Farletuzumab (a monoclonal antibody against folate receptor alpha) in relapsed platinum-sensitive ovarian cancer

Highlights

• Complete or partial ORR was 75% with combination therapy.

• Response rate among subjects with first progression-free interval < 12 months (75%) was comparable to subjects with progression-free interval ≥ 12 (84%).

• In 21% of evaluable subjects, second progression-free interval was longer than first progression-free interval.

Abstract

Objective

Farletuzumab is a humanized monoclonal antibody to folate receptor-α, which is over-expressed in most epithelial ovarian cancers but largely absent on normal tissue. We evaluated clinical activity of farletuzumab, alone and combined with chemotherapy, in women with first-relapse, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancers.

Methods

Fifty-four eligible subjects received open-label farletuzumab weekly, single agent or combined with carboplatin (AUC_5–6) and taxane (paclitaxel 175 mg/m² or docetaxel 75 mg/m²), every 21 days for 6 cycles, followed by farletuzumab maintenance until progression. Twenty-eight subjects with asymptomatic CA125 relapse received single-agent farletuzumab and could receive platinum/taxane chemotherapy plus farletuzumab after single-agent progression. Twenty-six subjects with symptomatic relapse entered the combination arm directly; 21 subjects entered after single agent. Primary endpoints included normalized CA125 and Overall Response Rate (ORR). Duration of each subject's second progression-free interval (PFI₂) was compared with her own first response interval (PFI₁).

Results

Farletuzumab was well-tolerated as single agent, without additive toxicity when administered with chemotherapy. Of 47 subjects who received farletuzumab with chemotherapy, 38 (80.9%) normalized CA125. In 9/42 (21%) evaluable subjects, PFI₂ was ≥ PFI₁, better than the historical rate (3%). There was a high response rate among subjects with PFI₁ < 12 months (75%), comparable to that in subjects with PFI₁ ≥ 12 months (84%). Complete or partial ORR was 75% with combination therapy.

Conclusion

Based on this study, farletuzumab with carboplatin and taxane may enhance the response rate and duration of response in platinum-sensitive ovarian cancer patients with first relapse after remission of 6–18 months.

Introduction

Ovarian cancer is a leading cause of death due to gynecological malignancies, as a result of advanced stage at diagnosis, lack of curative front-line strategies, and acquired drug resistance [1]. Despite modest gains in median survival, percentage cured has varied little in the past 30 years [2]; this continues to fuel the search for effective interventions.

Over the last decade, increasing emphasis has been placed on understanding biological mechanisms of disease proliferation, invasion, metastasis and drug resistance to develop pharmaceuticals that target promoters of malignant phenotypes. One such target is folate receptor-alpha (FRA), a 38-kDa glycosylphosphatidylinositol-anchored protein that binds folic acid with high affinity (K_D approximately 2 nM) and transports folate by receptor-mediated endocytosis [3], [4]. FRA is found in few normal tissues but is highly expressed on more than 90% of ovarian cancer cells, retaining expression in both metastatic and recurrent disease [3], [4]. Functionally, FRA serves as a folate scavenger in the uterine lumen during pregnancy and in the kidney for reduction of folate excretion; it may also provide an antibacterial function in the lung epithelium by removing folate from secretions. FRA allows cells to grow in low-folate environments, providing potential growth advantage to tumor cells [5], [6].

Farletuzumab is a humanized monoclonal antibody to FRA produced in Chinese hamster ovary (CHO-K1) cells and constructed by grafting complementarity-determining regions of a murine antibody into a human IgG_1/κ backbone [7]. Farletuzumab does not block FRA binding of folates and antifolates and minimally retards both folate delivery via FRA-mediated transport and cell growth in vitro [8]. In preclinical models, farletuzumab demonstrated growth-inhibitory effects on FRA-expressing ovarian cancer cells. Mechanistically, cytotoxicity is mediated via complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Anti-tumor activity in animals bearing FRA-expressing ovarian cancers has demonstrated synergy of farletuzumab with taxanes [9], [10].

Farletuzumab was initially evaluated as monotherapy in a Phase I study of 25 subjects with platinum-resistant epithelial ovarian cancer, administered intravenously (IV) weekly for 4 weeks in doses of 12.5 to 400 mg/m² [11]. Following 1 cycle of treatment, computerized tomography evaluation by Response Evaluation Criteria in Solid Tumors [12] (RECIST) identified 9 subjects with stable disease; 4 subjects had decreased CA125 levels. Based on the response seen following 1 treatment cycle, 3 subjects went on to receive farletuzumab as extended therapy. One subject exhibited a 48% decrease in CA125 after receiving 2 additional cycles. Radiolabeled tracer studies were conducted in 3 subjects, showing significant tumor uptake of labeled farletuzumab [13].

We report clinical activity of farletuzumab, both as single agent and in combination with platinum and taxane chemotherapy, in an open-label, Phase II study in women with platinum-sensitive, recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.