Maintenance farletuzumab following chemotherapy in combination with farletuzumab did not improve progression-free survival (PFS) for women with recurrent ovarian cancer, according to results from a study published in the Journal of Clinical Oncology.1
However, this global, multicenter, phase 3 study showed that risk for progression was reduced by 51% in a subset of patients with CA-125 not more than 3 times the upper limit of normal (ULN).
“These observations provide a dose-efficacy relationship for farletuzumab, and hence, proof of principle,” corresponding author Ignace Vergote, MD, chairman of the Leuven Cancer Institute, University Hospital Leuven, Belgium, told Cancer Therapy Advisor.
For women with epithelial ovarian cancer that has relapsed following initial response to a platinum-based regimen, treatment options are limited to further chemotherapy-based regimens.
“Despite a high initial response rate to first-line platinum doublet chemotherapy following surgical resection of EOC [epithelial ovarian cancer], there is an ongoing unmet need for improved treatment outcome,” the study investigators wrote.
Farletuzumab is a humanized monoclonal antibody against the folate receptor-alpha, which is expressed in 80% to 100% of epithelial ovarian cancers and is significantly absent in normal tissue. The study was undertaken following demonstrated antitumor activity in preclinical models of ovarian cancer and response rates seen in phase 2 studies.
Dr Vergote explained that the earlier phase 2 study, which provided initial observations on its efficacy, was small and might have overestimated the effect of farletuzumab, but added that it might still be effective.
MORab-003-004—the largest randomized trial in this population that attempted to expand treatment options for these women—was a double-blind, placebo-controlled study that involved 1100 women with epithelial ovarian tumors that relapsed after first-line treatment with platinum-based therapy. Patients were randomly assigned to placebo, farletuzumab 1.25 mg/kg, or farletuzumab 2.5 mg/kg administered once weekly in combination with the standard of care—6 cycles of carboplatin (area under the curve 5 to 6) and either paclitaxel 175 mg/m2 or docetaxel 75 mg/m2 given intravenously every 3 weeks.
Following 6 weeks of combination therapy, patients continued to receive placebo, farletuzumab 1.25 mg/kg, or farletuzumab 2.5 mg/kg administered once weekly until disease progression as determined from modified Response Evaluation Criteria in Solid Tumors version 1.0.
Approximately 27% of patients discontinued treatment after combination therapy with carboplatin and taxane. Single-agent maintenance therapy was initiated in approximately 75% of patients.
With PFS of 9.0, 9.5, and 9.7 months for women receiving placebo, farletuzumab 1.25 mg/kg, and farletuzumab 2.5 mg/kg, respectively, the study did not meet its primary endpoint. However, for women with CA-125 not more than 3 times the ULN, corresponding PFS was 8.8, 10.0, and 13.6 months, respectively.
For the 2.5 mg/kg dose, risk for disease progression was reduced by 51% (HR, 0.49; 95% CI, 0.30 – 0.79; P = .0028). This was a significant observation.
Similar observations were noted for overall survival (OS). In the study population, median OS was 29.1, 28.7, and 32.1 months for patients receiving maintenance placebo and farletuzumab 1.25 mg/kg and 2.5 mg/kg, respectively.
However, for women with CA-125 not more than 3 times the ULN, median OS was not reached for the women receiving farletuzumab 2.5 mg/kg, and it was 29.1 months for women receiving placebo (HR, 0.44; 95% CI, 0.23 – 0.84; P = .0108).
The observation of PFS being significant for women with CA-125 not more than 3 times the ULN may provide a clue to the future development of farletuzumab.
CA-125 has been used as a predictive biomarker to assess treatment response and recurrence in ovarian cancer. High levels of CA-125 may inhibit the antibody-dependent cellular cytotoxicity (ADCC)—a mechanism that is implicated in the efficacy of immunotherapeutic antibodies such as farletuzumab. ADCC is also why future clinical development may be restricted to women with CA-125 not more than 3 times the ULN.
Dr Vergote indicated that a new phase 2 trial evaluating a higher dose of farletuzumab (5 mg/kg) is ongoing in the recurrent platinum-sensitive ovarian cancer setting in women with a low CA-125.
“This study is pivotal for the future of the drug. Based on the findings of the JCO paper, the ADCC effect may occur in this group of patients,” he said.
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