FACT: Addition of CA4P in combination therapy improved OS in anaplastic thyroid cancer

2011 ASCO Annual Meeting

Chicago ¡ª Combination therapy with carboplatin, paclitaxel and combretastatin A4 phosphate, a tubulin binding vascular disrupting agent, was shown to reduce the overall risk of death by 35% in patients with anaplastic thyroid cancer, according to FACT study results presented here.

FACT is the largest prospective randomized trial conducted in ATC. CA4P had previously demonstrated a survival benefit when added to these agents in phase 2/3 studies. Results included final survival and safety data compiled from 40 sites in 11 countries.

"This is a rare cancer," said Julie A. Sosa, MD, associate professor of surgery and medicine and director of the Yale Endocrine Surgery Clinical and Health Services Research Group. She presented results at the 2011 ASCO Annual Meeting. "In the United States each year, it is estimated that there are fewer than 1,000 patients diagnosed with ATC. Unfortunately there are no effective treatments for anaplastic thyroid cancer. The combination of surgical resection, external beam radiation and chemotherapy have not resulted in significant improvements in overall survival once ATC has escaped the boundaries of the thyroid gland."

In the multicenter, open-label 2:1 randomized trial, 80 patients with histologically confirmed ATC were randomized to receive carboplatin (AUC 6 IV), paclitaxel (200 mg/m²) with CA4P (60mg/m²) or without CA4P (control group) for up to six cycles every 3 weeks. After six cycles of therapy, patients in the treatment group who did not show disease progression continued on treatment with CA4P until progression.

The primary objective was OS; secondary objectives were PFS, 1-year survival and safety. Seventy-five patients were followed up for a median of 4.7 months (range, 0.1 to 32.6 months).

The intent-to-treat analysis showed median survival in the treatment group was 5.2 months vs. 4 months in the control group (HR=0.72; 95% CI, 0.43-1.20). One-year survival was 25.5% in the treatment group, compared with 8.7% in the control group (P=0.065, Fisher¡¯s exact test). The results suggest that ¡°there was a 28% reduction in the risk of death with the addition of CA4P,¡± Sosa said.

In a pre-specified analysis of OS in patients ¡Ü 60 years, the median OS was 10.6 months for the treatment arm and 3.1 months for the control group, demonstrating a significant risk reduction of 62% (HR=0.38; 95% CI, 0.17-0.85). Another pre-specified analysis of OS in patients with tumors ¡Ý 6 m showed a median OS of 5.7 months in the treatment group and 3.9 months in the control group (HR=0.71; 95% CI, 0.33-1.53), with a risk reduction of 29%.

The treatment was generally well-tolerated. Adverse events reported in the treatment group included grade 1/2 hypertension and grade 3/4 neutropenia. Reported deaths were attributed to disease progression; two additional patients died from disease-related complications. -by Carey Cowles

For more information:

• Sosa J. #5502. Presented at: 2011 ASCO Annual Meeting; Chicago; June 3-7, 2011.

Disclosure: Dr. Sosa reported no relevant financial disclosures.

The results that Dr. Sosa presented suggest activity of combretastatin may be present in addition to paclitaxel and carboplatin and are worth pursuing in a larger trial. However the results also support activity that may be centered in a subset of patients with larger tumors or younger patients. This may be a consideration in future trials, for risk stratification. In order to do a very large trial It will be important to enroll as many people as possible and include as many sites and countries as possible. Due to the difficulty in completing these trials, success will require cooperation of the global community to execute and complete clinical trials for ATC if any progress is to be made.

- Marcia Brose, MD, PhD
Director of Thyroid Cancer Therapeutics Program,
Abramson Cancer Center, The University of Pennsylvania

Disclosure: Dr. Brose reported a consultant or advisory role with Bayer, Bristol-Myers Squibb, Exelixix and Onyx; honoraria from Onyx; and research funding from Bayer Schering Pharma, Exelixix and Novartis.

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