Sunitinib Effective for Rare Thymus Cancer

Sunitinib (Sutent; Pfizer), a tyrosine kinase inhibitor already approved for several cancers, slowed disease progression in a phase II trial of patients with advanced thymic carcinoma who failed the standard first-line chemotherapy. The drug might therefore offer the first effective second-line treatment option for patients with this rare and aggressive form of thymus cancer, whose 5-year survival rate is 30% to 50%.

The findings are exciting because there have been very little data to support any treatment options for patients whose cancers have progressed despite first-line platinum-based therapy, says Gregory Riely, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, NY, who specializes in treating thymic tumors. “This is certainly the most active drug we've seen for patients who have had prior therapy for thymic carcinoma.”

Several observations suggested that tyrosine kinase pathways—such as those that involve VEGFR, KIT, and PDGFR, which stimulate cell survival, proliferation, and/or angiogenesis—contribute to thymic epithelial cancers. For example, overexpression of these proteins or their ligands is associated with thymic carcinoma or other thymus pathology in humans. Furthermore, several small case studies have suggested that drugs that hinder VEGF, KIT, or PDGF signaling fight thymic epithelial tumors. Giuseppe Giaccone, MD, PhD, associate director for clinical research at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, and his colleagues therefore speculated that sunitinib, which targets these pathways, might curb the cancer's growth.

The open-label trial enrolled two cohorts with a total of 41 patients who had advanced thymic epithelial tumors—25 with thymic carcinoma and 16 with thymoma—whose tumors had progressed after one or more rounds of platinum-based chemotherapy. After a median follow-up of 17 months, 6 of the 23 assessable patients with thymic carcinoma (26%) had partial responses; 15 (65%) achieved stable disease; and 2 (9%) had progressive disease. The thymoma cohort closed early due to insufficient drug activity. The results were published in February (Lancet Oncol 2015;16:177–86).

“The take-home message is that there is a drug that works in thymic carcinoma and it is a relatively well-tolerated, well-known drug,” says Giaccone, the study's senior author. “This will become standard second-line treatment for patients with thymic carcinoma.”

Giaccone and colleagues attempted to identify somatic variations in genes, including those for sunitinib's targets, that might identify individuals who would benefit from the drug. No association was found between a specific mutation and response to sunitinib.

The researchers also probed the immunological effects of sunitinib administration. They documented an increase in expression of the checkpoint receptors PD-1 and CTLA4—molecular markers of regulatory T-cell activity. The result might reflect what typically would be a healthy attempt to keep inflammation in check, the authors suggest, but in this situation, a sunitinib-incited immune attack presumably shrinks the tumor and is desirable. Perhaps drugs that block checkpoint receptors would prolong sunitinib's assault on the cancer. To explore that idea, Giaccone's team recently opened a phase II trial of the PD-1 inhibitor pembrolizumab (Keytruda; Merck) in patients with advanced thymic carcinoma.

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