Mirvetuximab soravtansine for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer

ABSTRACT

Mirvetuximab soravtansine (MIRV) is FDA-approved for platinum-resistant ovarian cancer with high folate receptor alpha (FRα) expression. In the MIRASOL trial, MIRV improved median progression-free survival (5.6 vs. 3.9 months) and overall survival (16.5 vs. 12.8 months; HR 0.67) over chemotherapy. MIRV has a favorable safety profile but is associated with unique ADC-related toxicities, including blurred vision, keratopathy, and nausea. Ocular side effects are managed with regular eye exams and prophylactic drops, with no permanent damage reported. MIRV has also shown promising results in combination with bevacizumab and with carboplatin in platinum-sensitive disease. Ongoing research aims to optimize ADC components and explore synergistic combinations to expand MIRV’s role in FRα-expressing ovarian cancer.

Plain Language Summary

What is this article about? Antibody-drug conjugates (ADCs) are a type of cancer treatment that help deliver chemotherapy directly to cancer cells, while limiting damage to healthy cells. Mirvetuximab soravtansine (MIRV) is the first ADC approved for ovarian cancer. It targets a protein called folate receptor alpha (FRα), which is commonly found on ovarian cancer cells, and delivers a drug that disrupts cancer cell growth. This review summarizes what is currently known about MIRV based on published research.▪ What were the results? In the Phase III MIRASOL trial, MIRV improved overall survival for patients with ovarian cancer with high folate receptor alpha expression compared to physicians choice of chemotherapy with a median overall survival of 16.5 months vs. 12.8 months. MIRV is currently in trials for patients earlier in treatment and differing levels of FRα expression. MIRV has unique side effects, including manageable eye-related symptoms and lung toxicity.▪ What do the results of the study mean? MIRV is now approved by both the FDA and EMA for treating patients with platinum-resistant ovarian cancer whose tumors show high levels of folate receptor alpha (FRα). While this is an important advance, more research is needed to better understand how FRα expression affects treatment response and to uncover why some tumors become resistant to this therapy over time.

1. Introduction

Antibody-drug conjugates (ADCs) represent a rapidly expanding category of cancer treatments. These therapeutics pair the targeting ability of monoclonal antibodies with the power of cytotoxic drugs through three key components: (1) a monoclonal antibody that selectively binds to a tumor-specific surface antigen, (2) a potent cytotoxic drug designed to trigger cell death after being taken up by the target cell, and (3) a stable linker that remains intact in the bloodstream but releases the cytotoxic agent once inside the target cells [1]. ADCs are designed to enhance the therapeutic index of cytotoxic agents by selectively delivering them to cells that express the target antigen, thereby limiting systemic exposure. The therapeutic index is the ratio between the dose that causes toxicity to the dose that produces therapeutic benefit. Since ADCs deliver the payload directly to the antigen expressing cells, the drug can effectively treat the disease with lower risk of adverse effects.

While the concept of ADCs was developed in the 1980s, initial attempts yielded problematic drug toxicities without clear signs of efficacy. Recent advances in synthetic biochemistry have allowed a new generation of ADC development with improved tissue specificity and cytotoxicity. The first success of an ADC was seen with the Food and Drug Administration (FDA) approval in 2000 of gemtuzumab ozogamicin, a CD33 antibody conjugated to the antitumor antibiotic calicheamicin for the treatment of leukemia [2,3]. This drug was subsequently withdrawn from the market in 2010 due to concerns that when combined with chemotherapy the adverse events potentially outweighed the efficacy [4]. However, in 2011, the CD30-targeted ADC brentuximab vedotin was approved for relapsed refractory classical Hodgkin lymphoma, followed by the first solid tumor approval by the FDA of ado-trastuzumab emtansine (T-DM1) for metastatic breast cancer [5,6]. The pace of ADC development has been rapidly increasing over the last decade, as these drugs have shown impressive anti-cancer activity against treatment-resistant cancers [4].

Given the success of ADCs in cancers with limited treatment options, their development in gynecologic malignancies was a natural progression. Currently, more than 20 ADCs are in clinical trials for gynecologic cancers, exploring over 10 different targets with 3 FDA-approved ADCs already available for the treatment of gynecologic malignancies. These include tisotumab vedotin (anti-tissue factor mAb and MMAE payload) for cervical cancer, trastuzumab deruxtecan (anti-HER2 mAb and camptothecin deruxtecan payload) for all gynecologic cancers with increased HER-2 expression, and mirvetuximab soravtansine (anti-folate receptor alpha mAb and maytansinoid DM4 payload) for platinum-resistant ovarian cancer with high folate receptor expression the focus of this review [7].

