FDA Approval Summary: Mirvetuximab soravtansine-gynx for FRα-positive, Platinum-Resistant Ovarian Cancer

Abstract

On November 14, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% (95% CI: 22.9, 41.6) with a median duration of response of 6.9 months (95% CI: 5.6, 9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. 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.

Introduction

Ovarian cancer remains a deadly disease with a five-year overall survival (OS) of only 50%. There are approximately 20,000 new cases in the U.S. each year, and the majority are diagnosed at an advanced stage (1). Although most patients with advanced ovarian cancer have disease that is sensitive to platinum-based chemotherapy, approximately 80% of patients will experience relapse after platinum-based treatment. Almost all recurrent disease will eventually become platinum resistant, and patients with platinum-resistant ovarian cancer (PROC) have a poor prognosis with overall survival of 12–14 months from the time of platinum resistance (2).

Patients with PROC who have not received bevacizumab may be candidates for bevacizumab with chemotherapy (3). For patients who have received bevacizumab, treatment options are limited to single agent chemotherapy such as paclitaxel, topotecan, liposomal doxorubicin or gemcitabine. Historical data suggest that these therapies have overall response rates (ORRs) ranging from 6–27%(3, 4). However, these data were collected prior to establishment of current first-line standard-of-care treatment with a platinum-based doublet chemotherapy plus bevacizumab followed by maintenance bevacizumab and/or a Poly (ADP-ribose) polymerase (PARP) inhibitor for advanced ovarian cancer in the U.S. In more recent trials of patients with PROC, ORRs were 12–13% with median duration of response lasting 4–7.4 months for single agent chemotherapy(5).

Folate receptor-alpha (FRα) is upregulated on the surface of epithelial ovarian cancer cells, and its expression is often associated with more aggressive tumors(6–8). Herein, we provide a summary of FDA’s review of the marketing application that led to approval of mirvetuximab soravtansine-gynx for patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have received one to three prior systemic treatment regimens.

Regulatory History

Mirvetuximab soravtansine-gynx received Orphan Drug designation on July 14, 2014, and Fast Track designation on June 6, 2018. The Biologics License Application (BLA) was submitted on March 28, 2022, and was granted priority review(9, 10).

Mechanism of Action

Mirvetuximab soravtansine-gynx is an antibody-drug conjugate (ADC) containing a chimeric anti-FRα monoclonal antibody of IgG1 subtype produced in Chinese hamster ovary cells, a small molecule microtubule inhibitor DM4 (a maytansine derivative) produced by chemical synthesis, and a cleavable linker, sulfo-SPDB (1-(2,5-dioxopyrrolidin-1-yl)oxy-1-oxo-4-(pyridin-2-yldisulfanyl)butane-2-sulfonic acid) produced by chemical synthesis (6).

Mirvetuximab soravtansine-gynx binds to FRα expressed on cells, leading to internalization of the receptor-ADC complex and lysosomal degradation which in turn releases the DM4 payload from the antibody and results in cell cycle arrest and cell death. In vivo, mirvetuximab soravtansine-gynx demonstrated anti-tumor activity in mouse xenograft models of FRα-positive ovarian cancer(6).

Clinical Pharmacology

FDA reviewed subject-level data from Study 0401 (NCT01609556), Study 0403 (NCT02631876), and Study 0417 (NCT04296890) to evaluate the pharmacology of mirvetuximab soravtansine-gynx. The recommended dosage is 6 mg/kg every 3 weeks based on adjusted ideal body weight (AIBW). In Study 0401, doses ranging from 0.15–7 mg/kg total body weight and 5 to 6 mg/kg AIBW every 3 weeks were investigated. A small cohort of patients received doses ranging from 1.1 – 2.5 mg/kg AIBW in a modified weekly dosing regimen (3 weekly doses every 28-day cycle). The maximum tolerated dose (MTD) was 6 mg/kg AIBW every 3 weeks, and this dosage was used for Study 0417 (11).

Exposure-efficacy analyses at the 6 mg/kg AIBW every 3-week dosage showed that a lower AUC was associated with a lower ORR, but there was no exposure-efficacy relationship between C_max and ORR. Exposure-safety analyses demonstrated a positive association between C_max and Grade ≥2 ocular adverse reactions (ARs) and Grade ≥2 peripheral neuropathy. Data from a limited number of patients treated with the modified weekly schedule suggested that administering a lower dose more frequently may reduce ocular ARs. FDA issued a Post Marketing Requirement (PMR) to conduct a randomized dosage optimization trial evaluating efficacy and safety of at least 2 dosages: the 6 mg/kg AIBW every 3-week dosage and a dose(s) given on an alternate schedule (i.e., a modified weekly regimen). Fractionated dosing may improve benefit-risk for mirvetuximab soravtansine by maintaining AUC to achieve the desired efficacy and decreasing C_max to reduce safety concerns.

