Thyroid Cancer: Targeted Agents Show Promise Following Radioactive Iodine Resistance

Jonas de Souza, MD

A better understanding of the molecular pathways that confer resistance to radioactive iodine (RAI) in the treatment of differentiated thyroid cancer has led to success in targeting the vascular endothelial growth factor (VEGF) and the VEGF receptor pathways. Other signaling pathways may also be involved in RAI resistance and represent additional potential targets. A newer promising approach is to restore sensitivity to RAI through the mitogen-activated protein kinase (MAPK) pathway by the use of a MAPK kinase (MEK) inhibitor.

In about 5% of patients being treated for thyroid cancer, thyroid cells can no longer take up RAI. For these patients, the long-term prognosis has been grim, with a 10-year survival rate of about 10%. “We’ve long struggled [with] how to treat them,” said Everett Vokes, MD, chair, department of medicine, and professor of medicine and radiation oncology, University of Chicago Medical Center.

Martin Schlumberger, MD, on Results of the SELECT Trial in Thyroid Cancer

Schlumberger is a professor at University Paris-Sud.

Although typically slow growing, RAI-refractory thyroid tumors usually metastasize to the lungs and bone, eventually causing death.

“Thyroid cancers have several known and well-described molecular characteristics,” said Vokes, including increased expression of VEGF and VEGF receptor-1, VEGF receptor-2, and VEGF receptor-3. A multityrosine kinase inhibitor (TKI) of VEGF receptors 1-3 can shrink RAI-resistant thyroid tumors, result in responses, and prolong progression-free survival (PFS), according to Vokes.

In November 2013, the United States Food and Drug Administration (FDA) approved sorafenib, a multitargeted kinase inhibitor of VEGF receptor-1 and -2, for the treatment of metastatic differentiated thyroid cancer that is refractory to RAI. This approval was based on results from a clinical trial known as DECISION (Lancet 2014;384:319-328), in which 417 patients with RAI-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed in the prior 14 months were randomized to sorafenib, 400 mg twice daily, or placebo.

Progression-free survival, the primary endpoint, was significantly longer in patients assigned to sorafenib compared with placebo: 10.8 months versus 5.8 months (P <.0001), respectively, an advantage that was observed in subgroups based on age, the extent of disease, sites of metastases, or genetic biomarkers. Mutations inBRAForRASwere not associated with longer PFS in the sorafenib arm.

The objective response rates were 12% in the sorafenib group and <1% in the placebo group. There were no complete responses and overall survival was not significantly different between the two groups at the time of the analysis; the high rate of crossover from the placebo to the sorafenib arm (about 70%) at disease progression may have obscured any difference in overall survival, said Vokes.

Sorafenib was associated with more serious adverse events, as expected, but because RAI-refractory thyroid cancer is usually slow growing, sorafenib may not have to be used immediately, said Vokes.

A second multikinaseTKI to show substantial activity in this population is lenvatinib, which inhibits VEGF receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor alpha, RET, and c-kit. At the 2014 Annual American Society of Clinical Oncology meeting, a phase III study known as SELECT was presented. The 392 patients in the trial had measurable disease that had progressed within the past year. They were randomized to oral lenvatinib or placebo in a 2:1 ratio, and patients randomized to placebo were eligible for crossover to levantinib upon disease progression.

The median PFS was 18.3 months in the lenvatinib arm versus 3.6 months in the placebo arm (P<.0001). Sixty five percent of patients in the lenvatinib arm had an objective response, including 4 with complete response, compared with just 2% of the placebo arm. The crossover design may again have prevented a difference in overall survival, said Vokes.

There were 20 treatment-emergent deaths in the lenvatinib arm, 6 of which were deemed to be treatment-related by investigators, compared with 5 in the placebo arm, and significant side effects required dose reduction, dose interruption, and drug discontinuation in 68%, 82%, and 14% of patients randomized to lenvatinib, respectively.

A major distinction between the DECISION and SELECT trials is that patients enrolled in SELECT could have received other VEGF receptor inhibitors prior to enrollment, whereas those patients were excluded from participating in DECISION, said Vokes.

Clinical Pearls

• Better understanding of molecular pathways that confer resistance to RAI in the treatment of DTC has led to success in targeting the VEGF and the VEGF receptor pathways. November 2013, the FDA approved sorafenib, a multitargeted kinase inhibitor of VEGF receptor-1 and -2, for the treatment of metastatic DTC that is refractory to RAI based on results from the DECISION trial.
• A second multikinase TKI to show activity in this population is lenvatinib, which inhibits VEGF receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor alpha, RET, and c-kit.
• A multicenter, phase II trial of the oral multikinase inhibitor cabozantinib in a second-line setting in patients with differentiated thyroid cancer that progressed while on a prior VEGF receptor inhibitor is being conducted.
• Another approach to treating refractory patients is to administer a drug that can restore sensitivity to RAI.

Specifically targeting theBRAFgene is another promising line of investigation, said Jonas de Souza, MD, assistant professor of medicine, section of hematology/oncology, also at the University of Chicago Medical Center. Mutations inBRAFcan lead to chronic activation of thyroid cancer protein products. In this category, dabrafenib and vemurafenib act to disruptBRAFsignaling and may one day represent other options for RAI-resistant thyroid cancer.

The list of potential targeted agents for iodine-refractory disease is extensive, according to de Souza. &ldquo;As we learn more about the biology of the disease, includingBRAFandRASmutations and downstream signaling mechanisms, the list will keep growing. And I strongly believe that the future does lie in precision medicine, and different patients will receive different combinations of drugs, either in combination or sequentially, based on their tumor profiles.&rdquo;

Reactivating the Iodine Pathway

Under the direction of Manisha H. Shah, MD, at Ohio State University, Columbus, the International Thyroid Oncology Group (ITOG) is conducting a multicenter, open-label, phase II trial of the oral multikinase inhibitor cabozantinib in a second-line setting in patients who have had differentiated thyroid cancer that progressed while on a prior VEGF receptor inhibitor. Cabozantinib was selected because of its activity against both Met, an angiogenic protein thought to be critical in causing failure of VEGF receptor targeted therapy, and the VEGF receptor itself.Patients with RAI-refractory differentiated thyroid cancer often have an absence of iodine receptor expression. Another approach to treating refractory patients, therefore, is to administer a drug that can restore sensitivity to RAI, according to Vokes. Preclinical work conducted at Memorial Sloan Kettering Cancer Center in New York City and others showed that genetic alterations inBRAFcan activate MAPK pathway signaling to prevent iodine uptake.

&ldquo;We believe that the cell&rsquo;s ability to absorb radioiodine is controlled by the MAPK pathway,&rdquo; said de Souza.

This discovery led to the hypothesis that a MEK inhibitor might restore thyroid cell sensitivity to RAI. This was indeed the case when the selective MEK1 and MEK2 inhibitor selumetinib was used in an early phase study of patients with metastatic thyroid cancers (N Engl J Med2013;368:623-632).

The trial, led by Alan Ho, MD, at Memorial Sloan-Kettering, enrolled 20 patients, all of whom received selumetinib twice daily for 4 weeks. In 12 of the 20 patients, uptake of iodine was restored as verified by positron emission tomography. Four of 9 patients withBRAFmutations and all 5 withNRASmutations had increased uptake of iodine following treatment with selumetinib. In the 8 patients who resumed treatment with RAI, there were 5 partial responses and 3 patients had stable disease, and the responses were durable (&ge;6 months).