Bladder Cancer Patient With Rare Genetic Mutations Shows Exceptional Response to Everolimus/Pazopanib Combination

Get Permission

Nikhil Wagle, MD

...our goal moving forward is to be able to identify as many of these genetic features as possible and have as many drugs that target these genetic features as possible, so we can match the drugs to the patients.

—Nikhil Wagle, MD

A patient with advanced bladder cancer experienced a complete response for 14 months to the drug combination everolimus (Afinitor) and pazopanib (Votrient) in a phase I trial, and genomic profiling of his tumor revealed two alterations that may have caused this exceptional response, according to a study published in Cancer Discovery.1

This information can help identify patients with cancer who may respond to everolimus. “Exceptional responders” are those who had a complete or partial response for at least 6 months to treatment in a clinical trial in which less than 10% of patients responded, according to the National Cancer Institute.

“Studying exceptional responses can help us understand the specific reasons why some tumors are highly sensitive to certain anticancer agents,” said Nikhil Wagle, MD, an Instructor in Medicine at Dana-Farber Cancer Institute, Boston, and an Associate Member at the Broad Institute in Cambridge, Massachusetts. “We can use that information to identify patients whose tumors have genetic alterations similar to those found in exceptional responders, and treat them with those same agents.

Phase I Trial

“We conducted a phase I 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 that lasted for 14 months,” said Dr. Wagle. “We performed whole-exome sequencing of the patient’s tumor, and to our surprise, we identified two mutations in the gene MTOR, which is the target of everolimus.”

In this phase I trial, the investigators recruited nine patients with advanced solid tumors, including five with bladder cancer, whose diseases had progressed despite treatment with standard therapies. Patients received 1 to 13 cycles of everolimus and pazopanib.

One of five patients with bladder cancer had a complete response, as evaluated by imaging, which lasted for 14 months. To understand why his tumor responded dramatically, the investigators performed complete sequencing of the coding regions of his tumor genome, which included about 25,000 genes, and identified two mutations in MTOR.

Two Mutations

The two mutations, MTOR E2419K and MTOR E2014K, had never been identified in humans, according to Dr. Wagle, although one of the mutations had previously been well studied by scientists in yeast and in human cell lines.

Dr. Wagle and colleagues conducted further studies in a laboratory setting to understand the nature of the two mutations, and found that they activated the mTOR-mediated cell signaling pathway. These mutations likely rendered the patient’s cancer dependent on the mTOR pathway to survive, which is the likely reason the cancer became exquisitely sensitive to the mTOR inhibitor everolimus, explained Dr. Wagle.

Three other patients with bladder cancer in this clinical trial had stable disease for less than 6 months, and a patient with cancer in his adrenal gland had prolonged stable disease for 13 months. None of the patients with lung cancer benefited from this trial.

Study Implications

“Results of our study suggest that we should make a catalog of activating genomic alterations in the genes in the mTOR pathway,” said Dr. Wagle. “Patients with tumors that harbor these alterations might be particularly suitable for treatment with drugs like everolimus and other mTOR inhibitors,” he added.

“This study is yet another example of how therapies targeted toward the genetic features of a tumor can be highly effective, and our goal moving forward is to be able to identify as many of these genetic features as possible and have as many drugs that target these genetic features as possible, so we can match the drugs to the patients,” he continued. “There are many more patients out there with extraordinary responses to a variety of anticancer therapies, and it will be of great scientific and clinical value to study them.” ■

Disclosure: This study was funded by the Next Generation Fund at the Broad Institute of MIT and Harvard, the National Human Genome Research Institute, GlaxoSmithKline, and Novartis. Dr. Wagle is an equity holder and a consultant to Foundation Medicine.


1. Wagle N, Grabiner BC, Van Allen EM, et al: Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. March 13, 2014 (early release online).