There are limited data on mirvetuximab soravtansine-gynx in patients with moderate or severe hepatic impairment, and hepatic impairment may increase exposure of the payload, DM4. The USPI recommends avoiding use of mirvetuximab soravtansine-gynx in patients with moderate or severe hepatic impairment, and FDA issued a PMR to evaluate the starting dosage in patients with moderate hepatic impairment. DM4 is a CYP3A4 substrate, and strong CYP3A4 inhibitors may increase exposure of DM4. The USPI recommends monitoring patients who are taking strong CYP3A4 inhibitors for adverse reactions (ARs,) including ocular toxicity.

Clinical Trial

Approval of mirvetuximab soravtansine-gynx was primarily based on results from Study 0417 (SORAYA, NCT04296890), a single arm trial of 106 patients with PROC who had received 1 to 3 prior lines of therapy and had tumors positive for FRα expression as determined by the VENTANA FOLR1 (FOLR1–2.1) RxDx Assay(12)(13). The major efficacy outcome measures were confirmed ORR and Duration of response (DOR) as assessed by investigator according to RECIST v1.1.

Patients received mirvetuximab soravtansine-gynx 6 mg/kg AIBW IV every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or death. All patients underwent baseline ophthalmologic examination and were required to use corticosteroid eye drops and lubricating artificial tears during treatment; additional ophthalmologic examinations were conducted if patients reported ocular symptoms. Tumor imaging assessments occurred every 6 weeks (±1 week) for the first 36 weeks, and then every 12 weeks (±3 weeks) thereafter.

Efficacy Results

The efficacy evaluable population included 104 patients with FRα-positive platinum-resistant ovarian cancer, who had measurable disease and had received at least one dose of mirvetuximab soravtansine-gynx. Patient demographics and baseline disease characteristics are shown in Table 1. All patients (100%) had received bevacizumab, 47% had received a PARP inhibitor, and 50% of patients received 3 prior lines of systemic therapy. Mirvetuximab soravtansine-gynx demonstrated a confirmed ORR of 31.7% (95% CI: 22.9, 41.6) and median DOR of 6.9 months (95% CI: 5.6, 9.7 months) by investigator assessment (Table 2). Five patients experienced a complete response (CR). Assessment of ORR and DOR by blinded independent central review (BICR) was consistent with investigator assessment.

Table 1:

Demographics and baseline characteristics of patients in the efficacy-evaluable population in Study 0417

	Mirvetuximab soravtansine-gynx N=104 N (%)
Age, median (range)	62 (35, 85)
Age group
<65 years	59 (57)
≥65 years	45 (43)
Race
Asian	2 (2)
White	100 (96)
Not reported	2 (2)
Ethnicity
Hispanic or Latino	2 (2)
Not Hispanic or Latino	97 (93)
Not reported or unknown	5 (5)
ECOG Performance Status
0	59 (57)
1	45 (43)
Region
U.S.	23 (22)
Rest of World	81 (78)
Stage at diagnosis
I-III	63 (61)
IV	40 (38)
Number of Prior therapies
1	10 (10)
2	41(39)
3+	53 (51)
Prior Bevacizumab	104 (100)
Prior PARPi	49 (47)
BRCA mutation*
Yes	20 (19)
No	84 (81)

^*BRCA mutational status (any germline or somatic mutation in tumor tissue)

Source: Drug Approval Package: Elahere (mirvetuximab soravtansine-gynx). Drugs@FDA (22).

Table 2:

INV-Assessment of Efficacy (Efficacy Evaluable Population)

Endpoint	Mirvetuximab soravtansine-gynx N=104
Objective Response Rate (ORR)** % (95% CI)	31.7 (22.9, 41.6)
Complete Response, n (%) (95% CI)	5 (4.8) (1.6, 10.9)
Partial Response, n (%) (95% CI)	28 (26.9) (18.7, 36.5)
Median Duration of Response (95% CI)	6.9 (5.6, 9.7)

^*INV=Investigator

^**ORR data cutoff date: 11/16/21, DOR data cutoff date: 4/29/22.

Source: Drug Approval Package: Elahere (mirvetuximab soravtansine-gynx). Drugs@FDA (22).

