PHILADELPHIA—In the era of precision medicine, targeting the mutations driving cancer growth, rather than the tumor site itself, continues to be a successful approach for some patients. In the latest example, researchers from Penn Medicine and other institutions found that treating metastatic thyroid cancer patients harboring a BRAF mutation with the targeted therapy vemurafenib — originally approved for melanoma patients with the mutation — showed promising anti-tumor activity in a third of patients. The results were published in this week’s Lancet Oncology.
The phase II clinical study included results from 51 patients enrolled at 10 centers around the world with progressive, radioactive iodine-refractory (RAI) papillary thyroid cancer and a BRAF mutation who were no longer responding to prior therapies. After a 15-month follow up, 16 patients from two cohorts had partial responses, with an overall response rate of 38 and 27 percent in each of two cohorts.
“For this group of patients, who have little to no options, that’s a significant improvement,” said Marcia Brose, MD, PhD, an associate professor of Otorhinolaryngology: Head and Neck Surgery and Hematology/Oncology and director of the Center for Rare Cancers and Personalized Therapy and Penn’s Abramson Cancer Center. “This promising clinical trial is the next step in a series of trials to identify new drugs that are fundamentally shifting the horizon – improving the outcome for patients with advanced differentiated thyroid cancer.”
About 62,450 people were diagnosed with differentiated thyroid cancer in 2015. BRAF mutations, which occur in about 40 to 50 percent of these patients, have been associated with aggressive tumors and decreased ability of tumors to respond to radioactive iodine, typically the first line of treatment in these patients.
Patients are often cured by surgery, without or without RAI, but 50 percent of them with residual, recurrent or metastatic ultimately do not respond to RAI. Vemurafenib joins other multi-targeted kinase inhibitors (MKIs) (sorafenib, lenvatinib) shown to be effective in this patient population; in spite of responses to these drugs, the responses are temporary and additional treatment options are needed.
For the study, researchers enrolled a total of 51 patients between January 2011 and January 2013. Patients in cohort one (26 patients) had not been previously treated with MKIs, while patients in cohort (25) were treated with MKIs. Some in both groups had previously been treated with chemotherapy as well.
In cohort one, 10 patients had a partial response to vemurafenib, and an additional nine achieved stable disease for at least six months, for a combined disease control rate of 73 percent. The median progression free survival was 18.2 months.
In cohort two, which had patients that were heavily pretreated, six patients had a partial response, and six achieved stable disease for at least six months, for a combined disease control rate of 54.5 percent. The median progression free survival was 8.9 months and median overall survival was 14.4 months.
Overall, the side effects experienced by the patients were consistent with that of melanoma patients, except for the higher rates of weight loss, dysgeusia (distortion of taste), anaemia (lack of iron), increased creatine levels, and hepatic laboratory abnormalities. ”Due to our prior successes in treating these patients with sorafenib and lenvatinib, patients are doing better, but they still ultimately progress, and we need additional agents with different mechanisms of action,” Brose said. “Vemurafenib is the first non-VEGFR inhibitor to show activity in this patient population and as such is an important addition to our treatment options for these patients.”
Co-authors on the study include Maria E. Cabanillas and Steven I. Sherman, from MD Anderson Cancer Center, Ezra E. W. Cohen from the University of San Diego, La Jolla, Lori J. Wirth from Massachusetts General Hospital, Todd Riehl and Huibin Yue from Product Development Clinical Oncology and Biostatistics, and Eric J. Sherman from Memorial Sloan Kettering Cancer Center.
The study was funded by F. Hoffmann-La Roche.
##Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.
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