2. Overview of the field: epithelial ovarian cancer

Over 95% of ovarian malignancies are epithelial ovarian cancer (EOC) and high grade serous ovarian cancer (HGSOC) makes up 70% of cases [8]. HGSOC exhibits marked genomic instability, with TP53 mutations present in the vast majority of cases and homologous recombination repair deficiencies occurring in approximately 50% [9,10]. Most patients are diagnosed at an advanced stage, with standard therapy involving cytoreductive surgery followed by platinum-based adjuvant chemotherapy. Despite its introduction in the 1970s, platinum agents have remained the mainstay of therapy for HGSOC.

Despite recent advances with the incorporation of poly (ADP-ribose) polymerase (PARP) inhibitors and the use of bevacizumab to target angiogenesis, unfortunately up to 80% of patients eventually relapse with disease that ultimately becomes resistant to currently available therapies [11–13]. Outcomes for patients with platinum-resistant HGSOC remain particularly poor, with low response rates to further chemotherapy [14–16]. Moreover, subsequent lines of systemic therapy are often associated with cumulative toxicities and limited tolerability for patients. The development of novel therapies for patients with platinum-resistant recurrent disease represents an unmet medical need. As such, antibody-drug conjugates show early promise in improving outcomes for patients with platinum-resistant HGSOC [17]. The greatest potential of an ADC lies in its ability to improve the therapeutic index of the payload by restricting the systemic delivery to only cell that express the target antigen of interest [18].

3. Introduction to Mirvetuximab Soravtansine

MIRV, the first ADC to be FDA and EMA approved for gynecologic cancers, is a folate receptor alpha (FRα)-targeted antibody-drug conjugate that is conjugated via a cleavable linker to a microtubule inhibitor payload DM4. It is approved for the treatment of platinum-resistant HGSOC that demonstrates high levels of folate receptor expression after phase III results showed improvement in overall survival compared to chemotherapy [19].

4. Pharmacology

4.1. Chemistry- target antigen

Antigen selection is critical to ensuring the specificity of an ADC. One guiding principle in target selection is identifying cell-surface proteins that are abundantly expressed on tumor cells while exhibiting limited to no expression on nonmalignant tissues [17]. Since ADCs deliver their cytotoxic payload to all cells expressing the target antigen, selecting targets with tumor-specific or tumor-enriched expression enhances the therapeutic index and reduces the risk of off-target toxicity [17]. Additionally, the target should possess internalization properties to allow the ADC to transport the payload into the cell and in turn enhance the efficacy of the cytotoxic agent [18]. Finally, targets that are functionally oncogenic are less prone to downregulation as a mechanism of drug resistance and could be leveraged for enhanced ADC efficacy through antibody-mediated inhibition of downstream oncogenic signaling pathways [17].

Folate receptor alpha (FRα), a 38–40 kDa glycosyl-phosphatidylinositol (GPI)-anchored cell-surface glycoprotein, was found to be overexpressed in several epithelial malignancies, including ovarian, renal, lung and breast cancer [20]. Increased folate receptor expression is seen in approximately 70% of high-grade serous ovarian cancers [20]. In contrast, FRα has significantly lower expression in most normal tissues. Additionally, FRα allows internalization of folic acid, a property that would allow the ADC to be internalized into a cell. High expression of FRα has been associated with poorly differentiated more aggressive tumors [21]. For these reasons, FRα is an ideal target for an ADC.

The first proof of concept that folate receptor alpha is a druggable target was farletuzumab (MORAb-003), a nonconjugated humanized IgG1 antibody. This monoclonal antibody promoted cell death via antibody-dependent cellular cytotoxicity. The phase III study of farletuzumab plus paclitaxel ultimately did not meet its primary endpoint; however, this drug provided critical evidence that the folate receptor was a target worth pursuing [22].

Mirvetuximab soravtansine (originally named IMGN853) is comprised of a FRα-binding monoclonal IgG1 antibody (M9346A). IgG1 is used in a majority of ADCs due to its longer half-life, greater complement-fixation and FcγR-binding efficiencies [17]. M9346A was chosen from a panel of murine anti-FRα antibodies for its ability to effectively deliver the payload to FRα-positive cells [23]. Following selection of the antibody, it was then humanized by variable domain resurfacing to prevent anti-human antibodies that can reduce its efficacy [23].

