Bevacizumab plus chemotherapy improves OS in recurrent ovarian cancer

Issue: December 25, 2015

The addition of bevacizumab to a standard chemotherapy regimen conferred a median 5-month survival improvement among women with ovarian cancer, according to results of a phase 3 study presented at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.

Perspective from Leslie M. Randall, MD

Robert L. Coleman, MD, FACOG, FACS, the Ann Rife Cox chair in gynecology, vice chair of clinical research and professor in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, and colleagues sought to evaluate the addition of bevacizumab (Avastin, Genentech) to standard chemotherapy followed by bevacizumab maintenance in women with platinum-sensitive, recurrent ovarian cancer. Researchers also sought to evaluate the role of secondary cytoreduction before chemotherapy initiation in this population; however, enrollment for this phase is ongoing.

Robert L. Coleman

Researchers randomly assigned patients to 175 mg/m² paclitaxel and carboplatin alone (area under the curve [AUC] = 5; n = 374) or with 15 mg/kg bevacizumab followed by maintenance bevacizumab (n = 374). The median age of the population was 60 years, and 81% of the women had serous histology.

OS served as the study’s primary endpoint, and secondary endpoints included safety, PFS, rate for allergy and intervention-dependent quality of life.

Both cohorts received six cycles of chemotherapy. The bevacizumab group continued with the study drug as maintenance thereafter.

The addition of bevacizumab improved the stratified estimated treatment HR for death by 18.6% (HR for OS = 0.83; 95% CI, 0.68-1.005) compared with chemotherapy alone. Median OS was 42.2 months in the bevacizumab arm compared with 37.3 months in the chemotherapy alone arm.

Bevacizumab also was associated with a reduced risk for disease progression (HR for PFS = 0.61; 95% CI, 0.52-0.72). Median PFS was 13.8 months in the bevacizumab arm, whereas patients in the chemotherapy alone arm demonstrated a median PFS of 10.4 months.

Significantly more patients in the bevacizumab arm experienced gastrointestinal perforations necrosis fistula (14.8% vs. 4%; P ˂ .001), infections (13% vs. 5.8%; P = .002), joint pain (15.1% vs. 4.6%; P ˂ .001), proteinuria (8.1% vs. 0%; P ˂ .001) and venous thrombosis (3.9% vs. 1.2%; P = .046). Allergy of all grades occurred in a similar proportion of patients who received chemotherapy alone or with bevacizumab (25.1% vs. 26.7%).

Quality of life and the role of the secondary surgery assessments are ongoing.

“Most women whose ovarian cancer is recurring want every edge to extend their lives,” Coleman said in a press release. “This trial, while not completely definitive, builds on previous data, offering hope that we can hone in on treatments to achieve that goal.” – by Anthony SanFilippo

Reference:

Coleman RL, et al. Abstract #3. Presented at: Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 28-31, 2015; Chicago.

Disclosure: HemOnc Today was unable to obtain a list of relevant financial disclosures from the researchers at the time of reporting.

Perspective

Leslie M. Randall, MD

GOG 213 is the second adequately powered clinical trial to examine the efficacy of bevacizumab (Avastin, Genentech) in platinum-sensitive recurrent ovarian cancer. This phase 3, non-placebo–controlled trial enrolled women with platinum-sensitive recurrent ovarian cancer, defined as clinical recurrence after 6 months following completion of last platinum-containing regimen. Women were randomly assigned to standard carboplatin plus paclitaxel or gemcitabine with or without bevacizumab during treatment and maintenance. There was no maintenance treatment in the control group. GOG 213 also was designed to answer the question of whether secondary surgical cytoreduction benefits properly selected women. Per protocol, selection criteria included women with platinum-sensitive recurrent disease amenable to complete (R0) resection. Prior to chemotherapy, women considered suitable candidates for surgery were randomized to receive surgery or not, but surgical randomization was not mandated. Therefore, some women went straight to chemotherapy randomization. In contrast to previous ovarian cancer trials, OS was the primary endpoint, and this trial was designed to provide 81% power to detect a 25% improvement in OS with bevacizumab at 214 events (deaths). Patients were stratified by surgical participation, platinum-free interval and prior bevacizumab treatment. Currently, the chemotherapy results are available, but the surgical protocol remains ongoing.
For the 748 women randomized, the median age was 60 years, the predominant histology was high-grade serous and subjects were balanced across the three strata. The median OS in the experimental arm was 42.2 months compared with 37.3 months for those in the control arm. The addition of bevacizumab reduced the HR for death by 18.6%, and this result was nearly statistically significant (HR = 0.82; 95% CI, 0.68-1). PFS, a secondary endpoint, was significantly improved with bevacizumab by 39% (HR = 0.61; 95% CI, 0.52–0.72), consistent with the OCEANS and other trials of bevacizumab in ovarian cancer such as GOG 218, ICON 7 and AURELIA. Women on the bevacizumab arm experienced more grade 3 or worse toxicity, and those statistically different from control group included gastrointestinal perforation, necrosis or fistula (14.8% in the experimental arm), infection, arthralgia and proteinuria. Hypersensitivity to carboplatin of 26% was no different between the arms.
At this time it is uncertain what these results mean for clinical practice. Certainly it is encouraging to see the OS result nearly reaching statistical significance, but does this close margin justify the additional risks? Those of us who treat ovarian cancer have all had patients who enjoy long-term benefit from bevacizumab and those who only gain toxicity. Quality-of-life results from this protocol should help answer this question. As usual, the truth probably lies somewhere in the middle, and there are likely differential responses to anti-vascular therapy with certain disease biologies. Therefore, the translational science that will result from this protocol is anxiously awaited to provide markers predictive of benefit from bevacizumab.

References:

Aghajanian C, et al. J Clin Oncol. 2012;doi:10.1200/JCO.2012.42.0505.

Burger RA, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1104390.

Perren TJ, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1103799. Erratum in: N Engl J Med. 2012;doi:10.1056/NEJMx110087.

Pujade-Lauraine E, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.51.4489.

Leslie M. Randall, MD

University of California Irvine Health

Disclosures: Randall reports no relevant financial disclosures.