Sequencing Therapies in Differentiated Thyroid Cancer

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In November 2013, the FDA approved sorafenib as a treatment of patients with radioactive iodine (RAI)-resistant metastatic differentiated thyroid cancer (DTC). This approval was based a substantial prolongation in progression-free survival (PFS) experienced by patients in the DECISION trial, which evenly randomized 417 patients to either sorafenib (n = 207) or placebo (n = 210), notes Ezra Cohen, MD.

In the DECISION trial, the median PFS was 10.8 months with sorafenib compared to 5.8 months with placebo (HR=0.58; P <.0001). Tumor reduction was seen in 70% of sorafenib-treated patients versus 28% in the placebo arm, Cohen says. The rates of all-grade side effects were higher with sorafenib compared with placebo. The most frequent all-grade sorafenib-related adverse events were hand-foot syndrome (76% of patients), diarrhea (68%), alopecia (67%), and rash or desquamation (50%).

Following the FDA approval, sorafenib has become a standard first-line therapy for patients with advanced RAI-resistant DTC, notes the trial’s lead investigator Marcia S. Brose, MD, PhD. However, despite the improvement seen with this drug, patients eventually progress. If a patient shows signs of progression in multiple sites, treatment with a new systemic therapy or a clinical trial should be considered.

If progression is only apparent in one location, such as a bone or lymph node, then local therapy can adequately treat the disease and sorafenib can be continued, Brose states. It is important to involve a multidisciplinary team when deciding to treat progressive disease in this fashion, notes Naifa L. Busaidy, MD. This is particularly true if the treatment involves surgery or radiation, since the pharmacokinetics of the drug may impact the healing process.

Other TKIs have demonstrated promise in DTC; however, they are not yet FDA approved. In some situations, off-label treatment could be considered, although a clinical trial likely remains the optimal option. Pazopanib or sunitinib could be administered off-label following progression on sorafenib, notes Manisha H. Shah, MD. However, systemic data on this sequence is not available.

To address the second-line setting, a phase II study is exploring cabozantinib in patients with RAI-refractory DTC following progression on a VEGF-targeted therapy, Shah notes. The primary endpoint of this study is overall response rate with secondary endpoints focused on survival.

Without data it is difficult to determine which therapies would be effective in the second-line setting, since tumors change in response to treatment, Brose says. The VEGF agents pazopanib, axitinib, and sunitinib could be administered, but their efficacy is unclear. In general, diminishing returns can be expected as therapies move into the second- and third-line, notes Brose.

In a clinical study exploring the TKI lenvatinib, the median PFS across several lines of therapy was 18.3 months with 65% of patients experiencing tumor shrinkage. In patients who received prior VEGF therapy (n = 66), the PFS was 15.1 months. This observation provides some clues toward potential sequences, Brose suggests.

Now that several therapies have demonstrated promise, the next area of research will examine optimal sequences, notes Brose. Studies are still needed to cull out the final answer.