Elahere (mirvetuximab soravtansine-gynx) is an antibody-drug conjugate (ADC) that binds with high affinity to folate receptor α (FRα) expressed on the surface of tumor cells and promotes the internalization of the ADC/receptor complex through antigen-mediated endocytosis. Elahere is used to treat adult patients with platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who are FRα-positive and have previously received 1-3 systemic treatment regimens. Elahere is the first therapy to show improvement in overall survival (OS) in patients with platinum-resistant ovarian cancer.

Ovarian Cancer

Ovarian cancer is considered the most lethal type of gynecological malignancies and is known as the "king of gynecological cancers" in the medical community. According to statistics, the annual incidence of ovarian cancer ranks third among female reproductive system tumors, and the incidence of the disease is increasing year by year. The mortality rate of this malignant tumor is also the highest among female reproductive tract malignancies, posing a serious threat to women's health. It is generally believed in the clinic that platinum chemotherapy is the first-line treatment for ovarian cancer and has good results. However, many patients will develop platinum resistance after recurrence, making treatment more difficult. Once platinum resistance occurs, the total effective rate of second-line chemotherapy drugs is often less than 20%. However, due to the limited treatment options for platinum-resistant recurrent ovarian cancer worldwide, the current traditional non-platinum chemotherapy, anti-angiogenic drugs and PARP inhibitors cannot meet the treatment needs of platinum-resistant patients. However, it is gratifying that the FRα target has become a new hope for many patients with platinum-resistant recurrent ovarian cancer who have no drugs available. FRα is expressed at very low or no level in normal tissues, but is highly expressed in epithelial tumor tissues, and studies have found that it is involved in regulating the proliferation and metastasis of tumor cells. Therefore, FRα is considered a potential target for tumor therapy.

Elahere Reviews

• Elahere Indication

Elahere is suitable for adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have received 1 to 3 systemic treatments. In the trial of patients with FRα-positive tumors, the total Elahere response rate reached 31.7%, including a complete response rate of 4.8%, a partial response rate of 26.9%, and a median response duration of 6.9 months. Nearly one-third of the ovarian cancer patients participating in the trial responded to Elahere and their disease status was alleviated. After Elahere treatment, some patients' disease symptoms completely disappeared and achieved a state of complete remission. Among the patients who achieved remission, most of the patients' disease symptoms were partially improved, but not completely disappeared.

• Elahere Mechanism of Action

Elahere is an anti-FRα ADC, formed by a human IgG1 antibody coupled to a DM4 payload via a sulfo-SPDB cleavable linker. Structurally, DM4 binds to the antibody, inhibits tubulin, causes cell cycle arrest in the G2-M phase, and ultimately leads to cell death. DM4 is electrically neutral and lipophilic, and is therefore able to cross the cell membrane and cause a bystander effect. Elahere is also one of the first ADCs studied in ovarian cancer, and it is the only drug with available Phase III study results to date.

Fig. 1. The structure of Elahere (Drugs. 2023, 83(3): 265-273).

*Elahere related products:

FRα is a member of the folate receptor family and is a transmembrane protein present on the cell surface that mediates the transport of folate into cells. This protein is poorly expressed in normal tissues, but highly expressed on the surface of ovarian cancer, endometrial cancer, breast cancer, and non-small cell lung cancer cells. High expression of FRα on tumor cells indicates that the tumor requires an increased amount of folate to maintain tumor cell growth and proliferation. It is worth noting that high expression of FRα is a biomarker for ovarian cancer and poor prognosis, and is also associated with poor response to chemotherapy, shorter progression-free survival (PFS) and OS.

Elahere FDA Approval

Elahere was initially approved by the FDA under accelerated approval in November 2022 and converted to full approval based on data from the confirmatory Phase 3 MIRASOL trial. The trial compared Elahere treatment with investigator's choice (IC) chemotherapy in patients with platinum-resistant ovarian cancer (PROC). Patients in the trial had tumors that expressed high levels of FRα and had received up to three prior lines of therapy. The primary endpoint of MIRASOL was investigator-assessed progression-free survival (PFS), and key secondary endpoints included objective response rate (ORR) and overall survival (OS).

On March 22, 2024, the U.S. Food and Drug Administration (FDA) has fully approved Elahere for the treatment of adult patients with FRα-positive, platinum-resistant ovarian, fallopian tube, or primary peritoneal epithelial cancer who have received up to three prior lines of therapy. Patients with these tumors typically present with advanced disease and receive surgery followed by platinum-based chemotherapy. They may become resistant to that treatment and require additional treatments such as Elahere.

Fig. 2. Results of Elahere's Phase 3 confirmatory clinical trial of MIRASOL.

MIRASOL was a randomized, phase 3 trial comparing Elahere with IC single-agent chemotherapy (weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan). Eligible patients included PROC patients whose tumors expressed high levels of FRα as detected by the Ventana FOLR1 assay and who had received up to three prior lines of therapy. The primary endpoint of the trial was investigator-assessed progression-free survival (PFS). Key secondary endpoints included ORR and OS. The trial enrolled 453 patients. Patients were stratified by prior lines of therapy (14% had received prior first-line therapy, 39% had received prior second-line therapy, and 47% had received prior third-line therapy) and IC chemotherapy, with paclitaxel being the most commonly selected chemotherapy (41%), followed by PLD (36%) and topotecan (23%). 62% of patients had received prior bevacizumab; 55% had received prior PARP inhibitor therapy. According to the current results:

• The hazard ratio (HR) for overall survival was 0.67 (95% confidence interval [CI]: 0.50, 0.88; p=0.0046), and the risk of death in the Elahere group was reduced by 33% compared with the IC chemotherapy group.
• The hazard ratio for progression-free survival was 0.65 (95% CI: 0.52, 0.81; p<0.0001), and the risk of tumor or cancer progression in the Elahere group was reduced by 35% compared with the IC chemotherapy group.
• Compared with the IC chemotherapy control group, the Elahere group had fewer adverse events of grade 3 or above and a lower rate of discontinuation due to adverse events.

Antibody Drug Conjugate

ADC is a new type of targeted therapy drug. It is a kind of drug that couples specific monoclonal antibodies with cytotoxic drugs through special linkers, ultimately achieving high-precision targeted drug delivery. ADC uses the interaction principle between specific antibodies and tumor-associated antigens to directly deliver anti-tumor cytotoxic agents to targeted tumor cells, enhancing the killing effect of cytotoxic drugs on tumor cells and reducing the systemic toxic side effects of cytotoxic drugs on the body. It is like a bomb with "eyes" that can accurately blast tumor tissue. ADC mechanism of action: (1) The monoclonal antibody part of ADC binds to the antigen on the cancer cell and is internalized; (2) In the lysosome, the cytotoxic drug is released through the cleavage of the conjugate or the cleavage of the monoclonal antibody; (3) The cytotoxic drug has a toxic effect in the cell; (4) The cytotoxic drug diffuses and may also act on surrounding antigen-negative cells. Currently, 15 ADC drugs have been approved: