Improved Survival with Bevacizumab in Advanced Cervical Cancer

SUMMARY: Cervical cancer is the fourth most common cancer affecting women, worldwide. It is also the fourth most common cause of cancer death. With the availability of widespread screening techniques and HPV vaccination in the U.S., the incidence of cervical cancer is declining. Treatment of advanced cervical cancer continues to be a challenge. The FDA recently approved AVASTIN® (Bevacizumab) for the treatment of persistent, recurrent or metastatic cervical cancer, in combination with TAXOL® (Paclitaxel) and Cisplatin or TAXOL® and HYCAMTIN® (Topotecan). The approval was based on the results of an international, randomized, four-arm, 2×2 factorial design trial with two primary comparisons of Overall Survival (OS). The first comparison was between AVASTIN® plus chemotherapy versus chemotherapy alone. The second comparison of OS was between the platinum doublet versus the non-platinum doublet chemotherapy irrespective of addition of AVASTIN®. AVASTIN®, a humanized Vascular Endothelial Growth Factor (VEGF) targeted monoclonal antibody, has demonstrated single-agent activity in heavily pretreated patients with recurrent cervical carcinoma in phase II trials. In this randomized study, 452 enrolled patients with metastatic, persistent or recurrent cervical cancer received one of the four treatment regimens using a 2×2 factorial design. The four treatment groups included a) Cisplatin 50 mg/m2 plus TAXOL® (Paclitaxel) 135 or 175 mg/m2 (N=114), b) HYCAMTIN® (Topotecan) 0.75 mg/m2 given on D1 thru D3 plus TAXOL® 175 mg/m2 given on Day 1 (N=111), c) Cisplatin 50 mg/m2 plus TAXOL® 135 or 175 mg/m2 given along with AVASTIN® 15mg/kg on Day 1 (N=115) and d) HYCAMTIN® 0.75 mg/m2 given on D1 thru D3 plus TAXOL® 175 mg/m2 given on Day 1, along with AVASTIN® 15mg/kg on day 1 (N=112). Treatment was given every 21 days until disease progression, the development of unacceptable toxicities or a complete response was noted. The primary end point was Overall Survival and secondary endpoints included Progression Free Survival (PFS) and Response Rate (RR). When outcomes were analyzed, HYCAMTIN® based chemotherapy was not superior to Cisplatin based chemotherapy, regardless of prior exposure to Cisplatin. At a median follow-up of 20.8 months, the addition of AVASTIN® to chemotherapy resulted in a significantly longer median Overall Survival (17 vs 13.3 months; HR=0.71; P=0.004), significantly longer median PFS (8.2 vs 5.9 months; HR=0.67; P=0.002) and Response Rate (48% vs 36%; P=0.008), compared to combination chemotherapy alone. With regards to the second primary comparison of Overall Survival, the TAXOL® plus HYCAMTIN® with or without AVASTIN® groups did not demonstrate an improvement in Overall Survival compared to the TAXOL® plus Cisplatin with or without AVASTIN® groups. The benefit with added AVASTIN® was noted in all subgroups regardless of age, race, performance status and prior platinum exposure. Treatment was in general well tolerated without significant reduction in quality of life. As was seen in other tumor types, AVASTIN® based chemotherapy regimen was associated with a higher incidence of hypertension and thromboembolic events. The authors concluded that the addition of AVASTIN® to combination chemotherapy significantly decreased the risk of death in patients with recurrent, persistent, or metastatic cervical cancer. It can also be concluded from this study that the TAXOL® with HYCAMTIN® plus AVASTIN® is an acceptable alternative for women with advanced cervical cancer, who are not candidates for Cisplatin based chemotherapy. Tewari KS, Sill MW, Long HJ, et al. N Engl J Med 2014; 370:734-743