Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group.

Abstract

3 Background: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab (B), a humanized anti-VEGF monoclonal antibody, has shown single-agent activity in pretreated recurrent disease. We aimed to evaluate B in chemotherapy (CTX)-naive recurrent/persistent/metastatic cervical cancer. Methods: Using a 2x2 factorial design, patients were randomly assigned to CTX with or without B 15 mg/kg. The CTX regimens included cisplatin 50 mg/m2 plus paclitaxel 135-175 mg/m2 and topotecan 0.75 mg/m2 d1-3 plus paclitaxel 175 mg/m2d1. Cycles were repeated every 21 days until disease progression, unacceptable toxicity, or complete response. Overall survival (OS) was the primary endpoint with a reduction in the hazard of death by 30% using anti-VEGF therapy considered important (90% power, 1-sided alpha=2.5%). Final analysis was planned when 346 deaths were observed. Results: 452 patients were accrued from 4/6/09 to 1/3/12. The scheduled interim analysis occurred after 174 patients had died and showed that the topotecan-paclitaxel backbone was not superior to the cisplatin-paclitaxel backbone. A second interim analysis was conducted after 271 deaths. A total of 225 patients received CTX alone and 227 patients received CTX plus B. The randomized treatment groups were similar with regard to age, histology, performance status, previous platinum as a radiosensitizer, and recurrence, persistence, or advanced disease. The B-to-no-B hazard ratio (HR) of death was 0.71 (97.6% CI 0.54-0.95; 1-sided p=0.0035). Median survival was 17 m (CTX plus B) and 13.3 m (CTX alone). The RR were 48% (CTX plus B) and 36% (CTX alone) (p=0.0078). Treatment with B was associated with more grade 3-4 bleeding (5 vs 1%) thrombosis/embolism (9 vs 2%), and GI fistula (3 vs 0%). Conclusions: For the first time a targeted agent significantly improved OS in gynecologic cancer. The second interim analysis crossed the boundary for efficacy, warranting early release of this information. The nearly 4-month increase in median OS with the addition of B to CTX in women with recurrent cervical cancer is considered to be clinically significant. Clinical trial information: NCT00803062.

Platinum-free Interval in Second-line Chemotherapy for Recurrent Cervical Cancer

“…Recently, a 4-arm, phase III trial including a platinumbased combination regimen with or without the molecularly targeted agent bevacizumab and a nonYplatinum-based combination regimen with or without bevacizumab was performed in patients with advanced or recurrent cervical cancer. 16 The results showed that concurrent and sustained administration of bevacizumab substantially prolonged OS. Bevacizumab is also known to prolong PFS in ovarian cancer, not only when used with multiple agents in platinum-sensitive cases, 17 but also in conjunction with a single agent in platinum-resistant cases.…”

Patient-Derived Xenograft Models in Gynecologic Malignancies

“…30 Furthermore, standard of care combinations of platinum based chemotherapy and radiotherapy for the primary, potentially “curative” treatment of stage IB-IV cervical cancer have remained largely unchanged since the 1990s, as has outcome. 31–34 In some respects, our understanding of the biological and molecular heterogeneity of this disease has lagged behind that of other cancers.…”

Major clinical research advances in gynecologic cancer in 2013

“…In the plenary session of the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Dr. Tewari presented the interim analytical results of a phase III randomized trial conducted by the Gynecologic Oncology Group (GOG), GOG 240, which regarded the incorporation of BEV for the treatment of recurrent and metastatic cervical cancers [1]. A total of 452 patients with metastatic, recurrent, or persistent cervical cancers that were incurable with standard treatments were enrolled in this study and randomized to one of four treatment arms: (1) cisplatin (50 mg/m 2 ) plus paclitaxel (135 to 175 mg/m 2 ) alone; or (2) with BEV; or (3) topotecan (0.75 mg/m 2 on days 1 to 3) plus paclitaxel (175 mg/m 2 on day 1) alone; or (4) with BEV.…”