Bevacizumab OS Benefit Confirmed in Cervical Cancer

Krishnansu S. Tewari, MD

Adding bevacizumab (Avastin) to chemotherapy improved overall survival (OS) for women with cervical cancer, according to final results from the phase III GOG 240 trial published online in The Lancet.¹

There were 348 deaths by March 7, 2014, meeting the prespecified cutoff for final analysis. At that point, investigators determined that patients assigned to chemotherapy plus bevacizumab continued to show significant improvement in OS compared with chemotherapy-alone groups, at a median OS of 16.8 months versus 13.3 months (hazard ratio [HR], 0.77; 95% CI, 0.62-0.95; P = .007).

“To be able to even discuss new therapies in advanced cervical cancer is a statement that some progress has finally been made. The GOG has now completed 9 phase III randomized trials over 3 decades in this population and with this final OS analysis of the ninth trial, we have at last placed the proverbial ‘foot in the door,’” first study author Krishnansu S. Tewari, MD, Division of Gynecologic Oncology, University of California, Irvine Medical Center, and coinvestigators wrote.

“With some ground gained, the challenge exists to identify tolerable treatments that can extend survival further. Upcoming trials will probably emphasize different classes of antiangiogenesis agents, immune modulators and checkpoint inhibitors, chemotherapy- free combinations, and translational science,” the authors continued.

From April 2009 to January 2012, investigators recruited 452 women with metastatic, recurrent, or persistent cervical cancer. Patients were required to have recovered from the effects of surgery, radiation therapy, or chemoradiotherapy, and be free of active infection requiring antibiotics. Patients receiving chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible.

Participants were randomized into 4 groups:

• Arm A—50 mg/m² of cisplatin plus 135 mg/m² or 175 mg/m² of paclitaxel in 21-day cycles (n = 114)
• Arm B—0.75 mg/m² of topotecan plus 175 mg/m² of paclitaxel in 21-day cycles (n = 111)
• Arm C—50 mg/m² of cisplatin plus 135 mg/m² or 175 mg/m² of paclitaxel plus 15 mg/kg of bevacizumab in 21-day cycles (n = 115)
• Arm D—0.75 mg/m² of topotecan plus 175 mg/m² of paclitaxel plus 15 mg/kg of bevacizumab in 21-day cycles (n = 112)

A total of 225 patients in the chemotherapy alone groups were included in the efficacy analysis and 220 in primary safety analysis. In the bevacizumab groups, 227 were included in the efficacy analysis and 220 in primary safety analysis.

Patients were well-matched for GOG performance status, ethnicity, histology, disease status, and in-field pelvic recurrences. Three-quarters of the cohort had previously received platinum-based radiosensitizing chemotherapy, and this proportion was also evenly distributed between those receiving the 2 chemotherapy regimens.

Overall survival was 17.5 months in Arm C and 83 patients (72%) had a survival event compared with 15.0 months and 92 patients (81%) in Arm A. Researchers did not observe a significant survival advantage between Arm D and Arm B (16.2 vs 12.0 months; 87 [78%] vs 86 [77%]).

Post-progression OS was 8.4 months in bevacizumab groups, with 143 patients (83%) having survival events, versus 7.1 months and 153 (85%) survival events in the chemotherapy-alone groups. Post-progression OS was 8.3 months in Arm C versus 6.2 months in Arm A. For Arm D, post-progression OS was 8.7 months versus 7.5 months in Arm B.

Overall response rate (ORR) was 49% for patients treated with bevacizumab versus 36% in the chemotherapy-alone groups (P = .003). ORR was 50% in Arm C and 48% in Arm D. ORR was 46% in Arm A and only 25% in Arm B.

“Because the interaction term is significant, the effect of bevacizumab on the proportion of those responding depends on whether the regimen contains cisplatin or topotecan,” the investigators wrote. “Although bevacizumab significantly affects OS and PFS, it has a greater effect on response when given with topotecan plus paclitaxel than with cisplatin plus paclitaxel. Specifically, the proportion of patients with an overall response to topotecan plus paclitaxel is almost doubled when bevacizumab is incorporated into treatment.”

In the chemotherapy-alone groups, 119 patients discontinued for progression, 37 for toxicity, and 5 died. Sixty-six patients in the chemotherapy groups received salvage therapy, including 16 who received bevacizumab.

In the bevacizumab groups, 89 discontinued for progression, 58 for toxicity, and 6 patients died. Forty-six patients received salvage therapy, including 9 who received bevacizumab.

Thirteen patients (6%) in the bevacizumab groups, all of whom had been previously irradiated, experienced grade 3 fistula requiring intervention compared with 1 patient in the chemotherapy groups. Patients in the bevacizumab groups were also significantly more likely to experience grade ≥2 hypertension (25% vs 2%), grade ≥4 neutropenia (36% vs 26%), and grade ≥3 thrombosis or embolism (8% vs 2%).

“To see such continued separation of overall survival curves in advanced or recurrent gynecological cancer is rare and the authors are to be congratulated for providing the first proof of concept in the phase III setting that targeting of angiogenesis extends survival in patients with cervical cancer,” Susana Banerjee, MA, MBBS, MRCP, PhD, gynecology unit, Royal Marsden National Health Service Foundation Trust and Division of Clinical Studies, Institute of Cancer Research, Royal Marsden Hospital, wrote in an accompanying editorial^.2

References

1. Tewari KS, Sill MW, Penson RT, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240) [published online July 27, 2017]. Lancet doi: 10.1016/ S0140-6736(17)31607-0.
2. Banerjee S. Bevacizumab in cervical cancer: a step forward for survival [published online July 27, 2017]. Lancet doi: 10.1016/ S0140-6736(17)31965-7.