P1/2, N=374, Recruiting, ProfoundBio US Co. | N=134 --> 374 | Trial completion date: Sep 2025 --> Apr 2026 | Trial primary completion date: Jan 2025 --> Oct 2025

P2, N=114, Active, not recruiting, ImmunoGen, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2024 --> Jun 2025

P1/2, N=25, Not yet recruiting, Takeda

P2/3, N=600, Recruiting, Sutro Biopharma, Inc. | Phase classification: P2 --> P2/3 | N=140 --> 600

At the current price, MIRV for PROC with high-FRα expression is not the cost-effective strategy in the US. However, its treatment has higher health benefits in bevacizumab-naïve patients, which is likely to be an alternative.

This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum-sensitive, FRα-expressing ovarian cancer. Thrombocytopenia was the primary cause of dose modifications. These outcomes compare favorably to historical data reported for platinum-based chemotherapy plus bevacizumab regimens in similar patient populations.

P1, N=44, Completed, City of Hope Medical Center | Active, not recruiting --> Completed

Recently, the FDA approved mirvetuximab soravtansine for platinum-resistant ovarian carcinoma with FOLR1 overexpression, typically high-grade serous carcinoma... To our knowledge, this is the largest study to date of FOLR1 expression in USC. Nearly 1 in 5 USC patients are FOLR1+, independent of HER2 status. Further research testing the efficacy of FOLR1-targeted therapy in USC is needed, as approval could potentially double the proportion of patients with available targeted therapies.

P1/2, N=264, Completed, ImmunoGen, Inc. | Phase classification: P1b/2 --> P1/2

P1/2, N=132, Recruiting, Tasly Pharmaceutical Group Co., Ltd

Together, these data showed that the assay is highly reliable, consistently producing evaluable results in the clinical setting. The VENTANA FOLR1 Assay is a robust and reproducible assay for detecting FRα expression and identifying a patient population that derived clinically meaningful benefit from MIRV in the SORAYA study.

Folate receptor α (FR) was discovered many decades ago, along with drugs that target intracellular folate metabolism, such as pemetrexed and methotrexate...Current oncolytic therapeutics include mirvetuximab soravtansine, and ongoing clinical trials are underway to investigate chimeric antigen receptor T cells (CAR-T cells) and vaccines. Additionally, FRα has been used in a myriad of other applications, including as a tool in the identification of tumor types, and as a prognostic marker, as a surrogate of chemotherapy resistance. As such, FRα identification has become an essential part of precision medicine.

MIRV and gemcitabine demonstrate promising activity in platinum resistant EOC at RP2D, but frequent hematologic toxicities.

P2, N=136, Recruiting, AGO Research GmbH | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2025

The first FDA-approved ADC for recurrent or metastatic cervical cancer was tisotumab vedotin, a tissue factor-targeting agent, after demonstrating response in the innovaTV 204 trial. Mirvetuximab soravtansine targets folate receptor alpha and is approved for use in patients with folate receptor alpha-positive, platinum-resistant, epithelial ovarian cancer based on results from the SORAYA trial. While there are no FDA-approved ADCs for the treatment of uterine cancer, trastuzumab deruxtecan, an anti-human epidermal growth factor receptor 2 (HER2) agent, is actively being investigated. In this review, we will describe the structure and mechanism of action of ADCs, discuss their toxicity profiles, review ADCs both approved and under investigation for the management of gynecologic cancers, and discuss mechanisms of ADC resistance.

Cancer immunotherapy has been regarded as a silver lining in the treatment of patients with various immunological or oncological indications; however, mirvetuximab soravtansine (a folate receptor α-specific mAb) and bevacizumab (a VEGF-A-specific mAb) are the only immunotherapeutics approved for the treatment of ovarian cancer patients. In this review, we outline the principles of CAR-T therapy and then highlight its limitations in the context of solid tumors. Ultimately, we focus on preclinical and clinical findings achieved in CAR-T-mediated targeting of different ovarian cancer-associated target antigens.

The efficacy of mirvetuximab soravtansine in treating recurrent ovarian cancer with FRa-positive expression is satisfactory, and the safety is tolerable.

MIRV appears to be a significant asset in managing advanced or recurrent ovarian cancer. Further trials are needed to confirm these promising results, even in the neoadjuvant, adjuvant, and maintenance settings.

P3, N=418, Recruiting, ImmunoGen, Inc.

Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

This may have promising application in patients with platinum-resistant diseases. CRD42023428599.

P2, N=35, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2023 --> Oct 2024

453 pts with FRα high (Roche FOLR1 Assay) PROC were randomized 1:1 to MIRV 6 mg/kg, adjusted ideal body weight, Day 1 of a 21-day cycle or IC: paclitaxel, pegylated liposomal doxorubicin, or topotecan. MIRV is the first treatment to demonstrate a statistically significant PFS, ORR and OS benefit in PROC compared to IC and demonstrates clinical benefit across subgroups. The efficacy data, along with the well-characterized safety profile, position MIRV as a new, standard of care for pts with FRα positive PROC.

