Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations

Abstract

Purpose Somatic mutations and copy number variation in the ERBB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, irreversible inhibitor of the ErbB family) has activity in UC and if specific ERBB molecular alterations are associated with clinical response. Patients and Methods In this phase II trial, patients with metastatic platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance. The primary end point was 3-month progression-free survival (PFS3). Prespecified tumor analysis for alterations in EGFR, HER2, ERBB3, and ERBB4 was conducted. Results The first-stage enrollment goal of 23 patients was met. Patient demographic data included: 78% male, median age 67 years (range, 36 to 82 years), hemoglobin < 10 g/dL in 17%, liver metastases in 30%, median time from prior chemotherapy of 3.6 months, and Eastern Cooperative Oncology Group performance status ≤ 1 in 100%. No unexpected toxicities were observed; two patients required dose reduction for grade 3 fatigue and rash. Overall, five of 23 patients (21.7%) met PFS3 (two partial response, three stable disease). Notably, among the 21 tumors analyzed, five of six patients (83.3%) with HER2 and/or ERBB3 alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 6.3, and 5.0 months, respectively) versus none of 15 patients without alterations ( P < .001). Three of four patients with HER2 amplification and three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) met PFS3. One patient with both HER2 amplification and ERBB3 mutation never progressed on therapy, but treatment was discontinued after 10.3 months as a result of depressed ejection fraction. The median time to progression/discontinuation was 6.6 months in patients with HER2/ERBB3 alterations versus 1.4 months in patients without alterations ( P < .001). Conclusion Afatinib demonstrated significant activity in patients with platinum-refractory UC with HER2 or ERBB3 alterations. The potential contribution of ERBB3 to afatinib sensitivity is novel. Afatinib deserves further investigation in molecularly selected UC.

Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer

“…We identified 11 patients with amplification and/or activating hotspot mutation to ERBB2/ERBB3. A recent phase II trial evaluated afatinib (an irreversible inhibitor of the ERBB family) in bladder cancer and found that activity was confined to patients with alterations in ERBB genes (46). The future of other HER2-directed agents such as trastuzumab and lapatinib in bladder cancer also likely depends upon biomarker-driven patient selection (10).…”

Overexpression of the transmembrane protein BST-2 induces Akt and Erk phosphorylation in bladder cancer

“…Since the phosphorylation of Akt and Erk inhibits apoptosis (21), these results suggest that apoptosis could be induced in BST2-transfected KMBC2 UC cells. EGFR overexpression in UC is correlated with high tumor grade, muscle invasiveness, tumor recurrence and overall survival (22). Although the underlying mechanisms remain unclear, it is possible that a monoclonal antibody against BST-2 could inhibit EGFR signaling and induce apoptosis in UC cells.…”

SEOM Clinical Guideline for treatment of muscle-invasive and metastatic urothelial bladder cancer (2016)

“…Potential actionable genomic alterations, including activating mutations and RNA expression changes involving the PI3K/AKT/mTOR and RTK/RAS pathways have been frequently detected in the TCGA and other studies [7, 11, 51] Several studies have identified significant activity of targeted therapies in patients with these genomic alterations. For example, patients with mutations in PIK3CA (about 17% of tumors) can be sensitive to PI3K inhibitors, whereas patients with mutation/amplification of ERBB2 (about 9% of tumors) or ERBB3 mutations (about 6% of tumors) can respond to ERBB tyrosine kinase inhibitors, as has been recently demonstrated [52]. Moreover, inactivating mutations of genes involved in DNA repair pathways have also been identified in MIBC patients.…”