A patient with advanced bladder cancer experienced a complete response to the drug combination everolimus and pazopanib in a phase 1 clinical trial. Genomic profiling of his tumor revealed two mutations that may have caused this exceptional response. This information could help identify other patients with bladder cancer who may respond to everolimus and pazopanib.

Exceptional responders are cancer patients who have a complete or partial response to treatment for at least 6 months in a clinical trial in which less than 10% of patients responded. 

“Studying exceptional responders can help us understand why some tumors are highly sensitive to certain anticancer agents,” said Nikhil Wagle, MD, an instructor in medicine at Dana-Farber Cancer Institute, and an associate member at the Broad Institute in Cambridge, Massachusetts. “We can use that information to identify other patients whose tumors have similar genetic alterations, then treat them with the same agents.

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“We conducted a phase 1 clinical trial of two anticancer agents—the mTOR inhibitor everolimus, and pazopanib, another drug used to treat kidney cancer—and one of our patients developed near complete remission of his bladder cancer which lasted for 14 months,” said Wagle. “Sequencing of the patient’s tumor revealed two mutations in the gene mTOR, which is the target of everolimus.”

The two mutations, mTOR E2419K and mTOR E2014K, had never been identified in human, although one of the mutations had been studied by scientists in yeast and human cell lines.

In laboratory studies, Wagle and colleagues found that the two mutations activated the mTOR-mediated cell-signaling pathway. These mutations may have rendered the patient’s cancer dependent on the mTOR pathway for survival, explaining why the cancer became exquisitely sensitive to the mTOR inhibitor everolimus.

Three other patients with bladder cancer in this clinical trial had stable disease for less than 6 months, and a patient with cancer of the adrenal gland had prolonged stable disease for 13 months.

This study shows how therapies targeted toward the genetic features of a tumor can be highly effective. “Our goal is to identify more genetic features and have as many drugs that target these genetic features as possible, so we can match the drugs to the patients,” Wagle added. “There are many patients with extraordinary responses to a variety of anticancer therapies, and it will be of great scientific and clinical value to study them.”

This study was published in Cancer Discovery (2014; doi:10.1158/2159-8290.CD-13-0353).