Effect of EGFR inhibition with cetuximab on the efficacy of paclitaxel in previously treated metastatic urothelial cancer.

Abstract

243 Background: The benefit of salvage chemotherapy such as weekly paclitaxel (TAX) is modest in metastatic (met) urothelial ca, with median TTP of ≤3 months and ORR of 10% (95% CI 4-18% [combined results, Vaughn 2002; Joly, 2009]). Cetuximab (CET) is a monoclonal antibody against the epidermal growth factor receptor (EGFR). High-grade urothelial cancer overexpress EGFR. We conducted a multicenter randomized, noncomparative phase II study to measure the efficacy of CET ± TAX in patients (pts) with previously treated met urothelial cancer. Methods: Pts with met urothelial cancer who received one line of chemotherapy in the adjuvant, neoadjvuant, or met setting were enrolled. Pts were randomized to CET 250mg/m2 (after 400 mg/m2 load) ± TAX 80 mg/m2 weekly. A cycle was 4 weeks (wks). Response (RECIST) was assessed by imaging every 8 wks. We used early progression to assess futility (Litwin Stats Med 2007). Either arm would close if 7 of the initial 15 pts in that arm progressed at the first disease evaluation. Either arm would be considered promising if ≥9/28 patients had PFS>16 wks (90.4% power to detect an improvement in Median [Med] PFS from 8 to 16 wks with a 7.1% type 1 error). Results: We enrolled 39 evaluable pts (30 male). Median age was 69 years (range 49-79). All pts received prior platinum-based chemotherapy. CET arm closed after 9 of the first 11 pts progressed by 8 wks (ASCO GU 2009). CET-TAX arm completed full accrual (28 pts), of which 11 had visceral disease and 13 received chemo for met disease. 10/28 pts had PFS>16 wks. Overall RR was 28.5%, (8/28 pts, 95% CI 13-49%) (2 CR, 6PR). 4 additional pts had unconfirmed PR. 2 pts have maintained PR 3 and 4 months after discontinuing CET-TAX. Med PFS for the CET-TAX was 115 days (16 weeks)(95% CI 58-174 days). Med PFS for pts with visceral disease was 84 days (95%CI 50-NR). Med PFS for pts who received prior chemo for met disease was 142 days (95% 58-NR). Med number of cycles for the CET-TAX was 3 (range 0-25). Grade 3 AEs occurring in more than 2 pts were rash (5), fatigue (4), anemia (4), low magnesium (3). Conclusions: EGFR inhibition with CET appears to augment the antitumor activity of TAX in pts with previously treated urothelial cancers. The CET-TAX combination merits further study to establish its role in treatment of urothelial cancers. [Table: see text]

Urothelial carcinoma management in elderly or unfit patients

“…Furthermore, targeted agents combined with a cytotoxic drug (paclitaxel + cetuximab or docetaxel + vandetanib) in platinum-pretreated patients did not demonstrate additive activity and resulted in increased toxicities [94] , [95] .…”

“…Several single-agent phase II studies have tested targeted therapies in the second-line setting, but none have shown substantial activity. Trials are also testing targeted agents combined with a cytotoxic drug (paclitaxel + cetuximab or docetaxel + vandetanib), but the combinations exacerbated toxicity, and no synergistic or additive effects were reported [94] , [95] . More recent attempts at combining targeted agents with cytotoxic drugs have been more encouraging (docetaxel + ramucirumab versus docetaxel), based on the results of a phase II trial, although toxicity was increased in the combination arm [96] .…”

Clinical Significance of ErbB Receptor Family in Urothelial Carcinoma of the Bladder: A Systematic Review and Meta-Analysis

“…Cetuximab is a chimeric (mouse/human) monoclonal antibody for blocking EGFR signaling. A phase II clinical trial [ 38 ] of 39 pretreated patients with metastatic urothelial carcinoma demonstrated that combined cetuximab and paclitaxel chemotherapy yielded a better response rate (28.5%) than did cetuximab monotherapy, in which 9 of 11 patients had disease progression at 8 weeks.…”

Recent Advances in Treatment of Advanced Urothelial Carcinoma

“…Grade 3 adverse events occurring in more than two patients were rash ( n =5), fatigue ( n =4), anemia ( n =4), and low magnesium ( n =3). This study showed that EGFR inhibition with cetuximab appears to augment the antitumor activity of paclitaxel in patients with previously treated urothelial cancers, warranting further study [19]. Cetuximab is also being examined in front-line setting in combination with GC in a study for which accrual is complete and results are awaited [20].…”