P1/2, N=142, Recruiting, Eisai Inc. | N=66 --> 142

Part 1 is the dose-optimization stage, with ~50 subjects randomized 1:1 at 4.3 mg/kg Q3W or 5.2 mg/kg Q3W + prophylactic pegfilgrastim for 2 cycles followed by 4.3 mg/kg Q3W. Key exclusion criteria: primary platinum refractory disease and prior treatment with a FolRα ADC or ADC-containing tubulin inhibitor. Current Trial Status: Currently enrolling

Introduction: Mirvetuximab soravtansine (MIRV) is an anti-folate receptor alpha (FOLR1)-drug conjugate... 41 cervical squamous cell carcinoma (SCC), 35 endocervical adenocarcinoma, 21 uterine serous carcinoma, 14 uterine carcinosarcoma, and 48 ovarian clear cell carcinoma (OCCC) cases were represented in the TMAs and stained with FOLR1 (see Figure 1). 0% of cervical SCC, 0% of endocervical adenocarcinoma, 14% of uterine serous carcinoma, 0% of uterine carcinosarcoma, and 0% of OCCC cases met current FOLR1 positivity criteria (PS2 ≥ 75%) (see Table 1). Figure 1: Examples of H&E and FOLR1 staining in endocervical adenocarcinoma (A-B), uterine serous carcinoma (C-D), and ovarian clear cell carcinoma (E- F) Table 1: FOLR1 PS2 scores of different tumor types Conclusion/Implications: Variable FOLR1 expression was seen in different gynecologic tumor types.

All patients received prior bevacizumab; 77% of patients received a prior PARP inhibitor. As of the data cutoff of 25-April-2023, median follow-up was 4.5 months. In all of 35 evaluable patients by investigator per RECIST 1.1, confirmed and unconfirmed ORR was 31.4% (95% CI: 16.85%, 49.29%), and 3-month PFS rate was estimated as 73.5%(95% CI: 55.30%, 85.25%). The most common (≥20%) treatment-related adverse events (all grade and grade 3-4) were Keratopathy (57.1% and 14.3%) , Aspartate aminotransferase increased (45.7% and 0%), White blood cell count decreased (37.1% and 2.9%), Alanine aminotransferase increased (37.1% and 0%), Vision blurred (37.1% and 17.1%), Platelet count decreased (37.1% and 5.7%), Neutrophil count decreased (37.1% and 5.7%), and Xerophthalmia (20.0% and 14.3%).

There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. Dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.

P1, N=216, Recruiting, Bio-Thera Solutions | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

Antitumor activity has been observed at well tolerated dose levels. Dose escalation continues.

We highlight mirvetuximab soravtansine (MIRV), or Elahere (ImmunoGen), the first FRα-targeting ADC approved by the FDA to treat platinum-resistant ovarian cancer. We discuss potential mechanisms and management of ocular adverse events associated with MIRV administration.

No abstract available

However, it is my impression that addressing several pharmacological factors could improve the safety and efficacy of mirvetuximab soravtansine. This article summarizes the current pharmacological profile of mirvetuximab soravtansine and provides an expert opinion on pharmacological strategies for optimizing its safety and efficacy profile for the treatment of platinum-resistant ovarian cancer.

Mirvetuximab soravtansine is an ADC comprising an IgG1 monoclonal antibody against the folate receptor alpha (FRα) conjugated to the cytotoxic maytansinoid effector molecule DM4 that has shown promising clinical activity in patients with FR-α-positive ovarian cancer. This review summarizes current evidence of mirvetuximab soravtansine in platinum-resistant ovarian cancer, focusing on clinical activity, toxicity, and future directions.

The study will evaluate AZD5335 as monotherapy in patients with ovarian cancer or lung adenocarcinoma (Module 1), or AZD5335 in combination with AZD5305, a selective poly(ADP-ribose) polymerase 1 inhibitor, in patients with ovarian cancer (Module 2). Secondary objectives include assessment of objective response rate, duration of response, disease control rate, and progression-free survival by RECIST v1.1, and overall survival; characterising the pharmacokinetics of AZD5335 when given as monotherapy or in combination; and assessing immunogenicity. The study will be open to recruitment by 25 May 2023.

Part 1 consists of a dose-optimization stage and will randomize ∼50 subjects 1:1 to the treatment of luvelta at 4.3 mg/kg Q3W or luvelta 5.2 mg/kg Q3W + prophylactic pegfilgrastim for 2 cycles followed by 4.3 mg/kg Q3W. Key inclusion criteria are progressive PROC, up to 3 prior regimens, TPS of ≥25% for FolRα expression, and measurable disease. Key exclusion criteria are primary platinum refractory disease and prior treatment with a FolRα ADC or ADC containing a tubulin inhibitor.

Intratumoral imaging analysis using tumors on day 21st showed an association between the antitumor effect and intratumoral accumulation of eribulin. Conclusions These results suggest that FZEC may be a promising treatment for FRα-expressing EC of all four molecular subtypes.

Preliminary data indicate that luvelta has a predictable and manageable safety profile with encouraging clinical activity in pts with recurrent/progressive FolRα expressing EEC. Luvelta warrants further development as a targeted agent for EEC.

Methodology 453 PROC pts with high FRα expression (Roche FOLR1 Assay), 1-3 PLOT were randomized 1:1 to MIRV or IC: paclitaxel, pegylated liposomal doxorubicin, or topotecan. MIRV is the first treatment to demonstrate both an OS and a PFS benefit in a phase III trial in PROC. These efficacy data, along with the well-characterized safety profile, position MIRV as a new standard of care for pts with FRα positive PROC.

P1/2, N=150, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

The National Comprehensive Cancer Network (NCCN) ovarian cancer 2023 guidelines adopted mirvetuximab as 2A, and mirvetuximab combined with bevacizumab as 2B, recommendations. Mirvetuximab represents the first biomarker-directed therapy with an indication specifically for the treatment of PROC. The efficacy and favorable safety profile support further development of mirvetuximab and mirvetuximab combinations in platinum sensitive and newly diagnosed ovarian cancer.