Rodrigo Ruiz-Soto

Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha–Targeting Antibody–Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study

Purpose This phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody-drug conjugate consisting of a humanized anti-folate receptor alpha (FRα) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRα-positive and platinum-resistant ovarian cancer. Patients and Methods Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) once every 3 weeks. Eligibility included a minimum requirement of FRα positivity by immunohistochemistry (≥ 25% of tumor cells with at least 2+ staining intensity). Adverse events, tumor response (via Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), and progression-free survival (PFS) were determined. Results Forty-six patients were enrolled. Adverse events were generally mild (≤ grade 2), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4%). For all evaluable patients, the confirmed objective response rate was 26%, including one complete and 11 partial responses, and the median PFS was 4.8 months. The median duration of response was 19.1 weeks. Notably, in the subset of patients who had received three or fewer prior lines of therapy (n = 23), an objective response rate of 39%, PFS of 6.7 months, and duration of response of 19.6 weeks were observed. Conclusion IMGN853 exhibited a manageable safety profile and was active in platinum-resistant ovarian cancer, with the strongest signals of efficacy observed in less heavily pretreated individuals. On the basis of these findings, the dose, schedule, and target population were identified for a phase III trial of IMGN853 monotherapy in patients with platinum-resistant disease.

Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha–Targeting Antibody-Drug Conjugate, Potentiates the Activity of Standard of Care Therapeutics in Ovarian Cancer Models

Elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC), thus establishing this receptor as a candidate target for the development of novel therapeutics to treat this disease. Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) that targets FRα for tumor-directed delivery of the maytansinoid DM4, a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Here, combinations of IMGN853 with approved therapeutics were evaluated in preclinical models of EOC. Combinations of IMGN853 with carboplatin or doxorubicin resulted in synergistic antiproliferative effects in the IGROV-1 ovarian cancer cell line in vitro. IMGN853 potentiated the cytotoxic activity of carboplatin via growth arrest and augmented DNA damage; cell cycle perturbations were also observed in cells treated with the IMGN853/doxorubicin combination. These benefits translated into improved antitumor activity in patient-derived xenograft models in vivo in both the platinum-sensitive (IMGN853/carboplatin) and platinum-resistant (IMGN853/pegylated liposomal doxorubicin) settings. IMGN853 co-treatment also improved the in vivo efficacy of bevacizumab in platinum-resistant EOC models, with combination regimens causing significant regressions and complete responses in the majority of tumor-bearing mice. Histological analysis of OV-90 ovarian xenograft tumors revealed that concurrent administration of IMGN853 and bevacizumab caused rapid disruption of tumor microvasculature and extensive necrosis, underscoring the superior bioactivity profile of the combination regimen. Overall, these demonstrations of combinatorial benefit conferred by the addition of the first FRα-targeting ADC to established therapies provide a compelling framework for the potential application of IMGN853 in the treatment of patients with advanced ovarian cancer.

Phase 1 dose‐escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α‐targeting antibody‐drug conjugate, in patients with solid tumors

Mirvetuximab soravtansine (IMGN853) is an antibody‐drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose‐escalation study, the authors investigated IMGN853 in patients with FRα‐positive solid tumors.

Characterization of folate receptor alpha (FRα) expression in archival tumor and biopsy samples from relapsed epithelial ovarian cancer patients: A phase I expansion study of the FRα-targeting antibody-drug conjugate mirvetuximab soravtansine

