Afatinib Shows Promise for Metastatic Urothelial Carcinoma

Afatinib, a drug approved in 2013 to treat lung cancer, may help patients with metastatic urothelial carcinoma who have certain genetic abnormalities, a small study finds.

“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,” lead researcher Peter O'Donnell, MD, of the University of Chicago, stated in a press release. “There have been no other drugs approved in the US 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.”

For the phase 2 trial, Dr O'Donnell and his team enrolled 23 patients with urothelial carcinoma of the bladder, upper tract, or urethra whose disease had progressed despite platinum-based combination chemotherapy. Each patient received afatinib 40 mg per day continuously until their cancer progressed or intolerance developed. Afatinib is an oral, irreversible tyrosine kinase inhibitor of the ErbB receptor family. The main endpoint was 3-month progression-free survival (PFS3).

Five of the 23 patients experienced delayed tumor progression for at least 3 months: 2 with partial response to the drug and 3 with stable disease, according to results published online ahead of print in the Journal of Clinical Oncology. Based on an analysis of tumor specimens, the investigators determined that 3 of 4 patients with multiple copies of human epidermal growth factor receptor (HER2) and all 3 patients with somatic mutations of ERBB3 met the PFS3 endpoint. None of the patients without the molecular alterations responded to treatment. 

The single patient with both HER2 amplification and ERBB3 mutation did not progress with afatinib, but treatment was stopped after 10.3 months due to depressed ejection fraction. 
Toxicity was as expected. Two patients had dose reductions for grade 3 rash and fatigue. The most common side effect was diarrhea, experienced by 83% of patients.

The potential contribution of ERBB3 to afatinib sensitivity is a novel finding, according to Dr O'Donnell and colleagues. They expect to conduct a follow-up trial focused entirely on patients with at least 1 of the genetic alterations. 

​The study was funded in part by Boehringer Ingelheim Pharmaceuticals, Inc., manufacturers of afatinib.

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