Drug demonstrates significant activity in patients with platinum-refractory urothelial cancer. [National Cancer Institute]
Drug demonstrates significant activity in patients with platinum-refractory urothelial cancer. [National Cancer Institute]

Researchers from the University of Chicago reported on the results from a small trial aimed at patients with advanced metastatic urothelial cancer (UC). Many UC patients frequently have somatic mutations and copy number variation in the ERBB gene family, which are structurally related the epidermal growth factor receptor and the development of a wide variety of solid tumors.

The trial was designed to see if daily 40 milligram doses of the drug afatinib, a tyrosine kinase inhibitor typically given to non-small cell lung carcinoma patients, could prevent tumor progression for at least three months in patients who had developed resistance to the first-line treatment for metastatic bladder cancer.

A total of 23 patients were enlisted in the study, of which seven had HER2 and/or ERBB3 mutations. Among the patients who had one of the two mutations, averaged 6.6 months without progression of their cancers after treatment. That was more than four times longer than patients without the mutations, who averaged only 1.4 months.

“Seven out of 23, or nearly 30 percent of these patients, had one of these potentially treatable mutations,” explained study director and senior author Peter O'Donnell, M.D., assistant professor of medicine at the University of Chicago. “The connections linking afatinib with a better response to treatment for this group of patients are encouraging. Our next step is to organize a follow-up trial focused entirely on patients with at least one of these mutations.”

“Compared to other drugs which have been tried for refractory metastatic bladder cancer, including immune therapies which will likely be approved, the time to disease progression is significantly longer with afatinib in patients carrying the genetic abnormalities,” Dr. O’Donnell added. “There have been no other drugs approved in the U.S. in decades in this disease setting and only one drug approved in Europe. Its progression-free time was half of what we are seeing with afatinib in this same population of patients.”

The findings from this study were published recently in the Journal of Clinical Oncology “Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations.”

Urothelial carcinoma (UC) is the fourth most common cancer among males and, at 16,000 deaths a year, the eighth leading cause of cancer death in the United States. It affects the kidney, urinary bladder, and accessory organs.

In the last 25 years, there has been limited progress in developing effective new treatments for UC with the authors stating that platinum-based therapies are currently the only standard of care, with no approved second-line therapies.

In the current study, two patients had a partial response (some shrinkage of tumor), while seven had stable disease, and 14 had ongoing progression of the disease.

However, the key finding was that five out of the six patients with molecular alterations in at least one of two specific genes—multiple copies of Her2, or mutations and multiple copies of ERBB3, abnormalities associated with a worse prognosis in previous studies—responded to the treatment.

Yet, the authors noted that the study did have several limitations, particularly its small sample size. But the ability to detect such significant differences in outcomes “raises the possibility that these molecular alterations are indeed highly correlated with afatinib responsiveness.”

“In the era of personalized medicine,” the authors added, “a nuanced understanding of molecular studies is vital for identifying patients most likely to benefit from selected therapies.”

Also of Interest