Pegylated Doxorubicin/Carboplatin Plus Bevacizumab Improves PFS in Recurrent Ovarian Cancer

Jacobus Pfisterer, MD, PhD

The combination regimen of pegylated liposomal doxorubicin (CD-BEV) with bevacizumab (Avastin) was found to significantly improve progression-free survival (PFS) versus carboplatin/gemcitabine (CG-BEV) in patients with recurrent disease whose first recurrence was longer than 6 months following frontline platinum-based chemotherapy, according to phase III findings presented at the 2018 ESMO Congress.

In the prospective study, which included nearly 700 patients, the median PFS was 13.3 months (95% CI, 11.7-14.3) in patients randomized to CD-BEV versus 11.7 months (95% CI, 11.1-12.8) in the arm randomized to CG-BEV, reported Jacobus Pfisterer, MD, PhD. The 1.6 months of improvement in median PFS in the CD-BEV arm translated to a hazard ratio of 0.807 (95% CI, 0.681-0.956; stratified log-rank P = .0128).

“CD-BEV is a new treatment option for patients with recurrent ovarian cancer suitable for platinum-based retreatment, even after previous antiangiogenic treatment,” said Pfisterer, of the Gynecologic Oncology Center in Kiel, Germany.

The PFS advantage conferred by CD-BEV was also evident in subgroups examined according to platinum-free interval, the presence or absence of residual tumor, and whether patients were previously treated with antiangiogenic therapy.

There was also a trend toward an improvement in median overall survival (OS) with CD-BEV compared with CG-BEV that did not achieve significance (33.5 vs 28.2 months; HR, 0.833; 95% CI, 0.680-1.022; stratified log-rank P = .0787).

A total of 682 patients with recurrent ovarian cancer suitable for platinum-based retreatment were randomized 1:1 to standard treatment (CG-BEV) or the experimental treatment (CD-BEV). In the standard arm, bevacizumab was given as 15 mg/kg on day 1, followed by gemcitabine (1,000mg/m² on days 1 and 8) and carboplatin (AUC4 on day 1) every 3 weeks for up to 6 cycles in the absence of progression disease or unacceptable toxicities.

In the experimental arm, bevacizumab was given at 10 mg/kg on day 1 and 15 followed, by pegylated liposomal doxorubicin (30 mg/m² on day 1) and carboplatin (AUC5 on day 1) every 4 weeks for up to 6 cycles in the absence of progression disease or unacceptable toxicities.

Bevacizumab maintenance, at 15 mg/kg, was continued every 3 weeks until progression of disease or unacceptable toxicities in both arms. As of July 10, 2018, bevacizumab was ongoing in 3% of patients and 32% were alive and still being followed.

Median patient age was 62 years (range, 23-85); 62% had an ECOG performance status of 0 at baseline. Three-fourths (76%) of patients had residual tumor at enrollment. The platinum-free interval was 6 to 12 months in 31% and >12 months in 69%. The primary tumor type was epithelial ovarian cancer in 88%. Almost half (48%) of the patients had previous antiangiogenic treatment, the most common being prior bevacizumab in 41%.

The mean relative dose intensity of bevacizumab was 91.5%, at 92.2% (CG-BEV) and 85.3% (CD-BEV) in the chemotherapy phase of the trial and about 96% in both arms in the maintenance phase.

Almost all (97.7%) of the patients suffered an adverse event (AE); 9.2% overall had a serious AE, the rate of which was similar between arms, and 44.6% of the grade 3-5 AEs were of special interest. Grade 3 neutropenia was more common in the CG-BEV arm versus CD-BEV (22.2% vs 12.0%, respectively) while grade 3 hypertension occurred in 27.7% of the CD-BEV group versus 20.7% of the CG-BEV arm. Grade 5 AEs occurred in 11 patients (1.7%) between the 2 arms, 7 from standard therapy and 4 from the experimental treatment.

In an exploratory subgroup analysis for PFS, the benefit of CD-BEV was maintained whether patients had a platinum-free interval of 6 to 12 months (HR, 0.798) or >12 months (HR, 0.812), whether patients had residual tumor (HR, 0.841) or not (HR, 0.682), and whether they received antiangiogenic treatment previously (HR, 0.732) or not (HR, 0.881).

Biologic PFS by serum CA 125 was a median of 11.5 months with CD-BEV compared with a median of 10.0 months with CG-BEV (HR, 0.758; 95% CI, 0.641-0.896; stratified log-rank P = .001).

Global quality-of-life scores favored CD-BEV, but the difference was not significant over time.

“These are very strong data with robust evidence that CD-BEV is better than CG-BEV,” said invited discussant Sandro Pignata, MD, PhD, from the Istituto Nazionale Tumori di Napoli in Italy. The CD-BEV regimen has proven to be superior to carboplatin/gemcitabine/bevacizumab, carboplatin/paclitaxel, and carboplatin/paclitaxel for the treatment of recurrent ovarian cancer or in the first-line setting, but data on alopecia and hematologic toxicity are still needed when comparing these regimens, he said.

Another weakness is that BRCA and homologous recombination deficiency (HRD) statuses were not known in the trial, said Pignata. It is known that platinum-sensitive recurrence is enriched for HRD-deficient patients and that carboplatin plus pegylated liposomal doxorubicin may be more effective in such patients. Evidence also suggests that pegylated liposomal doxorubicin-based treatment is more effective in patients with BRCA-mutated ovarian cancer. For these reasons, BRCA and HRD statuses need to be investigated as possible biomarkers in clinical trials of ovarian cancer.

Pfisterer J, Dean AP, Baumann K, et al. Carboplatin/pegylated liposomal doxorubicin/bevacizumab (CD-BEV) vs. carboplatin/gemcitabine/bevacizumab (CG-BEV) in patients with recurrent ovarian cancer. A prospective randomized phase III ENGOT/GCIG-Intergroup study (AGO Study Group, AGO-Austria, ANZGOG, GINECO, SGCTG). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 933O.