Background: Cytotoxic chemotherapy remains the primary treatment for many gynaecological cancers. The anti-microtubule agent, eribulin, shows potential in the treatment of aggressive, poor prognosis gynaecological cancer subtypes. Antibody-drug conjugates (ADCs) facilitate the targeted delivery of potent cytotoxic agents. This study explores the effectiveness of two ADCs—farletuzumab ecteribulin (FZEC), targeting folate receptor alpha (FRA), and MORAb-109, targeting mesothelin (MSLN)—in treating aggressive gynaecological cancers.
Methods: We screened 41 patient-derived xenograft (PDX) models of gynaecological cancer, representing 11 subtypes with poor prognosis, to assess the frequency and distribution of FRA and MSLN expression. Based on the expression of these target antigens, we selected three high-grade serous ovarian carcinoma, three ovarian carcinosarcoma, six uterine serous carcinoma, and three ovarian clear cell carcinoma PDX models for in vivo testing with eribulin, FZEC, or MORAb-109.
Results: Eribulin demonstrated activity in 11 out of 15 gynaecological cancer models, outperforming the standard anti-microtubule agent, paclitaxel, despite 80% of models being resistant to cisplatin. Striking responses to FZEC and/or MORAb-109 were observed in PDX models with positive FRA (9/12, 75%) and/or MSLN (3/5, 60%) expression. These responses were generally deep and durable (lasting 80-100 days), leading to significantly extended survival. The four non-responder models, which also had positive target expression, exhibited high ABCB1 levels and were derived from patients previously treated with paclitaxel.
Conclusion: The 15 aggressive gynaecological cancer PDX models showed remarkable responses to FZEC and MORAb-109 when FRA and/or MSLN expression was positive and ABCB1 expression was low. Given the limited treatment options for advanced gynaecological cancer, our findings underscore the urgent need to include these cancers in eribulin ADC trials early in the disease course.