Safety Results

Nonclinical Toxicology

Administration of mirvetuximab soravtansine-gynx to cynomolgus monkeys at doses ≥ 4 mg/kg resulted in hematopoietic, skin, and ocular toxicity (involving the corneal epithelium and eyelids). Hematopoietic and ocular toxicity was reversible by the end of the 5-week recovery period. Toxicological findings in the hematopoietic system and eyes in cynomolgus monkeys were consistent with the adverse events observed in clinical trials whereas skin toxicity was not observed in the clinical trials. In genotoxicity studies, DM4 and its metabolite S-methyl-DM4 were negative in the in vitro bacterial reverse mutation assay but positive in the in vivo rat bone marrow micronucleus assay, consistent with the mechanism of action and primary pharmacological activity. Because mirvetuximab soravtansine-gynx is genotoxic, it is expected to cause teratogenicity and embryo-fetal death; Embryo-Fetal Toxicity was included in the Warnings and Precautions section of the U.S. Prescribing Information (USPI).

Safety in the Intended Population

The clinical safety evaluation was primarily based on the 106 patients who received at least one dose of mirvetuximab soravtansine-gynx in Study 0417. A pooled population of 464 patients with ovarian cancer who received at least one dose of mirvetuximab soravtansine 6 mg/kg AIBW every 3 weeks in Study 0417, Study 0401, or Study 0403 provided supportive safety data. For patients in Study 0417, the most common adverse reactions (ARs) are shown in Table 3. The most common grade ≥3 ARs included keratopathy (9%) and vision impairment (7%). Permanent discontinuation of mirvetuximab soravtansine-gynx due to ARs occurred in 11% of patients, most commonly due to intestinal obstruction (2%) and thrombocytopenia (2%). There were 20% of patients with dose reductions due to ARs, most commonly from visual impairment (9%) and keratopathy (7%). Dosage delays due to ARs occurred in 39% of patients, most frequently from visual impairment (15%) and keratopathy (11%).

Table 3:

Adverse reactions (≥ 10%) in patients who received mirvetuximab soravtansine in Study 0417

Adverse Reaction	All Grades N=106 (%)	Grade 3–4 N=106 (%)
Eye disorders
Vision impairment※	50	7
Keratopathy†	37	9
Dry eye‡	27	2
Cataract	18	3
Photophobia	17	0
Eye Pain§	10	0
General disorders
Fatigue	49	3
Gastrointestinal disorders
Nausea	40	0
Abdominal Pain*	36	7
Diarrhea	31	3
Constipation	30	1
Vomiting	19	0
Abdominal distension	11	0
Nervous system disorders
Peripheral neuropathy¶	33	2
Metabolism and nutrition disorders
Decreased appetite	18	1
Musculoskeletal and connective tissue disorders
Arthralgia	17	0
Myalgia	10	0
Respiratory, thoracic, and mediastinal disorders
Dyspnea	12	0

^※Visual Impairment includes vision blurred, vitreous floaters, visual acuity reduced, diplopia, presbyopia, accommodation disorder, visual impairment, refraction disorder.

^†Keratopathy includes corneal disorder, corneal epithelial microcysts, corneal epithelial defect, keratitis, keratopathy, corneal deposits, and punctate keratitis.

^‡Dry eye includes dry eye and lacrimation increased.

^§Eye pain includes eye pain and ocular discomfort.

^□Fatigue includes fatigue and asthenia.

^*Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort.

^¶Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, and neurotoxicity.

^{^}Dyspnea includes dyspnea and exertional dyspnea

Source: Drug Approval Package: Elahere (mirvetuximab soravtansine-gynx). Drugs@FDA (22).

Ocular toxicity is an important safety signal. In the pooled safety population, ocular ARs occurred in 61% of patients and Grade 3 ocular ARs, associated with a marked decrease in visual acuity and/or corneal disorders, occurred in 9% of patients. Grade 4 keratopathy occurred in one patient. The most common ocular ARs were visual impairment (49%) and keratopathy (36%). Fifty-one percent of patients experienced ocular ARs that did not resolve to baseline. Ocular toxicity is included as a Boxed Warning in the USPI. Patients should receive prophylaxis with ophthalmic topical steroids and lubricating eye drops. An ophthalmologic exam including visual acuity and a slit lamp exam is recommended at baseline, every other cycle for the first 8 cycles, and as clinically indicated. Recommended dosage modifications are based on ophthalmologic exam findings and ocular symptoms.

Peripheral neuropathy occurred in 36% of patients in the pooled safety population, with 2% of patients experiencing Grade 3 peripheral neuropathy. Of the patients with peripheral neuropathy, 13% had partial resolution only, and 59% had no resolution. The mirvetuximab soravtansine-gynx USPI lists peripheral neuropathy under Warnings and Precautions, and prompt dosage modification for new or worsening peripheral neuropathy is recommended.

