Addition of Bevacizumab to Platinum-Based Doublet Extends PFS in Platinum-Sensitive Recurrent Ovarian Cancer

Patients with platinum-sensitive recurrent ovarian cancer experienced improved progression-free survival (PFS) when frontline treatment with bevacizumab (Avastin) was continued beyond disease progression and combined with chemotherapy compared with standard chemotherapy alone, according to results from the phase 3 MITO16b/MANGO–OV2/ENGOT–ov17 study.

“Results from this study show that adding bevacizumab to a platinum-based doublet is safe and improves progression-free survival in patients with platinum-sensitive recurrent ovarian cancer already treated with bevacizumab during first-line therapy,” wrote the study authors led by Sandro Pignata, MD.

The MITO16b/MANGO–OV2/ENGOT–ov17 study (NCT01802749) was conducted based on findings from 2 prior studies. First, the study of bevacizumab added to carboplatin and gemcitabine in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer [OCEANS trial (NCT00434642)] showed that bevacizumab may improve PFS. Another phase 3 trial of bevacizumab as treatment of patients with metastatic colorectal cancer (NCT00700102), hinted that extending the use of the VEGF inhibitor may enhance efficacy.

To test the therapeutic strategy, 406 patients were randomized 1:1 to receive either bevacizumab plus chemotherapy or standard chemotherapy alone. Bevacizumab was administered at 1 of 2 doses. Some patients were administered the agent by intravenous infusion every 14 days and combined with pegylated liposomal doxorubicin/carboplatin. Other patients received bevacizumab 15 mg/kg every 21 days combined with gemcitabine/carboplatin or paclitaxel/carboplatin. In the event patients did not progress after combination therapy, bevacizumab maintenance was administered at 15 mg/kg every 21 days until disease progression or unacceptable toxicity.

The primary end point was investigator-assessed PFS, and secondary end points included

overall survival (OS), centrally-reviewed PFS, objective response rate (ORR) per RECIST, and safety. The study was 90% powered to detect a 0.67 hazard ratio (HR) of progression or death.

Patients who were analyzed in the study had a median age of 60 years (range, 53-68 years) in the standard chemotherapy group and 61 years (range, 52-68 years) in the bevacizumab group. The majority of patients had serous tumor histology, including 78% of the standard chemotherapy arm and 82% of the bevacizumab arm. Most patients also had an ECOG performance score of 9, including 84% of the chemotherapy alone arm and 82% of the bevacizumab arm. An ECOG performance status of 1 was identified in 16% of the standard chemotherapy arm and 17% of the bevacizumab arm.

Length of platinum-free interval and timing to recurrence were also assessed at baseline. In the chemotherapy-alone arm, the platinum-free interval was 6 to 12 months for 35% of patients and more than 12 months for 65% of patients. In the bevacizumab arm, the platinum-free interval was 6 to 12 months for 36% of patients and longer than 12 months for 64% of patients. In both arms, recurrence followed treatment with bevacizumab maintenance in 72% of patients and during bevacizumab maintenance for 28% of patients.

Chemotherapy regimens consisted of either carboplatin plus paclitaxel, carboplatin plus gemcitabine, or carboplatin with pegylated liposomal doxorubicin. Carboplatin plus gemcitabine was the most commonly observed backbone regimen.

Unknown BRCA mutations were found in 39% of the chemotherapy-only group and 34% of the bevacizumab group; BRCA wild-type was found in 49% of the chemotherapy only group and 51% of the bevacizumab group; and 11% of the standard chemotherapy arm had BRCA-mutated disease as did 15% of the bevacizumab arm.

At a median follow-up of 20.1 months (interquartile range, 12.9-27.8), the median PFS observed was 8.8 months (95% CI, 8.4-9.3) in the standard chemotherapy group versus 11.8 months (95% CI, 10.8-12.9) in the bevacizumab group (HR, 0.51; 95% CI, 0.41-0.65; log-rank P = .0001).

The PFS benefit of bevacizumab added to chemotherapy appeared to be even longer for patients with BRCA wild-type disease. Further, receipt of carboplatin plus gemcitabine as backbone chemotherapy was associated with a lower PFS compared with the other 2 chemotherapy regimens. No other significant correlations between subgroups and PFS were found in the study.

In terms of the secondary end points, it was shown that the median OS was statistically significant between the 2 treatment arms. Among patients treated with standard chemotherapy, the median OS was 27.1 months (95% CI, 22.0 to not reached) compared with 26.7 months (95% CI, 22.7-30.5) in the bevacizumab arm (HR, 0.99; 95% CI, 0.73-1.39; stratified log-rank P < .98).

ORR was assessable in 70% of the standard chemotherapy arm and 64% of the bevacizumab arm, and the analysis showed that complete or partial responses were achieved by 49.7% of patients in the standard chemotherapy group (95% CI, 41.2%-58.1%) compared with 69.25% of the bevacizumab arm (95% CI, 60.5%-77.0%).

Two hundred patients who were treated with standard chemotherapy and 201 who received bevacizumab were evaluated for safety in the study. The most common grade 1/2 adverse events (AEs) observed in the standard chemotherapy arm versus the bevacizumab arm were hypertension (83% vs 69%, respectively), anemia (57% vs 56%), fatigue (54% vs 62%), and nausea (45% vs 54%). More serious AEs were observed with the bevacizumab combination.

Overall, 3 patients in the study died, 2 of whom received treatment in the standard chemotherapy arm. Eighty-nine patients in the chemotherapy-only arm had dose reduction as did 96 patients in the bevacizumab arm. Dose delays were seen in 63% of the chemotherapy-only arm versus 51% of the bevacizumab arm. In addition, 40% of those who received bevacizumab maintenance experienced dose delays.

In the near future, investigators of this study will take a closer look at how mutational status is associated with response to bevacizumab. The authors wrote, “Further data will come from the MITO16b/MANGO–OV2/ENGOT–ov17 translational project, which will test biomarkers potentially predictive of response to bevacizumab, including somatic BRCA mutations and homologous recombination gene mutations.”

_Reference:

_{Pignata S, Lorusso D, Joly F, et al. Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial. Lancet Oncol. 2021;22(2): 267-276. doi: 10.1016/S1470-2045(20)30637-9}