4.2. Chemistry- Linker

The linker is used to ensure that the cytotoxic payload remains firmly attached to the antibody while the drug is circulating in plasma. If the linker is unstable in plasma, it could release the payload prematurely, resulting in excess toxicity and reducing the payload delivery at the tumor site. Additionally, the linker’s role is to enable efficient release of the payload within the tumor cells. If an ADC cannot release its payload, it has no therapeutic advantage over naked antibodies. Linkers are broadly classified into two classes, cleavable and non-cleavable. Cleavable linkers break down and release the payload in response to tumor-associated factors like the pH or enzymatic breakdown. Cleavable linkers enable efficient release of active payloads and may facilitate a bystander effect. Disulfide linkage and cathepsin-sensitive valine-citrulline dipeptides are commonly used for this purpose [24]. In contrast, non-cleavable linkers are more stable in plasma but are resistant to proteolytic degradation and rely on complete endocytosis and lysosomal degradation of the entire antibody-linker construct to release their payloads, which can result in retention of charged amino acids on the payload and could affect cell permeability.

MIRV uses a charged, cleavable disulfide linker, N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB). In order to optimize the linker, several linker combinations were tested and the disulfide linked conjugates were more active than the thioether conjugate in cell lines [23].

4.3. Chemistry- payload

Early ADCs which used traditional chemotherapies as their payload such as vinca alkaloids or methotrexate were not more effective than standard cytotoxic agents [25]. Additionally, data indicates that only a very small fraction of the administered dose actually reaches the target, implying that payloads need to be highly cytotoxic to be efficacious [17]. These observations have led to the development of ADCs with highly potent agents, including auristatins, calicheamicins, maytansinoids and camptothecin analogues, which can be cytotoxic at sub-nanomolar concentrations [25]. The drug-to-antibody ratio (DAR) is the average number of payload moieties attached to each monoclonal antibody. The range of DARs is from 2 to 8 and in general, higher DARs are expected to be more potent but have higher risk for instability, premature payload release and higher toxicity [26].

MIRV uses the maystinoid N2′-deacetyl-N2′-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) as its payload, after it exhibited the most potent antitumor activity in several FRα-expressing xenograft tumor models [23]. DM4 binds to tubulin, disrupting microtubule dynamics and resulting in mitotic arrest and apoptosis, and is 100 to 1000 times more potent than vinca alkaloids [27]. When the ADC binds FRα, MIRV is internalized and DM4 is released into the cell under lysosomal action. DM4 then causes cell-cycle arrest and apoptosis. Additionally, DM4 is electrically neutral and lipophilic, allowing it to penetrate into neighboring cells and induce further cell death via the bystander effect [28]. MIRV has a drug-to-antibody ratio (DAR) of 3.5:1.

4.4. Pharmacokinetics

During the phase I and phase III (FORWARD I) trials, patients’ blood samples were collected after each of the first three cycles to determine the plasma concentrations of MIRV, its payload DM4 and the cytotoxic metabolite S-methyl-DM4 [29]. Given the complexities of the mechanism of an ADC, a pharmacokinetic model was created that took into account the target component of tumor cells, minor deconjugation that happens systemically and hepatic methylation of the payload [29].

Using these properties, a final ADC payload-metabolite model was created and found that the mean exposure increased proportionally with each dose and the mean half-life ranged from 79 to 121 hours [30]. When taking into account covariates, the most notable effects were adjusted ideal body weight (AIBW), as patients with higher AIBW had higher clearance and larger volumes of distribution [29]. Additionally, higher albumin concentration was associated with a lower clearance of MIRV since both are cleared by the same mechanism [29]. The model also showed that there was little interaction in patients with mild or moderate renal impairment, mild hepatic impairment, or who used concomitant weak and moderate CYP3A4 inhibitors [29].

The exposure–response relationship was subsequently investigated and the trough concentration was consistently identified as the key predictor for response rate, PFS and OS [31]. For safety, the area under the concentration–time curve (AUC) was correlated with ocular adverse events.

4.5. Pharmacodynamics

In the phase I dose-finding study, there was an exposure–response relationship with increasing exposure associated with a higher incidence of mainly ocular events [32]. Upon completion of dose escalation, 6 mg/kg every 3 weeks was declared the recommended phase II dose and used in the expansion cohort of the study and subsequent phase II/III studies. The FDA has issued a post-marketing approval requirement for a further dose optimization plan including a randomized clinical trial of at least two dosing schedules as well as collecting and analyzing the safety and pharmacokinetic information including unconjugated DM4, and s-methyl DM4 to determine the appropriate starting dose which are both pending [33].