Mirvetuximab soravtansine-gynx is also associated with interstitial lung disease (ILD), including pneumonitis. Pneumonitis occurred in 10% of patients in the pooled safety population, including 0.8% with Grade 3 events, and 1 patient (0.2%) with a Grade 4 event. One patient with pneumonitis and lung metastases died from respiratory failure. In the USPI, pneumonitis is included under Warnings and Precautions, and careful monitoring with prompt dosage modification for grade ≥2 pneumonitis is recommended.

Companion Diagnostic Development

The VENTANA FOLR1 (FOLR1–2.1) RxDx Assay is a qualitative immunohistochemical assay that received contemporaneous approval as a companion diagnostic device for the safe and effective use of mirvetuximab soravtansine-gynx. The assay identifies FOLR1 protein (commonly known as FRα and encoded by the FOLR1 gene) expression in formalin-fixed, paraffin-embedded cancer tissue specimens. FRα positivity is defined as FOLR1 membrane staining of moderate and/or strong intensity in ≥75% of viable tumor cells. The analytical studies conducted to support the safety and effectiveness of VENTANA FOLR1 (FOLR1–2.1) RxDx Assay included sensitivity, specificity, precision, external reproducibility, robustness, and stability. Clinical performance of the assay was demonstrated in Study 0417 which enrolled patients with FRα-positive tumors as defined by the assay.

Regulatory Insights

Mirvetuximab soravtansine-gynx is the first ADC approved for the treatment of ovarian cancer as well as the first targeted therapy approved for FRα-positive PROC. Patients with PROC have limited treatment options, and there is an urgent need for safe and effective new therapies. Mirvetuximab soravtansine-gynx was associated with a confirmed ORR of 31.7% (95% CI: 22.9, 41.6) and a median DOR of 6.9 months (95% CI: 5.6, 9.7) in Study 0417 which constitutes a meaningful improvement compared to available chemotherapies. These efficacy results, along with an acceptable safety profile, supported granting accelerated approval with a requirement for verification of clinical benefit in a confirmatory trial (Table 4).

Table 4:

FDA benefit-risk assessment of mirvetuximab soravtansine-gynx

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	• An estimated 19,880 new cases of ovarian cancer and 12,810 deaths from ovarian cancer occurred in the U.S. in the past year. • Almost all patients with ovarian cancer eventually develop disease resistant to platinum chemotherapy. • Folate receptor alpha (FRα) is overexpressed in some epithelial tumors, particularly high-grade serous ovarian cancers.	• Platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer, including FRα disease, is a serious and life-threatening condition with limited overall survival.
Current Treatment Options	• If patients with platinum-resistant ovarian cancer have already received bevacizumab, treatment options are limited to single agent chemotherapy with paclitaxel, topotecan, pegylated liposomal doxorubicin (PLD), gemcitabine. • From recent trials, for single agent chemotherapy, ORRs are 12–13% and median DORs are 4–7.4 months. • There are no therapies targeting FRα approved for ovarian cancer.	• Patients with platinum-resistant ovarian cancer need treatment options that improve clinical outcomes.
Benefit	• All patients enrolled to Study 0417 (SORAYA) had received prior bevacizumab. • Mirvetuximab soravtansine-gynx was associated with a confirmed ORR assessed by investigator of 31.7% (95% CI: 22.9, 41.6) and a median DOR of 6.9 months (95% CI: 5.6, 9.7). • Study 0416 (MIRASOL) is an ongoing randomized trial comparing mirvetuximab soravtansine-gynx to investigator’s choice chemotherapy in patients with platinum-resistant ovarian cancer who have received 1–3 prior systemic treatment regimens.	Mirvetuximab soravtansine-gynx was associated with an improvement in ORR compared to available therapies which is reasonably likely to predict clinical benefit. • The confirmatory trial, Study 0416, is fully enrolled, which will allow for timely verification of clinical benefit.
Risk and Risk Management	• The most common adverse reactions (≥20%) included vision impairment, fatigue, transaminase elevation, keratopathy, abdominal pain, decreased lymphocytes, peripheral neuropathy, diarrhea, decreased albumin, constipation, increased alkaline phosphatase, dry eye, decreased magnesium, decreased leukocytes, decreased neutrophils, and decreased hemoglobin. • Ocular toxicity was included as a Boxed Warning and pneumonitis, peripheral neuropathy, and risk of embryo-fetal toxicity are listed under Warnings and Precautions in the USPI. • Ocular monitoring, premedication and risk mitigation strategies are outlined in the USPI.	• Mirvetuximab soravtansine-gynx has an acceptable safety profile for the intended patient population, which is manageable through labeling including a Boxed Warning for ocular toxicity. • Additional information on dosage optimization and ocular toxicity will be forthcoming from studies conducted under PMRs.

