Elahere

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, monoclonal antibodies and antibody drug conjugates, other monoclonal antibodies and antibody drug conjugates. ATC code: L01FX26 Mechanism of action Mirvetuximab soravtansine is an antibody-drug conjugate.​​​‍​​‍​​​​‍​​‍‍ The antibody is an engineered IgG1 directed against folate receptor alpha (FRα). The function of the antibody portion is to bind to FRα expressed on the surface of ovarian cancer cells. DM4 is a microtubule inhibitor attached to the antibody via a cleavable linker. Upon binding to FRα, mirvetuximab soravtansine is internalised followed by intracellular release of DM4 via proteolytic cleavage. DM4 disrupts the microtubule network within the cell, resulting in cell cycle arrest and apoptotic cell death. Pharmacodynamic effects Cardiac electrophysiology At the approved recommended dose, mirvetuximab soravtansine did not cause mean increases >10 msec in the QTc interval based on the results of concentration-QTc analysis. Clinical efficacy and safety Study IMGN853-0416 (MIRASOL) The efficacy and safety of mirvetuximab soravtansine were studied in Study IMGN853-0416, a multicentre, open-label, active-controlled, randomised, two-arm phase 3 study that enrolled platinum- resistant advanced high-grade serous epithelial ovarian, primary peritoneal or fallopian tube cancers patients whose tumours (including archival tissue) were FRα positive as determined by the FOLR1 (FOLR1-2.1) RxDx assay (≥75% of viable tumour cells with moderate (2) and/or strong (3) membrane staining intensity by immunohistochemistry (IHC)). Platinum-resistant disease was defined as EOC that recurred within 6 months of the last dose of platinum. The study excluded patients with primary platinum-refractory disease, patients with ECOG≥2 and patients with active or chronic corneal disorders, ocular conditions requiring ongoing treatment, Grade ≥2 peripheral neuropathy, or non-infectious ILD/pneumonitis. Patients were randomised 1:1 to receive either ELAHERE 6 mg/kg AIBW IV (N=227) at Day 1 of each 3-week cycle or one of the following chemotherapies (N=226) as decided by the investigator prior to randomisation: • Paclitaxel (Pac) 80 mg/m 2 administered once weekly within a 4-week cycle; • Pegylated liposomal doxorubicin (PLD) 40 mg/m 2 administered once every 4 weeks; • Topotecan (Topo) 4 mg/m 2 administered on Days 1, 8, and 15 every 4 weeks or for 5 consecutive days at 1.25 mg/m 2 from Days 1-5 of each 21-day cycle Randomisation was stratified by number of prior lines of therapy (1 vs 2 vs 3) and by Investigator's choice of chemotherapy (IC Chemo) (Pac vs PLD vs Topo). Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity. The primary efficacy outcome measure was progression free survival (PFS) based on investigator assessment using RECIST 1.1 criteria. Objective response rate (ORR) and overall survival (OS) were key secondary efficacy outcome measures. In total, 453 patients were randomised. The median age was 63 years (range: 29 to 88 years), and patients were predominantly white (66%; 12% Asian). Most patients (80%) had ovarian cancer of epithelial origin; 11% of the fallopian tube; 8% of primary peritoneal; all (100%) were of high-grade serous histology. Approximately half the patients (47%) received 3 prior systemic therapies, 39% had 2 prior lines, and 14% of patients had 1 prior line. The majority of patients received a prior poly ADP ribose polymerase (PARP) inhibitor (55%) and prior bevacizumab (62%). The platinum-free interval following the most recent line of therapy was ≤3 months in 41% of patients, and 3 to 6 months in 58% of patients. Fifty five percent (55%) of patients had an ECOG performance status of 0, and 44% had an ECOG of 1. The primary analysis demonstrated a statistically significant improvement in PFS and OS for patients randomised to ELAHERE as compared with IC chemotherapy. Table 5 summarises the efficacy results of study IMGN853-0416 (MIRASOL). Table 5: Efficacy results of Study IMGN853-0416 Efficacy parameter ELAHERE N=227 IC chemotherapies N=226 Progression-free survival (PFS) as assessed by investigator Number of events (%) 176 (77.5) 166 (73.5) Median, months (95% CI) 5.62 (4.34, 5.95) 3.98 (2.86, 4.47) Hazard ratio (95% CI) 0.65 (0.521, 0.808) p-value <0.0001 Overall survival (OS) Number of events (%) 90 (39.6) 114 (50.4) Median, months (95% CI) 16.46 (14.46, 24.57) 12.75 (10.91, 14.36) Hazard ratio (95% CI) 0.67 (0.504, 0.885) p-value 0.0046* Data cut-off 06 March 2023. *: pre-determined efficacy boundary = 0.01313, 2-sided (adjusted by observed number of deaths 204). The Kaplan Meier curves for investigator-assessed PFS (median follow-up of 11.2 months) and OS (median follow-up of 13.1 months) are presented in Figure 1 and Figure 2. Figure 1: Kaplan-Meier curve for progression-free survival by treatment arm in MIRASOL (intent to treat population) Figure 2: Kaplan-Meier curve for overall survival by treatment arm in MIRASOL (intent to treat population) At an additional descriptive analysis with median follow-up of 20.3 months, OS results were consistent with the primary analysis. Immunogenicity Anti-drug antibodies (ADA) were commonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited. Paediatric population The Medicines and Healthcare products Regulatory Agency has waived the obligation to submit the results of studies with ELAHERE in all subsets of the paediatric population in treatment of ovarian carcinoma, treatment of fallopian tube carcinoma, and treatment of peritoneal carcinoma (see section 4.2 for information on paediatric use).