INTRODUCTION

In November 2022, mirvetuximab soravtansine (Elahere) was approved by the FDA for adult patients with folate receptor alpha (FRα)-positive, platinum-resistant (i.e., failure of treatment with carboplatin) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had undergone one to three prior systemic treatments.¹ In ovarian cancer, FRα is a marker often associated with poorly differentiated and aggressive tumors and is overexpressed in 80% of ovarian cancers.² First-line treatment for ovarian cancer is platinum-based chemotherapy, but 15%–30% of patients with ovarian cancer develop platinum resistance upon disease progression, making mirvetuximab soravtansine a novel, targeted therapy that is now available to these patients.^3,4 With ovarian cancer being the fifth-most-common cancer among women, mirvetuximab soravtansine holds immense promise in the treatment of platinum-resistant ovarian cancer.⁵

MECHANISM OF ACTION

Mirvetuximab soravtansine consists of a humanized monoclonal antibody targeting FRα conjugated to a potent cytotoxic maytansinoid, DM4.⁶ Mirvetuximab soravtansine is a first-in-class FRα antibody-drug conjugate (ADC) that combines the targeted action of an antibody with the cytotoxic effect of a potent chemotherapeutic agent.⁷

The antibody component of mirvetuximab soravtansine recognizes and binds to FRα receptors expressed on tumor cells. Once the antibody binds to FRα on the cancer cell surface, the ADC is internalized into the cancer cell through receptor-mediated endocytosis. The potent cytotoxic payload maytansinoid, DM4, inhibits cell division by disrupting the function of microtubules, which play a key role in cell replication. Disrupting the microtubules ultimately leads to cell cycle arrest and apoptosis.⁸ Thus, mirvetuximab soravtansine selectively kills cancer cells while reducing toxicity to healthy cells.

CLINICAL TRIALS

SORAYA Trial

The SORAYA trial was a single-arm, phase III study that included patients (n=106) with platinum-resistant, FRα-positive epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received one to three prior lines of therapy. All patients were required to have received bevacizumab therapy. Platinum resistance was defined as disease recurrence within 6 months of treatment with platinum-based chemotherapy. FRα positivity was determined using the Ventana FOLR1 immunohistochemistry assay.⁹

Patients were administered mirvetuximab soravtansine according to adjusted ideal body weight at a dose of 6 mg/kg as an intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Follow-up assessments of tumor response were scheduled every 6 weeks for the first 36 weeks and then every 12 weeks after. The primary outcome was investigator-assessed overall response rate (ORR), and the key secondary outcome was median duration of response (mDOR). The ORR was 31.7% and mDOR was 6.9 months. The median overall survival (OS) was 15 months.^10,11 The most common adverse events included blurred vision (41%), keratopathy (36%), and nausea (29%). Adverse events led to discontinuations in 7% of patients.⁹

MIRASOL Trial

The MIRASOL study was a randomized phase III trial that compared the use of mirvetuximab soravtansine with a single-agent chemotherapy (paclitaxel, liposomal doxorubicin, or topotecan). Like the SORAYA trial, this study included patients (n=453) with platinum-resistant ovarian cancer with high levels of FRα, identified using the Ventana FOLR1 assay, who had been treated with up to three regimens in the past. The primary outcome measure of this trial was progression-free survival (PFS), and secondary outcome measures included ORR and OS.¹²

Mirvetuximab soravtansine was associated with a 35% reduction in the risk of tumor progression or death in patients who received mirvetuximab soravtansine versus a single-agent chemotherapy (HR 0.65; 95% CI, 0.52, 0.81; p<0.0001). The median PFS for patients who received mirvetuximab soravtansine was 5.62 months compared with 3.98 months for patients who received a single-agent chemotherapy. Mirvetuximab soravtansine also showed significant improvement in OS compared with a single-agent chemotherapy. The median OS was 16.46 months in the mirvetuximab soravtansine arm compared with 12.75 months in the single-agent chemotherapy arm. With an HR of 0.67 (95% CI, 0.50, 0.89; p=0.0046), there was a 33% reduction in the risk of death with mirvetuximab soravtansine compared with single-agent chemotherapy. The ORR was 42.3% for the mirvetuximab soravtansine arm compared with 15.9% for the single-agent chemotherapy arm.¹³ The most common adverse events with mirvetuximab soravtansine included predominantly low-grade ocular adverse events (56%) compared with 9% in the control arm and GI events (70%) compared with 66% in the control arm. Adverse events related to mirvetuximab soravtansine administration led to discontinuations in 9% of patients, which was lower than discontinuations in the single-agent chemotherapy control arm (16%).¹⁴

ADVERSE EFFECTS

Table 1 summarizes common adverse events associated with mirvetuximab soravtansine. It is also recommended that the patient use certain premedications (Table 2) to reduce the risk of infusion reactions and nausea. Table 3 provides an eye care plan to reduce the risk of ocular toxicity while receiving mirvetuximab soravtansine.^8,15

Table 1. Adverse Reactions with Mirvetuximab Soravtansine in SORAYA (n=106)

Table 2. Premedications Before MIRV Infusion to Prevent Infusion Reactions and Nausea/Vomiting

IV = intravenous; MIRV = mirvetuximab soravtansine.

Table 3. Required Eye Care to Prevent Ocular Toxicities

MIRV = mirvetuximab soravtansine.

