Pharmacist’s Application to Practice:
Mirvetuximab soravtansine-gynx

Elahere (mirvetuximab - soravtansine-gynx) for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer

What is the potential role for mirvetuximab soravtansine-gynx in the treatment of platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer?

• Ovarian cancer is the eighteenth most common cancer in the United States and is one of the most common causes of cancer-related deaths in women of developed nations.1
• Most of the cases are diagnosed at an advanced stage, which leads to poor outcomes of this disease.
• Though most patients initially respond to platinum-based chemotherapy, ~80% of patients will recur.2
  • At time of recurrence, patients are classified as platinum-sensitive (recurrence greater than 6 months from time of last platinum) or platinum-resistant (recurrence less than 6 months from time of last platinum).
• Current therapy options for platinum-resistant ovarian cancer are limited to non-platinum chemotherapy including liposomal doxorubicin, a taxane, and topotecan as single agent or in combination with bevacizumab.2,3
  • These regimens have low response rates and several toxicities.
• Mirvetuximab soravtansine-gynx is an antibody-drug conjugate which consists of 3 components, a folate receptor alpha (FRα)-directed monoclonal antibody (IgG1 subtype), a small molecule anti-tubulin agent DM4 (a maytansine derivative), and a linker that covalently attaches DM4 to the mirvetuximab antibody.4
  • The antibody portion is a chimeric IgG1 directed against folate receptor alpha (FRα). DM4 is a microtubule inhibitor attached to the antibody via a cleavable linker
  • Upon binding to FRα, mirvetuximab soravtansine is internalized and then intracellularly releases DM4 via proteolytic cleavage.
  • DM4 disrupts the microtubule network within the cell, resulting in cell cycle arrest and apoptosis.
• FRα positive tumors are defined as ≥ 75% tumor cells staining with 2+/3+ intensity.5
  • Up to 90% of ovarian cancers overexpress FRα; however, differential levels of expression have been observed across different ovarian cancer histotypes. Roughly 35% of patients with ovarian cancer are considered to have high levels of FRα expression as defined above.
  • VENTANA FOLR1 (FOLR1-2.1) RxDx Assay is used for the evaluation of FRα expression.
• Mirvetuximab soravtansine-gynx has a Category 2A recommendation for platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer per National Comprehensive Cancer Network (NCCN) for FRα positive tumors based on SORAYA and MIRASOL trials.
• SORAYA study,6
  • Single arm phase II study
  • Females ≥ 18 years of age with confirmed diagnosis of platinum-resistant high grade serous ovarian, peritoneal or fallopian tube cancer with high FRα tumor expression, an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, and one to three previous lines of systemic therapy were included.
  • Mirvetuximab soravtansine-gynx was administered at 6 mg/kg adjusted ideal body weight intravenously once every 3 weeks.
  • Primary outcome was objective response rate (ORR)
    • One hundred and six patients were enrolled
    • ORR was 32.4% (95% CI, 23.6 to 42.4; P <0.0001) with five patients achieving a complete response and 71.4% experiencing tumor reduction.
  • Secondary endpoints:
    • The median duration of response was 6.9 months (95% CI, 5.6 to 9.7).
    • The median progression free survival (PFS) was 4.3 months (95% CI, 3.7 to 5.2).
    • The median overall survival (OS) was 13.8 months (95% CI, 12.0 to not reached).
  • Treatment-related adverse events (AEs) were experienced by 86% of patients.
    • Blurred vision (41% all grades), keratopathy (29% all grades), and nausea (29% all grades) were the most common AEs.
• MIRASOL study7
  • Randomized phase III study
    • Females ≥ 18 years of age with platinum-resistant high grade serous ovarian, peritoneal or fallopian tube cancer with high FRα tumor expression, an ECOG of 0 or 1, and one to three previous lines of systemic therapy were included
    • Mirvetuximab soravtansine-gynx was compared to investigators’ choice (IC) chemotherapy: paclitaxel, pegylated liposomal doxorubicin, or topotecan.
  • Primary endpoint was PFS.
    • Four hundred and fifty-three patients were enrolled.
    • PFS in the mirvetuximab soravtansine-gynx arm was 5.62 months (95% CI, 4.34 to 5.95) vs. 3.98 months (95% CI, 2.86 to 4.47) in the IC arm.
  • Secondary endpoints:
    • The median ORR was 42.3% (95% CI, 35.8 to 49) in the mirvetuximab soravtansine-gynx arm vs 15.9% (95% CI, 11.4 to 21.4) in the IC arm.
    • The median OS was 16.46 months (95% CI, 14.46 to 24.57) in the mirvetuximab soravtansine-gynx arm vs 12.75 months (95% CI, 10.91 to 14.36) in the IC arm.
  • ImmunoGen will seek to turn the accelerated approval into a full FDA approval in the second half of 2023 based on the results of the confirmatory MIRASOL trial.
• Mirvetuximab soravtansine-gynx plus bevacizumab has a Category 2B recommendation for platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer per NCCN for FRα positive tumors based on the FORWARD II study8:
  • Phase 1b/2 study
  • Females ≥ 18 years of age with confirmed diagnosis of platinum-resistant high grade serous ovarian, peritoneal or fallopian tube cancer with high FRα tumor expression, an ECOG performance status score of 0 or 1, and one to three previous lines of systemic therapy (including bevacizumab) were included
  • Mirvetuximab soravtansine-gynx was administered at 6 mg/kg adjusted ideal body weight intravenously once every 3 weeks and bevacizumab was administered as 15 mg/kg once every 3 weeks
  • Primary outcome was ORR.
    • A total of ninety-four patients were enrolled
    • ORR was 44% (95% CI, 33 to 54) with five patients achieving a complete response and thirty-six patients achieving a partial response.
• Activity was seen across all FRα expression levels. Patients with tumors demonstrating FRα expression of ≥75% had a higher ORR and longer PFS interval.
• Patients who were bevacizumab-naïve responded better to combination treatment (ORR 56%, median duration of response (DOR) 10.4 months, PFS 10.6 months) compared with those who had received bevacizumab as part of earlier lines of therapy (ORR 35%, DOR 9.7 months, PFS 6.8 months).
• The most common events of any grade were blurred vision (57%), diarrhea (54%), nausea (51%), and fatigue (43%)

What role can the pharmacist play in the management of patients on mirvetuximab - soravtansine-gynx?

