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.

Fig 1.

Treatment response: Swimmer’s plot of the 23 enrolled patients, with time on therapy (months) shown for each patient. Blue color indicates that the patient met 3-month progression-free survival (PFS3, the primary end point). Specific ERBB molecular alterations are noted for each patient. The asterisk (*) indicates that patient 2 carried two alterations (ERBB3 somatic mutation and HER2 amplification, as shown adjacent to the asterisk).

Fig 2.

Progression-free survival: Kaplan-Meier curve of progression-free survival. The six patients (1, 2, 3, 19, 21, and 22) with ERBB molecular alterations had a median progression-free survival of 6.6 months, compared with 1.4 months for the 15 patients without alterations (P < .001, log-rank test).

Fig A1.

HER2 copy number assessment in a patient with robust HER2 amplification: A representative image of fluorescence in situ hybridization for patient 2 is shown. Within each nucleus, red color denotes HER2 signal and green color denotes the centromeric probe (D17Z1) for chromosome 17 used as the control. HER2/Cep17 ratio 9.6, average HER2/nucleus 28.3.

Fig A2.

Immunohistochemistry images for ErbB family proteins: Representative images from (A) HER2, (B) EGFR, and (C) ERBB3 are shown, with individual patients labeled. For HER2 and EGFR, the cases shown were selected to show the observed range across the cohort, which included samples with completely negative staining to some with marked overexpression. Patient 12, for example, was selected to demonstrate negative EGFR staining. Two images for patient 4 (HER2 staining) are shown side by side to demonstrate focality of staining. For patient 8, the histology of the tumor was mixed urothelial carcinoma (50%) and small-cell carcinoma (50%). Whereas the urothelial carcinoma component stained negative for ERBB3, the small-cell carcinoma component stained 2+ to 3+.