A randomized, double-blind, placebo-controlled, phase II study to assess the efficacy/safety of farletuzumab in combination with carboplatin plus paclitaxel or carboplatin plus pegylated liposomal doxorubicin (PLD) in women with low CA-125 platinum-sensitive ovarian cancer
Herzog T, Pignata S, Ghamande S, Rubio MJ, Fujiwara K, Vulsteke C, Armstrong D, Sehouli J, Coleman R, Gabra H, Scambia G, Monk B, Arija JA, Ushijima K, Hanna R, Zamagni C, Wenham R, Gonzalez-Martin A, Slomovitz B, Jia Y, Ramsay L, Tewari K, Weil S, and Vergote I. A randomized, double-blind, placebo-controlled, phase II study to assess the efficacy/safety of farletuzumab in combination with carboplatin plus paclitaxel or carboplatin plus pegylated liposomal doxorubicin (PLD) in women with low CA-125 platinum-sensitive ovarian cancer. Gynecologic Oncology 2021; 162:S38-S39.
Objectives: The primary objective of this study (MORAb-003-011/ENGOT-ov27) was to determine if farletuzumab (FAR) had superior efficacy compared with placebo (PLB) in improving progression-free survival (PFS) when added to carboplatin (carbo)/paclitaxel (pacli) or carbo/PLD, in subjects with platinum-sensitive ovarian cancer in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125). CA-125 inhibits target cell killing via antibody-dependent cellular cytotoxicity, thereby reducing the efficacy of immunotherapeutic antibodies. Subgroup analysis in a prior randomized Phase III study±FAR suggested that subjects with CA-125 levels ≤3 x upper limit of normal (ULN), showed superior PFS (hazard risk [HR] = 0.49) and overall survival (OS, HR = 0.44) compared with PLB.
Methods: Eligibility included age ≥18 years old, CA-125 ≤3 x ULN (105 U/mL), high-grade serous epithelial ovarian cancer, and previous treatment with debulking surgery and first-line platinum-based chemotherapy. Subjects received 6 cycles with either carbo/pacli every 3 weeks or carbo/PLD in combination with either FAR [5 mg/kg weekly] or PLB in a 2:1 ratio. Maintenance treatment with FAR (5 mg/kg weekly) or PLB was given until disease progression. Tumor assessments were every 6 weeks during the Combination Treatment Phase and every 9 weeks during the Maintenance Treatment Phase. The study was designed to detect a PFS HR of 0.667 (33.3% risk reduction) with FAR compared with PLB with approximately 85% power and a 1-sided type I error rate of 0.10. The comparison of PFS between treatment groups was based on the log-rank test. The HR was estimated based on Cox's proportional-hazards model.
Results: A total of 214 subjects were randomized and enrolled, 142 with FAR+chemotherapy (FAR-CT) and 72 with placebo+chemotherapy (PLB-CT). The median PFS in the Intent-to-Treat [ITT] Population was not significantly different between treatment groups; 11.7 months (95% confidence interval [CI]: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for FAR-CT and PLB-CT, respectively (HR = 0.89; 80% CI: 0.71, 1.11). An interim analysis of OS showed no significant difference between treatment groups. The overall response rate (ORR) was 69.6% in 96 subjects treated with FAR-CT versus 73.5% in 50 subjects treated with PLB-CT (p=0.53). No significant differences between treatment groups were observed for any other efficacy parameters. The safety profile of the 2 treatment groups was similar except for an increase in interstitial lung disease among the FAR cohort. Interstitial lung disease occurred in 7 of 141 (5.0%) subjects treated with FAR-CT (1 with Grade 1, 4 with Grade 2, and 2 with Grade 3) and none in subjects treated with PLB-CT.
Conclusions: The combination of FAR-CT did not show signals of superior efficacy compared with PLB-CT in improving PFS or other efficacy parameters in subjects with platinum-sensitive recurrent ovarian cancer in first relapse who had low CA-125 levels. No new safety concerns were identified with the combination of FAR-CT. Since FAR binds to the folate receptor alpha, a novel antibody-drug conjugate has been developed and clinical studies are ongoing to assess the safety/efficacy of this modification. Clinical Trial Registry: NCT02289950.