Afatinib Promising in Urothelial Cancer Patients With ERBB3, HER2 Alterations

Afatinib showed significant activity in a phase II trial of patients with metastatic platinum-refractory urothelial carcinoma (UC), and patients with HER2 or ERBB3 alterations had significantly better outcomes.

Recent research has shown that UC patients often have EGFR amplifications (11%), HER2 amplifications (7%), and ERBB3 somatic mutations (11%). Afatinib is a tyrosine kinase of the ErbB receptor family, approved to treat certain lung cancers. “Given the frequency and potential importance of ErbB family alterations in UC, we hypothesized that afatinib would demonstrate activity in this disease,” wrote study authors led by Peter H. O’Donnell, MD, of the University of Chicago.

The new study included 23 patients in a first enrollment stage; all received afatinib 40 mg/day continuously until progression or intolerance. The results were published online ahead of print in the Journal of Clinical Oncology.

Five of the 23 patients (21.7%) were progression-free at 3 months, which was the study’s primary endpoint; because seven or more patients did not achieve this outcome, a second stage of enrollment was not completed. The median progression-free survival for the full cohort was 1.4 months, and the median overall survival was 5.3 months. The overall response rate in the study was 8.6%; two patients had a partial response, and seven had stable disease.

Next-generation sequencing was conducted on 21 of the 23 patients, and molecular alterations of HER2 and ERBB3 were found to be predictive of afatinib efficacy. Six patients had ERBB molecular alterations (either HER2 copy number amplification and/or ERBB3 somatic mutations), and five of them (83%) were progression-free at 3 months, compared with none of the 15 patients without such alterations (P < .001). The median progression-free survival in those with alterations was 6.6 months, compared with 1.4 months in those without (P < .001).

One patient had both HER2 amplification and ERBB3 mutation, and never progressed while on therapy; treatment was discontinued in this patient after 10.3 months because of depressed ejection fraction.

The authors noted that the median progression-free survival for other agents in other studies has been shorter, including 3 months for vinflunine and 2.2 months for pembrolizumab. They did point out the study’s small size, though, as well as the possibility that HER2 amplification and ERBB3 mutation are simply associated with improved prognosis rather than acting as predictive biomarkers for afatinib efficacy.

Still, they wrote that “afatinib deserves examination in a larger number of patients with molecularly altered UC, including evaluation in those with negative prognostic variables such as liver metastases and histologic variants, to characterize the range of alterations that are predictive of benefit.”