Mirvetuximab soravtansine may lead to severe and/or life-threatening interstitial lung disease, including pneumonitis. However, these adverse effects are rare, and the drug’s overall benefit-risk profile remains favorable.¹⁵

DRUG INTERACTIONS

Strong CYP3A4 inhibitors (i.e., clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, and grapefruit) can increase the serum concentration of DM4. If strong CYP3A4 inhibitors are administered concomitantly with mirvetuximab soravtansine, patients should be monitored for increased toxicities with mirvetuximab soravtansine.

SPECIAL POPULATIONS

Lactation

Breastfeeding is not recommended during treatment with mirvetuximab soravtansine and for at least 1 month after the last dose.¹⁵

Hepatic Impairment

Patients with moderate or severe hepatic impairment (total bilirubin greater than 1.5 times the upper limit of normal) should avoid the use of mirvetuximab soravtansine.¹⁵ Mirvetuximab soravtansine has not been studied in patients with moderate or severe hepatic impairment.

PATIENT EDUCATION

Before Starting Mirvetuximab Soravtansine

• Eye problems are common when using this medication (Lexicomp 2023). Ensure you receive an eye examination, including a visual acuity and slit lamp examination, before starting mirvetuximab soravtansine every other cycle for the first eight cycles and as needed to monitor for ocular toxicities.

While Taking Mirvetuximab Soravtansine

• Use artificial tears or steroid eyedrops to help prevent eye problems, as prescribed and recommended by your oncology team.

• Avoid wearing contact lenses to help prevent eye problems.

Adverse Effects

• Let your physician know if you experience any worsening visual changes and/or new or worsening respiratory symptoms.

CONCLUSION

Mirvetuximab soravtansine is a breakthrough, targeted, first-in-class ADC approved for the treatment of platinum-resistant ovarian cancer. Given its proven efficacy in early-phase and large, randomized clinical trials, mirvetuximab soravtansine provides an effective treatment for patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The National Comprehensive Cancer Network guidelines list mirvetuximab soravtansine as a preferred treatment regimen for patients with FRα-positive, platinum-resistant ovarian cancer who have tried one to three prior treatments.¹⁶ Ocular adverse events were common with mirvetuximab soravtansine. It is important for the treating oncology team to counsel patients on ocular adverse events and adherence to the eye care plan described in Table 3 to reduce high-grade ocular adverse effects and prevent premature discontinuation of an effective therapy regimen.

REFERENCES

1. U.S. Food and Drug Administration (FDA). FDA D.I.S.C.O. Burst Edition: FDA Approval of Elahere (mirvetuximab soravtansine-gynx) for FRα-Positive, Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer. January 6, 2023. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-elahere-mirvetuximab-soravtansine-gynx-fra-positive-platinum.

2. Cheung A, Bax HJ, Josephs DH, et al. Targeting folate receptor alpha for cancer treatment. Oncotarget 2016;7:52553-74.

3. Vergote I, Denys H, De Greve J, et al. Treatment algorithm in patients with ovarian cancer. Facts Views Vis Obgyn 2020;12:227-39.

4. Lou E, Vogel RI, Hoostal S, et al. Tumor-stroma proportion as a predictive biomarker of resistance to platinum-based chemotherapy in patients with ovarian cancer. JAMA Oncol 2019;5:1222-4.

5. American Cancer Society (ACS). Key Statistics for Ovarian Cancer. January 12, 2023. Available at https://www.cancer.org/cancer/types/ovarian-cancer/about/key-statistics.html.

6. Fu Z, Li S, Han S, et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther 2022;7:93.

7. Biopharma PEG. FDA Accelerated Approval of ELAHERE™ (mirvetuximab soravtansine-gynx). November 16, 2022. Available at https://www.biochempeg.com/article/315.html.

8. Elahere. About Elahere. 2022. Available at https://www.elaherehcp.com/about-elahere.

9. Elahere. Efficacy. 2022. Available at https://www.elaherehcp.com/efficacy#results.

10. Helwick C. Final SORAYA Analysis Supports Mirvetuximab Soravtansine in Ovarian Cancer. ASCO Post. 2023. Available at https://ascopost.com/issues/may-10-2023/final-soraya-analysis-supports-mirvetuximab-soravtansine-in-ovarian-cancer/.

11. Matulonis U, 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 (LBA 4). Gynecol Oncol 2022;166:S50.

12. ImmunoGen. ELAHERE® Demonstrates Overall Survival Benefit in the Phase 3 MIRASOL Trial in Patients with FRα-Positive Platinum-Resistant Ovarian Cancer. May 3, 2023. Available at https://investor.immunogen.com/news-releases/news-release-details/elaherer-demonstrates-overall-survival-benefit-phase-3-mirasol.

13. ImmunoGen. ELAHERE® Demonstrates 35% Reduction in the Risk of Disease Progression or Death Versus Chemotherapy in FRα-Positive Platinum-Resistant Ovarian Cancer. June 4, 2023. Available at https://investor.immunogen.com/news-releases/news-release-details/elaherer-demonstrates-35-reduction-risk-disease-progression-or#:~:text=ELAHERE%20can%20cause%20severe%20ocular,ovarian%20cancer%20treated%20with%20ELAHERE.

14. Moore K, Angelergues A, Gottfried KE, 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. Abstract presented at: 2023 ASCO Annual Meeting II. J Clin Oncol 2023;41. Available at https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.17_suppl.LBA5507.

15. Elahere [package insert]. ImmunoGen, 2022.

16. National Comprehensive Cancer Network (NCCN). Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 2.2023. Available at https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf.