Data presented at ASCO from the phase III DECISION trial showed treatment with the TKI sorafenib (Nexavar) delayed disease progression by 5 months in patients with metastatic differentiated thyroid cancer that had progressed on radioactive iodine.
Ball-and-stick model of sorafenib
At the 2013 meeting of the American Society of Clinical Oncology (ASCO), there were promising results for patients with metastatic differentiated thyroid cancer (DTC) refractory to standard treatment with radioactive iodine (RAI). Investigators from the international randomized phase III DECISION (Study of Sorafenib in Locally Advanced or Metastatic Patients With Radioactive Iodine Refractory Thyroid Cancer) trial found treatment with the multitargeted tyrosine kinase inhibitor (TKI) sorafenib (Nexavar), which inhibits tumor growth signaling and angiogenesis, delayed disease progression by 5 months in patients with metastatic DTC that had progressed on RAI therapy.
Sorafenib, an oral agent targeting VEGFR1–3, PDGFRB, BRAF, RET, and c-Kit, is approved by the US Food and Drug Administration (FDA) to treat advanced cancers of the kidney and liver. A news release in mid May from ASCO, describing the DECISION study and its results, noted that if sorafenib is approved by the FDA for treatment of RAI-refractory DTC, “[it] would become the first new active drug for this form of thyroid cancer in 40 years.”
At the ASCO meeting, DESCISION trial investigator Marcia S. Brose, MD, PhD, highlighted the study results (plenary abstract 4) and their potential for improving care in this patient population. Dr. Brose is assistant professor of otolaryngology and head and neck surgery and director of the Thyroid Cancer Therapeutics Program at the Abramson Cancer Center, University of Pennsylvania, Philadelphia. The study was completely funded by the University of Pennsylvania, with only the study drug provided by Onyx and Bayer.
Dr. Brose explained that thyroid cancer is the most common type of endocrine cancer, with an estimated 60,000 new cases and 1,850 deaths from the disease in the United States in 2013. The three main subtypes of thyroid cancers are anaplastic, medullary, and differentiated, with differentiated cancers being most common. “The vast majority of these will be [DTC]-that accounts for over 80% [of cases]. The majority of patients diagnosed with [DTC] will be cured by standard treatment involving surgery [thyroidectomy] and radioactive iodine, to suppress thyroid stimulating hormone (TSH), which acts as a growth hormone for these tumors. However, between 5% and 15% of patients with [DTC] will develop resistance to radioactive iodine, and once this happens, the overall survival for these patients drops to 2.5 to 3.5 years, and…clinically significant in this patient population is that a continuous progression of their disease results in significant morbidity, with frequent bone, pulmonary, and brain complications,” she said. “Thus, radioactive iodine–refractory thyroid cancer represents an orphan cancer.”
Currently, she emphasized, “there are no treatment options for patients, and the standard of care has been palliative care, or more recently, referral to a clinical trial.”
DECISION was carried out by oncologists at 89 cancer centers in the United States (at the University of Pennsylvania and the University Texas MD Anderson Cancer Center), Europe (at centers in the United Kingdom, Italy, France, Germany, Poland, the Netherlands, and Denmark), and Asia (at the University of Ulsan College of Medicine, Seoul, South Korea).
Conducted from October 2009 to July 2011, DECISION enrolled 417 patients who had locally advanced (4%) or metastatic (96%) RAI-resistant DTC (with at least one target lesion without RAI uptake, or progression following a treatment dose of RAI, or a cumulative lifetime RAI treatment dose ≥ 600 mCi) that had progressed (based on RECIST criteria) in the preceding 14 months, and had not received prior chemotherapy, targeted therapy, or thalidomide, since the trial was designed to assess the efficacy of sorafenib in the first-line setting. Patients also had to have adequate TSH suppression (with TSH levels < .5 mU/L), as part of the standard of care for patients with persistent metastatic thyroid disease. Enrolled patients were required not to be candidates for surgery or radiotherapy with curative intent; to have adequate bone marrow, liver, and renal function; and to have an ECOG (Eastern Cooperative Oncology Group) performance status of 0–2. Median patient age was 63 years, and 52% of patients were female. Independent tumor histology showed 57% papillary, 25% follicular, and 10% poorly differentiated disease.
