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


Key Points

  • A phase I study of a two-drug combination of everolimus and pazopanib in patients with advanced solid tumors has identified a patient with bladder cancer who had a 14-month complete response.
  • Whole-exome sequencing of the patient’s tumor identified two mutations, MTOR E2419K and MTOR E2014K, that activated the mTOR-mediated cell-signaling pathway.
  • Studying exceptional responders has the potential to identify novel genomic and molecular mechanisms of sensitivity to many different anticancer therapies.

A phase I study by Wagle et al of a combination of everolimus and pazopanib in patients with advanced solid tumors has identified a patient with bladder cancer who had a 14-month complete response. The patient had two concurrent mutations in mTOR, the target of everolimus (Afinitor), which may have caused this exceptional response. The study is published in Cancer Discovery.

Nine patients were enrolled in the phase I study, including five with bladder cancer, one with small cell lung cancer, one with non–small cell lung cancer, one with atypical carcinoid tumor of the lung, and one with adrenocortical carcinoma. All the patients had experienced disease progression on standard therapies.

Study Findings

The patients received 1 to 13 cycles of everolimus and pazopanib (Votrient). Of the five patients with bladder cancer, one patient had a complete response, as evaluated by imaging, which lasted 14 months. The patient with adrenocortical carcinoma experienced a meaningful clinical benefit of stable disease for 13 months. Three other patients with bladder cancer had stable disease for less than 6 months. None of the lung cancer patients benefited from this trial.

To understand why this one patient was such an exceptional responder to the therapy, the researchers performed whole-exome sequencing of the patient’s tumor, which included about 25,000 genes, and identified two mutations in MTOR—MTOR E2419K and MTOR E2014K. They then conducted additional studies in the laboratory to understand the nature of the two mutations, and found that they activated the mTOR-mediated cell-signaling pathway, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient.

“Results of our study suggest that we should make a catalog of activating genomic alterations in the genes in the mTOR pathway,” Nikhil Wagle, MD, lead author of the study, an instructor in medicine at Dana-Farber Cancer Institute, and an associate member of the Broad Institute of Harvard and MIT, said in a statement. “Patients with tumors that harbor these alterations might be particularly suitable for treatment with drugs like everolimus and other mTOR inhibitors.”

Importance of Studying Exceptional Responders

According to the National Cancer Institute, exceptional responders are defined as cancer patients who had 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 responders holds the promise of a better understanding of the mechanisms that underlie sensitivity to targeted anticancer therapies, according to the study authors.

“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,” said Dr. Wagle. “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.”

Levi A. Garraway, MD, PhD, of Dana-Farber Institute, and Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center, are the corresponding authors for the Cancer Discovery article.

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

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.