Roxanne Nelson

June 02, 2013

CHICAGO — The targeted agent sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals) could become the first new drug for metastatic thyroid cancer in 40 years and opens up a new field in medical oncology, says the lead author of a study presented here at a plenary session of the 2013 Annual Meeting of the American Society of Clinical Oncology.

"Up until now, patients in this population haven't even come to medical oncology because there wasn't any treatment for them," commented Marcia Brose, MD, PhD, an 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.

She explained that this is really the beginning of a new field in medical oncology. Previously, thyroid cancer was generally treated by endocrinologists because medical oncology had no effective treatments once a patient became resistant to radioactive iodine.

Thyroid cancer has a reputation of being a "good cancer" because it can be easily cured, Dr. Brose explained. "But that's only for 90% of the patients, and for the other 10%, it will kill them eventually. Once surgery can no longer be used and the tumor no longer takes up radioactive, overall survival drops to about 2 and a half to 3 years."

"It is now important for the doctors who see these patients early on to refer them to medical oncologists, because now we have a treatment," said Dr. Brose. "For medical oncologists, it is important for them to know that we now have a treatment, and hopefully our data will lead to FDA approval."

Dr. Marcia Brose

Dr. Brose presented results from a phase 3 clinical trial, known as DECISION, in 417 patients with progressive RAI-refractory differentiated thyroid cancer. The results show a significant improvement in median progression-free survival to 10.8 months in the sorafenib group compared with 5.8 months in the placebo arm.

Sorafenib has been used off label for this purpose, Dr. Brose noted, but some physicians are not comfortable prescribing off label. "But the added level of rigor from a pivotal phase 3 study that is not just positive but highly significant — a doubling of progression-free survival — will hopefully help more physicians feel comfortable prescribing it," she said.

Chemotherapy Not Effective

"Conventional cytotoxic chemotherapy has not been effective in the management of differentiated thyroid cancers in spite of significant toxicities," commented Yujie Zhao, MD, PhD, assistant professor of oncology, Roswell Park Cancer Institute, Buffalo, New York.

"This randomized, placebo-controlled phase 3 study confirmed previous phase 2 results and also demonstrated a statistically significant progression-free survival improvement of 5 months compared with the placebo arm," said Dr. Zhao, who was not involved in the study.

Dr. Zhao noted that because stable disease of 6 months or longer was also seen in 33% of patients who received placebo, this suggests the importance of proper selection of patients who need treatment.

Sorafenib blocks the enzyme RAF kinase, which is a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation, and it also inhibits the VEGFR-2/PDGFR-beta signaling cascade. It is currently approved to treat hepatocellular carcinoma and advanced renal cell carcinoma.

The primary endpoint of the study was progression-free survival, which was assessed every 8 weeks. Secondary endpoints included overall survival, response rate (complete and partial response), and drug safety.

Within the cohort, tumor histology was 57% papillary, 25% follicular, and 10% poorly differentiated, and the vast majority (96%) of patients had metastatic disease. The most common target lesions were lung (71%), lymph node (40%), and bone (14%).

The authors note that their primary endpoint of progression-free survival was met (hazard ratio, 0.58; P < .0001). The median overall survival has not yet been reached in either study arm, and 70% of placebo patients have started open-label sorafenib.

All reported responses were partial — 12.2% in the sorafenib group vs 0.5% for placebo (P < .0001). Stable disease ≥ 6 months was 42% and 33%, respectively.

Tolerability was consistent with the known sorafenib safety profile, the authors note. 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. There was 1 death in each study arm that was attributed to sorafenib use.

For Select Patients

"There is a huge unmet need for an effective treatment in this population," said Lori Wirth, MD, who was approached by Medscape Medical News for an independent commentary. "While this is a relatively uncommon disease, patients do live for years with it, so there is a sizeable population in need of treatment."

"This was a positive study, and I believe that it will be adapted as standard of care in this population," said Dr. Wirth, medical director, Center for Head and Neck Cancers, Massachusetts General Cancer Center, Boston.

However, Dr. Wirth pointed out that this study was designed for patients with progressive disease. "That means that there is a caveat to the excitement over these results," she said. "There was toxicity associated with this treatment, and so it may not be suitable for every patient."

This type of cancer is a "grab bag of different pathologies," she continued, and she noted that some patients will have a low disease burden and be asymptomatic. "Disease progression may not occur for a while, and while sorafenib may shrink the tumor, it can affect their quality of life."

"Patients with a large tumor burden, and for those with symptoms, they will need treatment, and we can justify the side effects," Dr. Wirth explained. "But we need to differentiate who needs to be treated and who doesn't."

This research was supported in part by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc. Dr. Brose and several coauthors report relationships with industry, including Bayer and Onyx, as noted in the abstract.

2013 Annual Meeting of the American Society of Clinical Oncology. Abstract 4. Presented June 2 2013.


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