Abstract C170: Preclinical evaluation of mirvetuximab soravtansine (IMGN853) combination therapy in ovarian cancer xenograft models

Abstract

Abstract Background: IMGN853 is a folate receptor α (FRα)-binding antibody-drug conjugate (ADC) that utilizes the potent tubulin-targeting maytansinoid, DM4, as its cytotoxic agent. FRα is highly expressed in many solid tumors, particularly epithelial ovarian cancer (EOC), endometrial cancer and non-small cell lung adenocarcinoma. IMGN853 is currently being evaluated as monotherapy in FRα-positive solid tumors in a Phase 1 trial (NCT01609556), with encouraging results recently reported in 17 evaluable patients treated at 6.0 mg/kg adjusted ideal body weight (AIBW) with platinum-resistant EOC (Moore K et al, 2015). Methods: EOC cell line xenograft models plus EOC patient derived xenograft (PDX) models that had FRα expression representative of patients enrolled in the Phase 1 trial were used to assess IMGN853 single agent and combination therapy activity. Anti-cancer therapies used in EOC were assessed. Results from studies with bevacizumab (Bev), carboplatin and pegylated liposomal doxorubicin (PLD) are reported herein. Results: IMGN853 plus Bev was assessed in multiple models including OV90 and IGROV-1 EOC cell line xenografts and a platinum-resistant EOC PDX model, and was consistently more active than either agent alone. In most studies, monotherapy IMGN853 or Bev was active with few partial or complete regressions. In contrast, combination IMGN853 + Bev was highly active, with a majority of the animals having partial or complete tumor regression. The combination activity was substantially more than additive and studies to understand the mechanism(s) responsible for the enhanced activity are ongoing. Combination carboplatin + IMGN853 was more active than carboplatin + paclitaxel in OV90 EOC xenografts. The addition of Bev to carboplatin + paclitaxel enhanced activity compared to carboplatin + paclitaxel. Carboplatin + IMGN853 was more efficacious than the triple combination of carboplatin + paclitaxel + Bev. Carboplatin + IMGN853 + Bev was the most active combination with all mice having tumors that completely regressed. Finally, the combination of PLD and IMGN853 was highly active in a platinum-resistant EOC PDX model, and much more active than PLD or IMGN853 alone. All combinations with IMGN853 described above were well tolerated. Conclusion: Combination therapy efficacy of IMGN853 with Bev was substantially more than additive in multiple models of platinum resistant EOC. Combination IMGN853 + PLD is more efficacious than either monotherapy and combination IMGN853 + carboplatin is more efficacious than carboplatin + paclitaxel in the models studied. Addition of Bev to the carboplatin + IMGN853 combination further enhanced activity. Studies to understand the mechanism(s) responsible for the enhanced combination activity are under way. The efficacy observed in these models suggests that IMGN853 in combination with PLD, or Bev and/or carboplatin may be promising regimens to evaluate in clinical trials of EOC both in the relapsed and upfront settings. A phase1b clinical study assessing doublet combinations of IMGN853 with PLD, Bev and carboplatin in relapsed EOC is planned for 2015. Citation Format: Jose F. Ponte, Jennifer Coccia, Leanne Lanieri, Rabih Gabriel, Jan Pinkas, Rodrigo Ruiz-Soto. Preclinical evaluation of mirvetuximab soravtansine (IMGN853) combination therapy in ovarian cancer xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C170.