Patients were randomized 1:1 to sorafenib at 400 mg bid (n = 207) or placebo (n = 210). The experimental and control groups “were well balanced with regard to gender, age, region [of disease] and performance status,” Dr. Brose said. Crossover from placebo to open-label sorafenib upon disease progression at the investigator’s discretion was allowed.
Regarding dosing on trial, Dr. Brose pointed out that “the dose-reduction scheme for adverse events was modified from prior studies to include a mean 75% dose rate…to allow us to increase the ability to manage adverse events while minimizing the decrease in active drug.” She reported that 64.3% of patients on the sorafenib arm required a dose reduction, compared with 9.1% of patients on placebo. Permanent discontinuation from the study occurred in 18.8% of patients in the sorafenib arm vs 3.8% of patients on placebo. The mean dose that patients received was 651 mg in the sorafenib arm vs 793 mg in the placebo arm, but mean treatment duration was about twice as long in the sorafenib arm vs the placebo arm (about 40 weeks vs about 20 weeks, respectively), Dr. Brose said.
The primary endpoint, progression-free survival (PFS), was assessed every 8 weeks by independent radiologic review using modified RECIST 1.0 criteria. Secondary endpoints included overall survival (OS), response rate (which included both complete responses and partial responses), and safety.
Median PFS was 10.8 months with sorafenib group vs 5.8 months with placebo (hazard ratio [HR] 0.58; P < .0001). This short PFS in the placebo group “reflects that, unlike radioiodine-sensitive disease that can be indolent, the patients that were enrolled on DECISION represent a group of patients with clearly progressing disease,” Dr. Brose noted.
The response rate (all partial responses, defined as tumor shrinkage of 30% or greater) in the sorafenib vs placebo arms was 12.2% and 0.5%, respectively (P < .0001). Tumor shrinkage of any degree was seen in 73% of patients on sorafenib vs 27% of patients on the placebo arm. An important point, Dr. Brose emphasized, is that “while tumor shrinkage may not always reach the 30% cutoff for partial response, the shrinkage observed was often sufficient to alleviate symptoms in the symptomatic patients.” In the sorafenib arm, 42% of patients had stable disease for 6 months or longer compared with 33% in the placebo arm (for a disease control rate of 54% with sorafenib vs 34% in the placebo arm; P < .0001). “The median duration of partial responses [with sorafenib] was 10.2 months, which is close to the median [PFS] in this study,” Dr. Brose commented. OS has not been reached in either arm. About 70% of patients on the placebo arm have crossed over to the sorafenib arm, Dr. Brose said.
Adverse events (any grade) were generally manageable with over-the-counter medications and reflected some known toxicities of sorafenib; they included hand–foot skin reaction, diarrhea, alopecia, rash/desquamation, fatigue, weight loss, and hypertension. The most frequent serious adverse events reported in the double-blind period of the study included secondary malignancy, which was 4.3% in the sorafenib arm vs 1.9% in the placebo arm. “This difference is accounted for entirely by the incidence of squamous cell carcinoma of the skin, a known side effect of sorafenib and easily controlled,” Dr. Brose said. Two drug-related deaths, one in the sorafenib arm and one in the placebo arm, occurred during the double-blind period.
“In conclusion, sorafenib is a potential new treatment option for patients with locally active or metastatic radioiodine-refractory differentiated thyroid cancer,” Dr. Brose said. She noted that DECISION investigators are planning further data analysis to identify markers predictive of response to sorafenib. Because most patients will progress following treatment with sorafenib, she indicated that the study results serve as a starting point for development of newer treatment options for second-line therapy and beyond in these patients.
At ASCO, the DECISION trial findings were discussed by Ezra E.W. Cohen, MD, associate professor, department of medicine, and co-director of the Head and Neck Cancer Program, University of Chicago Comprehensive Cancer Center. In beginning his evaluation of the clinical impact of the DECISION trial results, Dr. Cohen commented on the title of his discussion, “Decisions in Thyroid Cancer: Patients Finally Have Options,” noting that treatment options for this disease truly have expanded in recent years, and patient management in 2013 “is very much different from the scenario for this disease even a just a few short years ago.”
He said that the incidence of thyroid cancer globally is “increasing dramatically,” and that thyroid cancer, “irrespective of gender or race, is one of the fastest-growing cancers that we have in the United States,” and “is coupled with an increase in mortality,” but the full explanation for this is as yet unknown. He noted that thyroid cancer is still a very curable malignancy, though, with most patients surviving their disease, with the exception of selected patients, such as those with DTC who develop refractory disease, for whom prognosis is poor.
