Elahere (mirvetuximab soravtansine-gynx)

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

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

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.).

P1, N=102, Enrolling by invitation, Shattuck Labs, Inc. | Recruiting --> Enrolling by invitation | Phase classification: P1b --> P1

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.

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%).

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.

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.

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

Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies.

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.

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.

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.

P2, N=53, Recruiting, University of Colorado, Denver | Not yet recruiting --> Recruiting

P2, N=70, Recruiting, University of Alabama at Birmingham | Trial completion date: May 2025 --> May 2028 | Trial primary completion date: May 2023 --> May 2026

P1, N=25, Active, not recruiting, Ohio State University Comprehensive Cancer Center | Trial completion date: Mar 2023 --> Dec 2023

This manuscript, describing the pharmacological aspects of eleven anticancer novel drug therapies approved by the FDA, shall serve as a helpful document for cancer patients, concerned academicians, researchers, and clinicians, especially oncologists.

P2, N=53, Not yet recruiting, University of Colorado, Denver

In ovarian cancer, mirvetuximab soravtansine, an ADC targeting alpha-folate receptor (FRα), received US Food and Drug Administration (FDA) accelerated approval in November 2022 after data from the single-arm phase III SORAYA trial. A second ADC targeting FRα, STRO-002, received FDA fast track designation in August 2021. Multiple studies with upifitamab rilsodotin, an ADC comprising a NaPi2B-binding antibody, are underway. In cervical cancer, tisotumab vedotin, an ADC-targeting tissue factor, received FDA accelerated approval in September 2021 after the phase II innovaTV 204 trial...Trastuzumab-deruxtecan (T-DXd), an ADC targeting human epidermal growth factor receptor 2 (HER2), is currently approved for HER2-positive and HER2-low breast cancer and shows promise in endometrial cancer. Like all anticancer treatments, the decision for a patient to undergo therapy with an ADC is a personal choice that balances the potential benefits with the side effects and requires thorough and compassionate support of their physician and care team and shared decision making.

This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx.

453 PROC pts with high FRα expression (Roche FOLR1 Assay) with 1-3 priors 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 PFS and OS benefit in PROC compared to IC. The efficacy data, along with the well-characterized safety profile, position MIRV as a new, standard of care for pts with FRα positive PROC. Clinical trial information: NCT04209855.

Close collaboration between all care team members, including oncologists and eye care professionals, will help patients benefit from this novel and promising anticancer agent. This review focuses on the etiology, rates, prevention, and management of MIRV-associated ocular events.