Purpose. To characterize folate receptor alpha (FRα) expression in archival and fresh biopsy tumor samples from relapsed ovarian cancer patients. Methods. Patients with ovarian tumors amenable to biopsy were eligible to enroll. Eligibility included a minimum requirement of FRα positivity in archival tumor samples (≥25% of cells with ≥2+ staining intensity). Patients received mirvetuximab soravtansine at 6 mg/kg once every 3 weeks. Core needle biopsies were collected before and after treatment and FRα levels assessed by immunohistochemistry. Descriptive statistics were used to summarize the association between receptor expression and response. Results. Twenty-seven heavily pre-treated patients were enrolled. Six individuals (22%) did not have evaluable pre-treatment biopsies due to insufficient tumor cells. The concordance of FRα expression in archival and biopsy tissues was 71%, and no major shifts in receptor expression were seen in matched pre- and post-treatment biopsy samples. Adverse events were generally mild (≤grade 2) with keratopathy (48%), fatigue (44%), diarrhea, and blurred vision (each 37%) being the most common treatment-related toxicities. The confirmed objective response rate (ORR) was 22%, including two complete responses and four partial responses. Superior efficacy measures were observed in the subset of patients with the highest FRα levels (ORR, 31%; progression-free survival, 5.4 months). Conclusion. Concordance of FRα expression in biopsy versus archival tumor samples suggests that archival tissue can reliably identify patients with receptor-positive tumors and is appropriate for patient selection in mirvetuximab soravtansine clinical trials. Regardless of the tissue source analyzed, higher FRα expression was associated with greater antitumor activity.

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

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.

Abstract C47: Association of folate receptor alpha (FRα) expression level and clinical activity of IMGN853 (mirvetuximab soravtansine), a FRα-targeting antibody-drug conjugate (ADC), in FRα -expressing platinum-resistant epithelial ovarian cancer (EOC) patients (pts)

Background: IMGN853 is a FRα-targeting ADC comprising a FRα-binding antibody conjugated with the potent maytansinoid, DM4, a tubulin-targeting agent. FRα is a membrane protein that is highly expressed in many solid tumors, particularly epithelial ovarian cancer (EOC), endometrial cancer and lung adenocarcinoma. An immunohistochemistry (IHC) assay was developed to support the FRα-expression based patient selection strategy for the clinical development of IMGN853. The assay was optimized to detect a broad dynamic range of FRα expression, allowing discrimination among weak (1+), moderate (2+) and strong (3+), levels of expression (AACR 2015 Zhao J et al). In the EOC expansion cohort of the ongoing phase 1 trial (ASCO 2015 Moore K, et al), 80% of the patients with platinum-resistant EOC screened were found to meet the FRα expression inclusion criteria of ≥ 25% of cells with at least moderate expression. Methods: Here we report the preliminary analysis evaluating the association of FRα expression with overall response rate [partial response (PR) or complete response (CR)] for the first seventeen evaluable patients with platinum-resistant EOC who received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) IV q3wk. Patients were grouped based on their FRα expression into low (25-49% of cells with ≥ moderate expression), medium (50-74% of cells with ≥ moderate expression) and high (≥ 75% of cells with ≥ moderate expression) groups. Analysis to assess the association between expression level and clinical response was performed. Results: Of the 17 patients in the analysis, 2/17 (12%) had low, 5/17 (29%) had moderate and 10/17 (59%) had high FRα expression. In the overall cohort, clinical response was observed in 9/17 patients (1 CR and 8 PRs), for an objective response rate (ORR) of 53%. When the cohort of 17 patients was grouped based on FRα expression, clinical response was observed in 0/2 low, 1/5 moderate and 8/10 high expression patients. The majority of adverse events were CTCAE grade 1 or 2, with diarrhea, blurry vision, cough, fatigue, decreased appetite, neuropathy and nausea reported in > 20% of patients. Conclusion: In these heavily pretreated platinum-resistant ovarian cancer patients, IMGN853 demonstrates promising preliminary clinical activity, with an ORR of 53% in the overall cohort and 80% in the high FRα expression subset. Preliminary analysis suggests that FRα-expression correlates well with IMGN853 activity. The association of FRα expression with IMGN853 activity will continue to be assessed as the phase I trial continues to enroll patients in the expansion cohort. Citation Format: Lainie P. Martin, Kathleen Moore, David M. O9Malley, Shelley Seward, Todd M. Bauer, Ramon Perez, Woondong Jeong, Yinghui Zhou, Joseph Ponte, Maurice Kirby, Mohammed Al-Adhami, Rodrigo Ruiz-Soto, Michael Birrer. Association of folate receptor alpha (FRα) expression level and clinical activity of IMGN853 (mirvetuximab soravtansine), a FRα-targeting antibody-drug conjugate (ADC), in FRα -expressing platinum-resistant epithelial ovarian cancer (EOC) patients (pts). [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 C47.