For most of the last 40 years, however, treatment options in this setting have been limited, with systemic chemotherapy therapy with doxorubicin (Adriamycin) used in the treatment of certain patients with treatment-refractory DTC. “[Doxorubicin] became the approved drug for differentiated thyroid cancer, and truly the only thing that we had at our disposal for decades.” However, he added “[it] was hardly used for these patients, not only because of its toxicity but because of the feeling that its efficacy was less than desirable.”
The scenario of thyroid cancer management began to change dramatically just a few years ago, he said, beginning with several phase II trials assessing the efficacy of VEGF receptor inhibition in the setting of DTC-using agents such as axitinib (Inlyta), lenvatinib (E7080), motesanib (AMG 706), pazopanib (Votrient), sorafenib, and sunitinib (Sutent)-and with a number of studies showing activity, with response rates ranging from 15% to 50%, and a median PFS of about 1 year. “Clearly this is a class of agents that is active in this disease,” he said. In fact, he added, a randomized double-blind phase II study of vandetanib (Caprelsa) vs placebo (Leboulleux et al. Lancet Clin Oncol. 2012;13:897–905) has shown that treatment with active drug extended PFS in patients with locally advanced or metastatic DTC (with a median PFS of 11.1 months for patients in the vandetanib group vs 5.9 months for patients on placebo; P = .008).
The intriguing question, then, said Dr. Cohen, is “Why do VEGF receptor inhibitors work in DTC?” While patients with DTC commonly have a very high rate of mutations in BRAF, RAS, or PIK3CA, he said, studies indicate that “the presence of these mutations does not seem necessary nor sufficient for activity of [VEGFRi agents] in patients with these mutations.” In fact, he said, his colleague Dr. Rebecca B. Schechter, in a poster session at ASCO this year (abstract 6066, which assessed possible correlations of genetic profiling data and response to axitinib in advanced RAI-resistant DTC), reported a study that demonstrated no evidence of putative VEGFR mutations or amplifications in the tumors of patients with DTC. “It doesn’t appear, at least in the studies that have been performed so far, that a genomic-level alteration explains the activity [seen with VEGFRi].”
Regarding the effect of VEGFRi on tumor angiogenesis, he noted that, “enigmatically,” while DTCs are highly vascular and express VEGF and VEGFR, ligand-directed therapy (such as with ziv-aflibercept [Zaltrap] or bevacizumab [Avastin]) is not effective.
Now, availability of the DECISION study results “begs the question, ‘Is sorafenib the new standard of care for differentiated thyroid cancer?’ ” Commenting on the promising activity in terms of PFS and the overall manageable adverse events seen in this trial, Dr. Cohen noted that, nevertheless, sorafenib does not appear to induce complete responses. He also said that it is unlikely that an OS benefit will be seen in DECISION, since patient crossover was allowed and most of the patients on placebo crossed over to the sorafenib arm. In addition, he emphasized that not all iodine-refractory patients need treatment, commenting that at 400 days on the DECISION trial, about 25% of the placebo-group patients did not have disease progression. Dr. Cohen also noted that most “most refractory [DTC] patients are asymptomatic.”
The question, he said, becomes “whom to treat and when,” commenting that this will depend on factors such as patient symptoms, the location of disease, and the growth rate of anatomic disease. Because progression of DTC patients on sorafenib or treatment with another targeted TKI is “not unusual,” of course the question of how to treat refractory patients must be addressed, said Dr. Cohen.
He described several interesting clinical trials in thyroid cancer that are being developed or already underway, including a phase I/II trial of cediranib with or without lenalidomide that is still accruing but so far has shown a high tumor response rate; a phase III multicenter randomized double-blind trial of lenvatinib in RAI-refractory DTC which has completed accrual, and the results of which he said will likely reinforce the DECISION trial findings with sorafenib; and a trial reported in the New England Journal of Medicine in February by Dr. Alan Li Ho (with colleagues from Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College; N Engl J Med. 2013;368:623–632) of the MEK inhibitor and radiosensitizer selumetinib (AZD6244) in advanced thyroid cancer, with most of the responding patients having Ras or BRAF mutations. Noting that “60% of papillary thyroid cancers harbor V600E BRAF,” Dr. Cohen also suggested vemurafenib (Zelboraf) may be an option for selected patients with thyroid cancer.