A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma

Abstract

BACKGROUND Epidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated. METHODS Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m2) on day 1 plus gemcitabine (1000 mg/m2) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m2) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to-event endpoints. RESULTS Eighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CI = 37%–76%) and 61.4% for arm B (95% CI = 48%–74%). The median progression-free survival times were 8.5 months for arm A (95% CI = 5.7–10.4 months) and 7.6 months for arm B (95% CI = 6.1–8.7 months). The median overall survival times were 17.4 months for arm A (95% CI = 12.8 months to unreached) and 14.3 months for arm B (95% CI = 11.6–22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death. CONCLUSIONS GC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes.

Incidence and risk of severe infections associated with anti-epidermal growth factor receptor monoclonal antibodies in cancer patients: a systematic review and meta-analysis

“…According to the inclusion criteria of each trial, patients were required to have adequate hepatic, renal and hematological function. Underlying malignancies included colorectal cancer (eleven trials) [14,15,[22][23][24][25][26][27][28][29][30][31], non-small-cell lung cancer (seven trials) [32][33][34][35][36][37][38], head and neck cancer (four trials) [5,13,39,40], breast cancer (one trial) [41], urothelial carcinoma (one trial) [42], pancreatic cancer (one trial) [43] and esophagogastric cancer (one trial) [44].…”

Phase III, Double-Blind, Randomized Trial That Compared Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 1/2–Positive Metastatic Bladder Cancer

“…[4][5][6] Clinical studies that tested these agents in unselected patients failed to reproduce this in vivo activity. [7][8][9] Three possible reasons account for these results. First, the combination of chemotherapy and targeted therapy in the UBC population, which has multiple comorbidities, is difficult.…”

“…First, the combination of chemotherapy and targeted therapy in the UBC population, which has multiple comorbidities, is difficult. 7,8,10,11 Second, none of the randomized phase III trials to date have selected patients based on expression of molecular targets. Finally, UBC has a high frequency of mutations, therefore the targeting of only one protein may be inadequate to achieve clinical benefit.…”

Letter to the editor

“…In contrast, our own search yielded a total of 6777 records of which 45 [3][4][5] were RCTs. Of the 37 [3][4][5][6][7][8][9][10][11][12][13][14][15][16]19,20,[22][23][24][25][26][27][28][30][31][32][33][34][36][37][38]40,41,43,45,47,48 trials of cetuximab, 32 [3][4][5][6][8][9][10][11][12][14][15][16]…”