Everolimus benefited bladder cancer patient with rare genetic mutations

Genomic profiling of the tumor of an “exceptional responder” with advanced bladder cancer revealed two mutations that may have been responsible for the patient’s 14-month complete response to combined treatment with everolimus and pazopanib.

Exceptional responders, as defined by the NCI, are patients who exhibited a complete response or partial response for at least 6 months to treatment in a clinical trial in which less than 10% of patients responded.

“Studying exceptional responses can help us understand the specific reasons why some tumors are highly sensitive to certain anticancer agents,” Nikhil Wagle, MD, an instructor in medicine at Dana-Farber Cancer Institute, said in a press release. “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.”

Nikhil Wagle, MD 

Nikhil Wagle

In the phase 1 trial, researchers evaluated nine patients with advanced solid tumors. All patients progressed while on standard treatments.

Patients underwent treatment with a combination of the mTOR inhibitor everolimus (Afinitor, Novartis) and pazopanib (Votrient, GlaxoSmithKline), in a regimen of one to 13 cycles. It was confirmed by imaging that one of the five patients with bladder cancer achieved a complete response, and this response lasted for 14 months.

To determine the cause of this outstanding tumor response, the researchers conducted complete sequencing of the coding area of the tumor genome, which consisted of approximately 25,000 genes. They discovered two concurrent mutations in mTOR, targeted by everolimus — mTOR E2419K and mTOR E2014K.

Through in vitro experiments, researchers found that these mTOR alterations were activating mutations, suggesting that this patient’s unusual sensitivity to everolimus may have a biologic mechanism.

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. However, none of the patients with lung cancer benefited from this trial.

According to researchers, screening cancer patients for mutations in the mTOR pathway may be valuable in identifying other patients with this heightened sensitivity to mTOR inhibitors.

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

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. Wagle is an equity holder and a consultant to Foundation Medicine.