VIENNA – Trastuzumab appears to have a limited impact on advanced HER2-positive bladder cancer, despite its transformative role in HER2-positive breast cancer.
In a multicenter, randomized phase II trial, no difference was observed in response, survival, or quality of life when gemcitabine (Gemzar) plus platinum-based chemotherapy was compared with the same gemcitabine-plus-platinum regimen plus trastuzumab (Herceptin) in 61 patients with stage IV advanced or metastatic urothelial cancer overexpressing HER2.
There was, however, the intriguing finding that overall survival was related to baseline platinum treatment, which included cisplatin or carboplatin.
Patients receiving cisplatin chemotherapy plus trastuzumab lived a median of 33.1 months, compared with 14.5 months in those receiving cisplatin without trastuzumab and just 9.4 months for patients given carboplatin chemotherapy with trastuzumab, Dr. Stéphane Oudard reported at the European Society for Medical Oncology Congress.
"Trastuzumab could have a synergistic effect with cisplatinum, leading to a longer overall survival," he said.
Urothelial cancer is the fourth most common cancer among men, with about 111,000 new cases reported in 2011. It has proven difficult to target with novel agents, despite the variety of molecular pathways that play a significant role in the formation of these tumors. The incidence of HER2 overexpression and/or amplification remains uncertain, ranging from 23% to 80% in various publications, Dr. Oudard observed.
An earlier phase II trial reported a response rate of 70%, including five complete and 26 partial responses, when trastuzumab was added to paclitaxel (Taxol), carboplatin, and gemcitabine chemotherapy in 44 patients with advanced urothelial cancer not previously treated with chemotherapy for metastasis. Median survival was 14 months, but 22% of patients experienced grades 1-3 cardiac toxicity (J. Clin. Oncol. 2007;25:2218-24).
A more recent phase II double-blind trial reported that adding the oral tyrosine kinase inhibitor vandetanib (Caprelsa) to second-line docetaxel (Taxotere) in advanced urothelial cancer did not significantly improve the overall response rate, progression-free survival, or overall survival, which reached a median of just 7 months (J. Clin. Oncol. 2012;30:507-512).
Treatment in the current trial included gemcitabine 1,000 mg/m2 on days 1 and 8 every 21 days plus cisplatin 70 mg/m2 on day 1 if creatinine clearance was more than 60 mL/min or carboplatin area under the curve (AUC) 5 on day 1 every 21 days if creatinine clearance was 60 mL/min or less, or the same chemotherapy regimen plus trastuzumab at a loading dose of 8 mg/kg then 6 mg/kg every 21 days until progression.
Prior neoadjuvant or adjuvant chemotherapy was allowed if it occurred at least 6 months prior to study entry. Prior trastuzumab therapy was not permitted.
Of the 563 patients tested for HER2 status, only 75 patients (13.3%) were positive on immunohistochemistry, and 14 of these were excluded from the trial for various reasons. The remaining 61 patients had an ECOG performance status of 2 or less, three-fourths had metastatic disease, and half received cisplatin-based chemotherapy.
The 32 patients in the trastuzumab arm received a median of eight chemotherapy cycles vs. a median of six cycles for the 29 patients in the control group, and their median time on therapy was longer, at 5.3 months vs. 3.9 months. Trastuzumab was given for a median of 10 months. Median follow-up was 33.3 months.
The median time to progression was 10.5 months in the control group and 8.3 months with trastuzumab (P = .33), and median overall survival was 15.7 months vs. 14.2 months (P = .56), said Dr. Oudard, of the Georges Pompidou European Hospital, Paris.
Using a Cox regression analysis, baseline serum HER2 was found to be predictive of progression-free survival, whatever the treatment arm (P = .03).
In multivariate Cox regression analysis, the main predictive factors for progression-free survival were ECOG performance status 0-1 vs. 2 (hazard ratio, 3.66) and baseline serum HER2 (HR, 1.01). Trastuzumab was not predictive (P = .49), nor was platinum analogue cisplatin vs. carboplatin (P = .77), he said.
Patients treated with trastuzumab did not have improved quality of life scores, and experienced more grade 3/4 febrile neutropenia (6.5% vs. 0%), dyspnea (3.2% vs. 0%), and decreased left ventricular ejection fraction (3.2% vs. 0%).
Future urothelial cancer trials with HER2-targeting therapy should be performed, but it is unclear whether a trastuzumab combination should be proposed for patients who can only receive cisplatin chemotherapy, whether patient selection should be based on baseline serum HER2, or whether a more powerful drug such as T-DM1 should be used, Dr. Oudard said.
Dr. Oudard reported honoraria from Sanofi-Aventis, Bayer, and other companies.