Bevacizumab Appears to Benefit High-Risk Patients

Two phase 3 trials presented at the 2013 European Cancer Congress suggest that the optimal role of bevacizumab will be in high-risk patients.

AURELIA is the first phase 3 study to evaluate the addition of bevacizumab to chemotherapy in platinum-resistant ovarian cancer (defined as progression within 6 months of last platinum-containing therapy).¹ The addition of bevacizumab to chemotherapy significantly improved progression-free survival (PFS) from 3.4 months to 6.7 months (P <.001), and median overall survival (OS) was improved from 13.3 months with chemotherapy alone to 16.6 months, but this did not reach statistical significance. Chemotherapy agents included paclitaxel, topotecan, and liposomal doxorubicin.

“No single agent has shown superiority to weekly paclitaxel, topotecan, or liposomal doxorubicin. Median survival in platinum-resistant ovarian cancer is typically around 12 months,” said lead author Petronella Witteveen, MD, DCOG, of University Medical Centre Utrecht, in the Netherlands.

AURELIA randomized 361 patients to receive bevacizumab plus investigator’s choice of chemotherapy versus chemotherapy alone. Treatment was continued until disease progression, unacceptable toxicity, or consent withdrawal.

At progression, patients in the chemotherapy arm were allowed to cross over to bevacizumab monotherapy; bevacizumab was discontinued after progression in the bevacizumab plus chemotherapy arm.

An exploratory subgroup analysis of OS suggested that weekly paclitaxel was the best partner for bevacizumab. In the weekly paclitaxel cohort, median OS was 22.4 months for bevacizumab versus 13.2 months in controls, representing a 35% relative improvement favoring bevacizumab. By contrast, in the cohort treated with liposomal doxorubicin, median OS was 13.7 months in those randomized to receive bevacizumab plus chemotherapy versus 14.1 months with chemotherapy only. For the topotecan-treated cohort, median PFS was 13.8 months for those treated with bevacizumab plus chemotherapy versus 13.3 months for chemotherapy only.

“The effect of weekly paclitaxel should be considered exploratory and requires prospective validation,” Witteveen said.

No new safety concerns were identified in an updated safety analysis. The main grade ≥3 toxicities in the bevacizumab arm were hypertension (7.8%) and proteinuria (2.2%).

The ICON7 trial evaluated bevacizu- mab in women with newly diagnosed ovarian cancer. The primary analysis (previously reported) showed a median PFS of 17.3 months for chemotherapy alone versus 19 months for bevacizumab added to chemotherapy (P = .004).²

In the final survival analysis presented at the European Cancer Congress, median OS was 58 months in the study for both arms; however, poor-prognosis patients experienced a 4.8-month prolongation of survival (from 34.5 months to 39.3 months) if they received bevacizumab.³

“The survival benefit in the overall trial of 0.9 months is not clinically meaningful. However in the high-risk subgroup, bevacizumab did show a clinically meaningful benefit of 4.8 months,” said Amit Oza, MD, Princess Margaret Cancer Centre, University of Toronto, Canada.

The international study randomized 1528 women to 6 cycles of every-3-week carboplatin/paclitaxel versus carboplatin/paclitaxel plus bevacizumab for 5 or 6 cycles followed by bevacizumab for 12 additional every-3-week cycles until disease progression. Patients were prestratified according to stage, extent of debulking, and time of therapy. A third of the women were considered high risk (stage III with >1 cm residual disease, stage IV, and nondebulked).

At a median follow-up of 49 months, PFS was not significantly different between the 2 arms, similar to the first interim analysis presented previously.

Over 4 years, the difference between the 2 curves was gradually eroded, Oza said. Because the curves are nonproportional, the final OS analysis was conducted using a restricted means analysis, and the difference between the 2 arms was 0.9 months, which was not statistically or clinically meaningful.

In a predefined high-risk subgroup of patients, the curves for the 2 arms separated and the bevacizumab arm was superior throughout the study, with a 4.8-month improvement over the control arm.

Oza said the difference in survival for high-risk patients given bevacizumab was clinically meaningful.

References

1. Witteveen P, Lortholary A, Fehm T, et al. Final overall survival (OS) results from AURELIA, an open-label randomized phase III trial of chemotherapy (CT) with or without bevacizumab (BEV) for platinum-resistant ovarian cancer. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract LBA5.
2. Perren TJ, Swart AM, Pfisterer J, et al; the ICON7 investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484-2496.
3. Oza AM, Perren TJ, Swart AM, et al. ICON7: final overall survival results in the GCIG phase III randomized trial bevacizumab in women with newly diagnosed ovarian cancer. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract LBA6.