Disease-Related Variables Predictive of Outcomes With Sorafenib in DTC

Martin Schlumberger, MD

Numerous disease-related variables could serve as prognostic and predictive factors for treatment outcomes with sorafenib (Nexavar) in patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (RAI-rDTC), according to a new multivariate Cox model analysis of the DECISION trial data presentation by Martin Schlumberger, MD, at the 2014 ATA Annual Meeting.

"Patients with RAI-rDTC have a poor prognosis, and there is a lack of effective treatments. Median survival for patients with metastatic RAI-rDTC is estimated to be 2.5 to 3.5 years," explained Schlumberger, of the Service de Médecine Nucléaire et Cancérologie Endocrinienne, Gustave Roussy, in Villejuif, France. “Overall, subgroup analyses indicated that patients whose maximum individual target tumor size was <1.5 cm had a longer progression-free survival and appeared to have less benefit from sorafenib treatment than patients with lesions ≥1.5 cm. Additionally, lesions >1.5 cm, as well as lung-only metastases with no bone metastases, were predictive for better treatment effect with sorafenib.”

The FDA approved sorafenib in November 2013 for the treatment of RAI-rDTC based on the results of the phase III, randomized, placebo-controlled, double-blind DECISION trial. In the trial treatment with sorafenib extended the median progression-free survival (PFS) time by 5 months, from 5.8 months with placebo to 10.8 months with sorafenib (HR = 0.59; 95% CI, 0.45-0.76, P <.0001). In a predefined subgroup analysis, sorafenib showed benefit across all patient subgroups. Specifically, BRAF and RAS mutations were not independently prognostic of outcome, nor did these mutations predict PFS benefit from sorafenib.

In the new analysis, a number of baseline or disease-related variables were prognostic for longer PFS for all patients enrolled in the study. These included papillary histology, individual target lesion size <1.5 cm, a lower tumor burden, baseline thyroglobulin levels below the median (486 ng/mL), site of metastases (lung-only), and geographic region (Asia versus Europe or North America).

Tumor burden and histology were both prognostic and predictive factors for PFS in patients treated with sorafenib. The relative benefit of sorafenib increased in patients with a higher tumor burden. Patients with maximum target lesions <1.5 cm appeared to derive less benefit in terms of relative risk in PFS from sorafenib treatment.

Papillary histology was a positive prognostic factor for all patients and a predictive factor for benefit from sorafenib. Thyroglobulin levels at baseline were prognostic for all patients, but were not predictive for improved relative risk in PFS; both low and high thyroglobulin groups benefited from sorafenib. An absence of bone metastases and presence of lung-only metastases was also a positive predictive factor for relative risk in PFS.

Additional post-hoc exploratory analyses of PFS outcomes by presence or absence of thyroid cancer-related symptoms at study entry were conducted. From a total of 417 patients who received either sorafenib (n=207) or placebo (n=210), 48 sorafenib- and 45 placebo-treated patients were identified as having symptoms that were consistent with thyroid cancer, which included dyspnea, exertional dyspnea, pleural effusion, dysphagia, hemoptysis, chest, bone, or tumor pain, spinal cord compression, cough, obstructive airway disorder, or pulmonary embolism. The rest of the patients were asymptomatic.

"Here, both symptomatic and asymptomatic patients at entry had improved PFS following treatment with sorafenib," said Schlumberger. "Patients appeared to benefit from sorafenib treatment, irrespective of disease-related symptoms at baseline. Thus, based on these post-hoc exploratory analyses, patients with progressive RAI-rDTC and maximum tumor size <1.5 cm appear to have a good prognosis and may be candidates for "watch and wait" before initiating sorafenib.”

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