• Indication: FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer5
• Dosing: 6 mg/kg adjusted ideal body weight (AIBW) intravenously once every 3 weeks
  • AIBW = ideal body weight (IBW) + 0.4 x (actual weight – IBW)
  • IBW = (0.9 x height in centimeters) - 92)
  • There are no recommendations for dose adjustments for renal or hepatic dysfunction
• Rate: Administer the first dose at the rate of 1 mg/min; if well tolerated after 30 minutes, the infusion rate can be increased to 3 mg/min; if well tolerated after 30 minutes, the infusion rate can be increased to 5 mg/min
  • If no infusion-related reactions occur with the previous dose, subsequent infusions should be started at the maximally tolerated rate and may be increased up to a maximum infusion rate of 5 mg/min, as tolerated.
• Pre-medications:
  • Acetaminophen 325 mg oral (given at infusion center)
  • Ondansetron 8 mg IV (given at infusion center)
  • Dexamethasone 10 mg IV (given at infusion center)
  • Diphenhydramine 50 mg IV (given at infusion center)
  • Steroid eye drops (example: prednisolone acetate 1% ophthalmic suspension): 1 drop into each eye 6 times daily starting the day prior to each infusion and continue until day 4, then administer 1 drop into each eye 4 times daily for days 5 to 8 of each cycle
  • Preservative-free lubricating eye drops four times a day and as needed, given at least 10 minutes after the steroid eye drops
• Dose modifications: 6 mg/kg AIBW → 5 mg/kg AIBW → 4 mg/kg AIBW
• Eye care:
  • Patients should receive a baseline ophthalmic exam from an eye care provider, including visual acuity and slit lamp exam, prior to treatment initiation, and follow-up exams during every other cycle for the first 8 cycles and as clinically indicated.
  • Patients should avoid use of contact lenses.
• Mirvetuximab soravtansine-gynx is a substrate of CYP3A4 (minor) and P-glycoprotein/ABCB1 (minor).
  • Closely monitor patients for adverse reactions with mirvetuximab soravtansine-gynx when used concomitantly with strong CYP3A4 inhibitors.
• Adverse events (AE’s)5,6:
  • Visual impairment (accommodation disturbance, blurred vision, decreased visual acuity, diplopia, error of refraction, presbyopia, and vitreous opacity) 49-50%
  • Fatigue 49%
  • Nausea 40%
  • Corneal disease (corneal deposits, epithelial keratopathy, keratitis, and punctate keratitis) 36-37%
  • Abdominal pain 36%
  • Neuropathy 33-36%
  • Diarrhea 31%
  • Constipation 30%
  • Rare: pneumonitis (8-10%), infusion-related reaction (<9%), intestinal obstruction (8%)

Clinical Pearls

• VENTANA FOLR1 (FOLR-2.1) RxDx Assay is the laboratory test designed to detect folate receptor alpha (FOLR1) protein in patients with ovarian cancer, peritoneal cancer, or fallopian tube cancer. FRα expression should be obtained in all patients with platinum-resistant disease.5
• Mirvetuximab soravtansine-gynx has become one of the preferred regimens for heavily pre-treated patients with FRα-expressing, platinum-resistant ovarian cancer, peritoneal cancer, or fallopian tube cancer that have received up to 3 prior lines of therapy, including bevacizumab and/or poly ADP-ribose polymerase inhibitor (PARPi)2
• Mirvetuximab soravtansine-gynx must be diluted prior to administration with 5% Dextrose Injection, USP to a final concentration of 1 mg/mL to 2 mg/mL It is incompatible with 0.9% Sodium Chloride Injection.5
• Access5,9
  • Mirvetuximab soravtansine-gynx is available as a 100 mg/20 mL (5 mg/mL) clear to slightly opalescent, colorless solution in a single-dose vial.
  • Mirvetuximab soravtansine-gynx is ordered via specialty distributors.
  • Assistance is available through Access Support, Copay Assistance, or Patient Assistance Program from ImmunoGen.

References

1.Ovarian Cancer - Cancer Stat Facts. SEER. Updated June 8, 2023. Accessed June 22, 2023. https://seer.cancer.gov/statfacts/html/ovary.html.

3.National Comprehensive Cancer Network. Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2023). https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed June 20, 2023.

3.Sambasivan, S. Epithelial ovarian cancer: Review article. Cancer Treat Res Commun 2022;33:100629

4.Moore KN, Martin LP, O'Malley DM, et al. A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer. Future Oncol. 2018;14(2):123-136.

5.Elahere (mirvetuximab - soravtansine-gynx) [prescribing information]. Waltham, MA: ImmunoGen Inc; 2022.

6.Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41(13):2436-2445.

7.Moore KN, Angelergues A, Konecny GE, et al. Phase III mirasol (Gog 3045/ ENGOT-OV55) study: initial report of mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. J Clin Oncol. 2023;41(17_suppl).

8.Gilbert L, Oaknin A, Matulonis UA, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2023;170:241-247.

9.Elahere Support Resources. https://www.elahere.com/support#elahere-support-resources. Accessed July 1, 2023.