Thursday, August 13, 2009

New Agents in Thyroid Cancer Trials Suggest Treatment Paradigm Shift is "Not Far Off"

June 25, 2008 — Several new agents have shown activity in refractory thyroid cancer in phase 2 clinical trials. As the process of translating these research advances into therapeutic benefits for patients continues, it appears that a related paradigm shift in the treatment of this cancer is "not far off."

This is the conclusion of David Pfister, MD, and James Fagin, MD, from the Memorial Sloan-Kettering Cancer Center, in New York, writing in an editorial published online June 9 in the Journal of Clinical Oncology.

The editorial was prompted by 2 papers published online at the same time. They detail, separately, the results from phase 2 clinical trials with axitinib (under development by Pfizer) and sorafenib (Nexavar, Bayer and Onyx; marketed for use in kidney and liver cancer). Preliminary data from these studies have already been reported by Medscape Oncology. The editorialists draw attention to several other agents that have shown activity in phase 2 studies in thyroid cancer, but to date they are published only as abstracts (they were presented at the American Society of Clinical Oncology 43rd Annual Meeting in 2007). These include motesanib (under development by Amgen), vandetanib (under development by AstraZeneca), and gefitinib (Iressa, AstraZeneca and Teva; marketed for non-small-cell lung cancer).

Rush of Activity in Contrast to Limited Interest in the Past

This rush of activity is in contrast to past limited interest in developing therapeutics for thyroid malignancies, the editorialists comment. This limited interest can be partly explained by the natural history of the disease, they say. The vast majority (>90%) of thyroid malignancies are differentiated tumors, and standard treatment with surgery and thyroid-stimulating hormone (TSH) suppression often suffices. In many cases, ablation of the thyroid remnant with radioactive iodine 131 (RAI) is added to complete the treatment. This collective strategy has an overall survival rate of about 90% at 20 years, and the prognosis remains very favorable even among patients who relapse. Indeed, many patients with recurrent disease, even when incurable, will have an indolent course over months or years, with few or no symptoms and no treatment other than TSH suppression.

In this clinical setting, the efficacy of chemotherapy drugs has been disappointing. They benefit only a minority of patients, and might have significant toxicity, the editorialists write. In fact, there is only 1 drug — doxorubicin — approved so far for use in thyroid cancer by the US Food and Drug Administration.

However, the favorable prognosis for most patients with thyroid cancer should not lead to complacency, the editorialists comment. "Some patients do much less well," they write, and "better drugs are clearly needed to treat refractory thyroid cancers."

Axitinib and Sorafenib Reports Bring "Welcome News"

The reports on axitinib and sorafenib show that both drugs are active in a population of patients with thyroid cancer resistant or refractory to RAI.

Although no complete responses were reported, a significant minority of patients had a major response to therapy (30% on axitinib and 23% on sorafenib), according to Response Evaluation Criteria in Solid Tumors (RECIST). Also, it appears that most patients with stable disease had some disease regression, albeit of an insufficient magnitude to fulfill partial-response RECIST criteria. This suggests that the reports of stable disease "reflected at least in part therapeutic effect rather than simply slow growth of the disease," the editorialists write. Median progression-free survival rates were similar in both studies (about 18 months).

However, both drugs had adverse effects, and these were not mild. Axitinib was associated with grade 3 or worse adverse effects in 32% of patients, and 13% of patients discontinued because of toxicity. With sorafenib, 47% of patients required dose reductions and 20% discontinued because of toxicities.

Drug tolerability is particularly important in this patient population, the editorialists comment; many of these patients will be relatively asymptomatic and rapid disease progression is not imminent.

The reports on axitinib and sorafenib bring "welcome news," Drs. Pfister and Fagin write. This represents the first wave of such reports, they add, pointing out that the phase 2 trials currently available only as abstracts should be published soon.

However, the editorialists also emphasize the need for confirmation of these data. "Well-designed clinical trials will be critical to realizing these benefits in a timely way."

The preferred mechanism for this would be a randomized comparison of each agent to a standard approach, making the potential benefits of each drug clear. Taking into consideration the natural history of the disease and the fact that cytotoxics have shown minimal efficacy, the editorialists argue that phase 3 trials in patients with RAI-refractory differentiated thyroid carcinomas should have a placebo control (with early stopping rules) and should look at freedom from progression or progression-free survival rather than overall survival, given the potential for indolent disease behavior.

Dr. Pfister reports receiving research funding from AstraZeneca and Exelixis.

J Clin Oncol. Published online before print June 9, 2008.

American Society of Clinical Oncology 43rd Annual Meeting: Abstracts 6017, 6018, and 6020. Presented June 1–5, 2007.

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