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CHICAGO -- Women with advanced ovarian cancer previously treated with bevacizumab (Avastin) had a 3-month improvement in progression-free survival (PFS) when they received second-line therapy that included bevacizumab, European investigators reported.

Median PFS increased from 8.8 months with platinum-based chemotherapy to 11.8 months with chemotherapy plus bevacizumab, although overall survival did not improve significantly with the addition of the angiogenesis inhibitor, Sandro Pignata, MD, of the Instituto Nazionale Tumori "Fondazione G. Pascale"-IRCSS in Naples, Italy, said here at the American Society of Clinical Oncology meeting.

"In ovarian cancer patients relapsing 6 months or more after last platinum-based chemotherapy, previously treated with bevacizumab in first line, rechallenge with bevacizumab in combination with a platinum-based doublet is associated with a significantly prolonged progression-free survival with no unexpected toxicity," said Pignata. "Rechallenge with platinum-based chemotherapy and bevacizumab is a clinical option in recurrent patients already treated with bevacizumab."

Beyond the PFS benefit, the trial provided important insights into the biology of cancer and the role of angiogenesis inhibitors, said invited discussant Charlie Gourley, PhD, of the University of Edinburgh in Scotland. By directly targeting the cancer cell, chemotherapy triggers resistance mechanisms that are "hard-wired into the cell." Consequently, reexposure to the same agent at disease progression "probably isn't a good idea."

In contrast, angiogenesis inhibitors take away the "goodies" in the tumor microenvironment. When the treatment is stopped, the "goodies" return.

"That may not be a good thing to do," said Gourley. "Maybe we need to think about resistance to antiangiogenic therapies differently."

In support of the comments, he noted that the hazard ratio associated with the 3-month improvement in PFS reported by Pignata (0.51) is consistent with hazard ratios of prior trials of second-line bevacizumab involving patients who had not received the angiogenesis inhibitor as part of first-line therapy. In the current study, prior exposure to bevacizumab did not appear to blunt the drug's effect in second line.

"This was a well-powered, well-conducted study with an inclusive design," Gourley said in conclusion. "These are potentially practice-changing results. This study improves our understanding of what we are trying to achieve with antiangiogenic therapy."

Though not addressed in the study design, the cost associated with extended use of bevacizumab will be an issue, Gourley added.

When added to first-line platinum-based chemotherapy, concurrent bevacizumab plus maintenance improves PFS in advanced ovarian cancer. The angiogenesis inhibitor also provides benefit for patients with recurrent disease (platinum-sensitive or platinum-ineligible) and no prior exposure to bevacizumab, said Pignata, noting that 70%-80% of patients with recurrent disease are eligible for rechallenge with platinum-based therapy.

No previous trial had specifically evaluated the efficacy of adding bevacizumab to chemotherapy for patients with disease recurrence after first-line treatment that included bevacizumab.

Investigators at centers affiliated with cooperative research groups in Italy, France, Switzerland, and Greece enrolled patients with recurrent, platinum-sensitive ovarian cancer treated with bevacizumab in the first-line setting. They were randomized to receive platinum-based chemotherapy only or with bevacizumab.

The trial had a primary endpoint of PFS, and secondary endpoints included overall survival, safety, and objective response rate. The study population comprised 405 patients who had a median age of 61. About 80% of the patients had serous cancers, and 10% had BRCA mutations, although mutation assessment had yet to be performed for more than half the patients.

Two-thirds of the patients had a platinum-free interval >12 months. The most commonly used chemotherapy regimens were carboplatin-gemcitabine (48.6%) and carboplatin-pegylated liposomal doxorubicin (41.0%). A little more than half the patients had surgical debulking to <1 cm residual disease.

Three 3-month difference in PFS met prespecified criteria for statistical significance (HR 0.51, 95% CI 0.41-0.65, P<0.001). Subgroup analysis showed a consistent benefit for the addition of bevacizumab to chemotherapy. Median overall survival was 27.1 months with chemotherapy alone and 26.6 months with the addition of bevacizumab. The response rate also was similar (65.7% with chemotherapy, 74.6% with bevacizumab).

The most common grade ≥3 toxicities with bevacizumab were neutropenia (39.8%), thrombocytopenia (30.3%, P=0.04 versus the control arm), hypertension (28.9%, P<0.001), and anemia (10.9%). Proteinuria also occurred more often in the bevacizumab arm (3.9% vs 0, P=0.007).

An extensive biomarker analysis is ongoing, said Pignata.

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