The randomized phase III DECISIONstudy, which was supported in part by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, finds that the targeted drug sorafenib (Nexavar?; Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals) stalls disease progression by five months in patients with locally advanced or metastatic differentiated thyroid cancer or DTC that has progressed despite standard radioactive iodine (RAI) therapy. The results of the trial were presented during the 49th Annual Meeting of the American Society of Clinical Oncology(ASCO)being held in Chicago, Ill. May 31 – June 4, 2013.

If approved by the FDA, sorafenib will be the first new active drug for this form of thyroid cancer in 40 years.

Thyroid cancer has become the fastest-increasing cancer in the world in recent years and is the sixth most common cancer in women. There are more than 213,000 new cases of thyroid cancer annually and approximately 35,000 people die worldwide each year.

Papillary, follicular and H?rthle cell types of thyroid cancer are classified as ?differentiated thyroid cancer?. This is the mostcommon subtype of thyroid cancer, accounting for about 85% of the 60,000 thyroid cancer cases diagnosed each year in the United States. While the majority of differentiated thyroid cancers are very treatable, RAI-refractory locally advanced or metastatic disease is more difficult to treat and is associated with a lower patient survival rate. Roughly 5-15% of patients develop RAI resistance.

Sorafenib extends progression-free survival for patients with differentiated thyroid cancer that is resistant to standard radioiodine therapy

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?While most patients with differentiated thyroid cancer are cured, there is a major treatment gap for patients whose cancer no longer responds to standard therapies, suffer from progression and ultimately die of their disease,” said Marcia Brose, M.D., Ph.D., lead study author, principal investigator of the DECISION trial and Assistant Professor in the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania, PA. “The DECISION trial results demonstrate for the first time that sorafenib may extend the progression free period for thyroid cancer patients.”

Treatment options
Based on the approved clinical recommendations from the European Society of Medical Oncology(ESMO) Guidelines Working Group, initial treatment of DTC includes careful exploration of the neck by ultrasound to assess the status of lymph node chains. This is followed by total or near-total thyroidectomy whenever the diagnosis is made before surgery, when the nodule is ?1 cm, or, regardless of the size of the nodule, if there is metastatic, multifocal or familial DTC.[1]

In most cases surgery is followed by the administration of 131I, a process which is designed to ablate any remnant thyroid tissue and potential microscopic residual tumor. This procedure decreases the risk of locoregional recurrence and facilitates long-term surveillance based on serum Tg measurement and diagnostic radioiodine whole body scan or WBS.[1]

Based on the “Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer” developed by the American Thyroid Association Guidelines Task-force, chemotherapy has modest benefit in patients with RAI resistance. [2]

Patients with progressive disease should first be considered for clinical trials. However, if there are no clinical studies ongoing or the patient prefers standard cytotoxic chemotherapy, doxorubicin, used as a single agent is only approved treatment for patients with RAI resistance.[2]

Increased toxicity
When dosed appropriately, doxorubicin monotherapy may be effective in up to 40% of patients (most partial response or stable disease)(60?75 mg/m2 every 3 weeks), but, in general, durable responses are uncommon. As a result of low efficacy and increased (high) toxicity, this option is rarely used.

The DECISION (stuDy of sorafEnib in loCally advanced or metastatIc patientSwith radioactiveIodine refractory thyrOid caNcer) trial was the first international, multicenter, placebo-controlled studyassessing a kinase inhibitor for the treatment of RAI resistance locally advanced or metastatic differentiated thyroid 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,? Brose said. ?For these patients, a longer progression-free survival 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.?

In this study, 417 patients with metastatic, RAI-resistant differentiated thyroid cancer were randomly assigned to receive sorafenib or placebo. Patients were allowed to cross over to the sorafenib arm upon disease progression. The median progression-free survival was 10.8 months in the sorafenib group vs. 5.8 months in the placebo arm. Tumor shrinkage of 30% or more was observed in 12.2% and 0.5% of patients in the sorafenib and placebo arms, respectively. An additional 42% of patients in the sorafenib arm had stable disease for 6 months or longer for a disease control rate of 54%, compared with a disease control rate of 34% in the placebo arm. Overall survival data are not yet mature.

There was no statistically significant difference in overall survival between treatment arms, which was expected due to the cross-over design of the study. After progression, patients receiving placebo had the option to begin open-label sorafenib at the discretion of the investigator. A total of 71% of placebo patients ultimately began open-label sorafenib during the trial. Median overall survival has not yet been reached in either arm.

Safety and tolerability in the study were generally consistent with the known profile of sorafenib. The most common treatment-emergent adverse events in the sorafenib arm were hand-foot skin reaction, diarrhea, alopecia, rash/desquamation, fatigue, weight loss and hypertension.

Renewed hope
?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 progression-free survival. Future studies will help identify which patients can benefit most from this therapy, and how other targeted therapies may further improve the outcome for these patients,? said Gregory Masters, MD, head and neck cancers expert and ASCO spokesperson.

Further analysis of data from this clinical trial is planned to find markers that w
ould help identify patients that respond well to sorafenib and those that may need additional therapy. Unfortunately, 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 and beyond.

Sorafenib is a multi-targeted drug that blocks two distinct proteins ? Raf kinase and VEGF receptor kinase ? which control tumor cell division and growth of tumor blood vessels, respectively. The drug is already approved by the FDA for the treatment of advanced kidney cancer and inoperable liver cancer.

?Already the standard of care in HCC and an important treatment option in RCC [a], sorafenib?s utility may also be extended to differentiated thyroid cancer given these positive trial results,? said Kemal Malik, M.D., Member of the Bayer HealthCare Executive Committee and Head of Global Development. ?This trial is representative of our continued commitment to fully understanding sorafenib?s applicability across tumor types, especially in hard-to-treat cancers where there are limited treatment options.?

Bayer plans to submit the Phase III DECISION data as the basis to apply for marketing authorization of sorafenib in the treatment of RAI-refractory differentiated thyroid cancer.

[1] Pacini F, Castagna MG, Brilli L, Pentheroudakis G. Differentiated thyroid cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol (2009) 20 (suppl 4): iv143-iv146.
doi: 10.1093/annonc/mdp156 [Abstract]
[2]Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2006 Feb;16(2):109-42.[Full Article]
[a] Sorafenib is approved for the treatment of hepatocellular carcinoma (HCC) and for the treatment of patients with advanced renal cell carcinoma (RCC) who have failed prior interferon-alpha or interleukin-2 (rIl2) based therapy or are considered unsuitable for such therapy.

For more information:
Abstract #4: Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial.
Plenary Session Study Author: Marcia Brose, MD, PhD, of Medicine at the University of Pennsylvania, Abramson Cancer Center, Perelman School, School of Medicine, Philadelphia, PA
Date: Sunday, June 2, 2013, 3:20 ? 3:35 PM CDT
Location: Room: N Hall B1

Clinical Trial
NCT00984282– Nexavar? Versus Placebo in Locally Advanced/Metastatic RAI-Refractory Differentiated Thyroid Cancer

Photo:Marcia Brose, M.D., Ph.D., lead study author, principal investigator of the DECISION trial and Assistant Professor in the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania, PA.Photo Courtesy:?ASCO/Silas Crews

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