Source: Drug Approval Package: Elahere (mirvetuximab soravtansine-gynx). Drugs@FDA (22).

It was important to FDA’s decision-making that the confirmatory trial, Study 0416 (MIRASOL; NCT04209855), was fully enrolled when accelerated approval was granted. Study 0416 is a randomized trial of mirvetuximab soravtansine-gynx compared to investigator’s choice chemotherapy in patients with FRα-positive PROC who received 1–3 prior lines of systemic therapy; the primary endpoint is PFS, and OS is a secondary endpoint. An FDA analysis showed that for oncology indications receiving accelerated approval, the time to either conversion to a traditional approval or withdrawal of the indication was shorter if the confirmatory trial was well underway at time of accelerated approval(14, 15). The recently enacted Food and Drug Omnibus Reform Act (FDORA) will strengthen the accelerated approval pathway by permitting FDA to require that confirmatory trials be ongoing at time of approval which can decrease the period of uncertainty between availability of a drug and verification of clinical benefit(16).

Although the benefit:risk assessment supported approval for mirvetuximab soravtansine-gynx, ocular toxicity was a concerning safety signal, and some patients experienced severe vision impairment. In Study 0417, patients received an ophthalmologic exam at baseline, but future exams were only triggered by symptoms. In addition, ocular toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 which largely relies on symptoms to assign severity. Certain ocular toxicities may be asymptomatic until ocular damage is advanced (17). Assessment based on symptoms without incorporation of routine ophthalmologic monitoring may result in under-reporting the incidence and/or severity of ocular ARs and lead to delayed detection and intervention. Ocular toxicity is listed as a Boxed Warning to alert providers to the risk of severe ocular toxicity and the need for routine monitoring. FDA also issued a PMR to incorporate prospective ophthalmologic assessments into a new or ongoing trial for better characterization of the incidence and severity of ocular ARs.

An alternate dosing regimen may improve the benefit:risk profile for mirvetuximab soravtansine-gynx by decreasing ocular and other toxicities. Exposure-response analyses suggested that a fractionated dosing regimen (i.e., when a lower dose is administered more frequently) could achieve similar efficacy to the approved dosage and improve safety. FDA issued a PMR for dosage optimization, however dosage optimization prior to drug approval is preferable. Better characterization of dosage in the premarket setting could improve safety and tolerability, allowing patients to avoid serious toxicities and remain longer on a potentially efficacious therapy. Project Optimus, an FDA Oncology Center of Excellence (OCE) program, aims to reform oncology drug dosing by advancing a paradigm in which characterization of drug dosages prior to approval is the norm (18). A recently released FDA draft guidance outlines key principles for achieving dosage optimization in the premarket setting (19).

The trial population for Study 0417 was not representative of a U.S.-based population with PROC with respect to race and ethnicity. Ninety-six percent of enrolled patients were White, and no patients were Black; only 2% of patients were Hispanic or Latino. FDA issued a post marketing commitment (PMC) to further characterize the safety and efficacy of mirvetuximab soravtansine-gynx in patients from underrepresented groups; however, having adequate representation during premarket drug development is preferable. Project Equity is an FDA OCE initiative to emphasize equitable access to investigational therapies and ensure that data supporting the approval of oncology products are adequately assessed in the intended population (20). An FDA draft guidance encourages sponsors to implement a plan to enroll patients from underrepresented racial and ethnic populations early in drug development, rather than deferring evaluation to the post market setting (21).

Conclusion

Mirvetuximab soravtansine-gynx represents a new targeted treatment option for patients with FRα-positive PROC, a disease with significant unmet medical need and few therapeutic advancements in the past two decades. The overall benefit: risk assessment for mirvetuximab soravtansine-gynx is favorable. Results from Study 0417 are reasonably likely to predict clinical benefit and supportive of an accelerated approval. Ocular toxicity is an important safety signal and included as a Boxed Warning in the USPI to alert providers to the need for specialized monitoring. The potential confirmatory trial, Study 0416, was fully enrolled at time of approval which will allow for timely verification of clinical benefit. Inadequate dosage optimization and the lack of diversity in the enrolled patient population were limitations of this application and will be further investigated in the post-marketing setting.