastic thyroid cancer patients.
In her Discussant remarks, Papdimitrakopoulou commented that the PFS time of 16 months was “good” and the 76 percent overall survival rate was “respectable”—“The most dramatic result is with anaplastic thyroid cancer,” she said. “There was some toxicity, but there were notable somatic alterations. The drug activates the mTOR pathway in patients who responded. This is a very impressive finding that needs recapitulation in a clinical trial.”
In summarizing both trials, Papdimitrakopoulou said, “Everolimus has significant anti-tumor “activity in patients with advanced thyroid cancer. Activation of autophagy could account for the high rate of disease stability. Sequencing may identify the mechanistic basis and predictive markers for treatment response.
“There is impressive activity in anaplastic thyroid cancer, and further clinical trials are warranted,” she continued. “Combinations of targeted therapy may enhance activity, notably with sorafenib. The combination of sorafenib and everolimus shows promising results, especially in the Hürthle cell and medullary subgroups compared with use of sorafenib alone.”