5. Clinical efficacy

5.1. Phase I studies

The final results of the phase I dose–escalation study (IMGN853–401) were released in 2017 [32]. A summary of the results can be found in Table 1. This study aimed to evaluate the maximum tolerated dose (MTD) and recommended phase 2 dose (R2PD) in patients with solid tumors with known high incidence of FRα positivity, which included HGSOC, endometrial cancer, lung cancer, and renal cell carcinoma. MIRV was given intravenously once every 3 weeks at escalated doses including 0.15, 0.5, 1.0, 2.0, 3.3, 5.0, and 7.0 mg/kg with a standard 3 + 3 design [32]. Most patients (23 out of 44) on this study had ovarian cancer. At the first four dose levels, no dose limiting toxicities were observed. Ultimately, after switching from total body weight to adjusted ideal body weight (AIBW), the RP2D was determined to be 6.0 mg/kg every 3 weeks, where no DLTs were observed [32]. The DLTs experienced at higher dose levels were punctate keratitis, corneal opacity, pulmonary edema, and hypophosphatemia, all of which were reversible. In the safety analysis, the most frequent treatment-emergent AEs were diarrhea (34%), fatigue (32%), nausea (25%), and blurred vision (25%), most of which were mild (grade 1 or 2) [32].

Table 1.

Summary of phase I and II trials for MIRV in platinum-resistant ovarian cancer.

	MIRV monotherapy	MIRV monotherapy	MIRV monotherapy	MIRV + Bev	MIRV + Pembrolizumab
Study Design	Phase I	Phase I	Phase II	Phase Ib/II	Phase Ib/II
Patient Population	Refractory solid tumors wo standard treatment with historically high FRα expression (epithelial ovarian cancer, EEC, NSCLC, RCC)	Platinum-resistant HGSOC with FRα expression of at least 2+ in ≥ 25% of cells, up to five prior lines	Platinum-resistant HGSOC with high FRα expression, at least 2+ in ≥ 75% of tumor cells, up to three lines of treatment	Platinum-resistant HGSOC with FRα expression of low to high (≥25%)	Platinum-resistant HGSOC FRα low to high (≥25%) after 2–4 lines
Trial	Safety and dose-finding [32]	Expansion study [34]	SORAYA [35]	FORWARD II [36]	FORWARD II [37]
n	44 (23 ovarian)	46	106	94	14
ORR	5%	26%	32%	44%	43%
PFS	NR	4.8mts	4.3mts	8.2mts	5.2mts
DOR	NR	19.6wks	6.9mts	9.7mts	6.9mts
CBR	23%	NR	NR	NR	NR
AEs: total % (Grade 3/4%)
Blurry vision	25%	41% (0%)	41% (6%)	57% (1%)	NR
Diarrhea	34%	44% (2%)	22% (2%)	54% (1%)
Nausea	25%	37% (2%)	29% (0%)	51% (1%)
Neuropathy	22%	28% (2%)	13% (0%)	38% (1%)
Dry eye	NR	13% (0%)	25% (0%)	28% (2%)
Neutropenia	NR	NR	13% (2%)	NR
Keratopathy	16%	26% (0%)	29% (9%)	34% (0%)
Anemia	NR	13% (2%)	NR	NR
Hypertension	NR	NR	NR	28% (15%)
Thrombocytopenia	NR	NR	NR	30% (4%)

MIRV, mirvetuximab soravtansine; Bev, bevacizumab; HGSOC, high grade serous ovarian cancer; FRα, folate receptor alpha; ORR, objective response rate; NR, not reported; PFS, progression free survival; DOR, duration of response; AE, adverse events; Gr, grade; mts, months; wks, weeks; wo, without.

Following this study, a phase I expansion study evaluated the safety and clinical efficacy of MIRV in patients with platinum-resistant HGSOC who had FRα positivity by immunohistochemistry ($\ge$25% of tumor cells with at least 2+ staining intensity) at 6.0 mg/kg [34]. This study enrolled 46 heavily pre-treated patients (50% had received $\ge$4 lines) and found a confirmed objective response rate (ORR) of 26% with 1 complete response, median progression free survival (mPFS) of 4.8 months (mts) and median duration of response (mDOR) of 19.1 weeks. The drug was well tolerated with generally mild adverse events (AEs). The patients were sorted by FRα positivity by IHC into low (≥25%), medium (≥50%) or high (≥75%), and in all groups there were patients who responded. Patients who had three or less prior lines of therapy had an ORR of 39% and mPFS of 6.7 months, suggesting improved response in less heavily pretreated patients.

5.2. Phase II studies

The SORAYA trial was a single-arm phase II study evaluating the efficacy and safety of MIRV in patients with platinum-resistant HGSOC who had received 1–3 prior lines of therapy and had high FRα expression ($\ge$75% of viable tumor cells exhibiting at least 2+ by IHC) [35]. The results of this study are summarized in Table 1. This study enrolled 106 patients with 105 evaluable for efficacy. The ORR was 32% with 5 complete responses and 29 partial responses and the mDOR was 6.9 months. The ORR was 38.0% in patients with a prior PARP inhibitor and 27.5% in those without. The most common treatment-related adverse events included blurred vision (41% all grades, 6% grade 3/4), keratopathy (29% all grade, 9%), nausea (29%, 0% grade 3/4), dry eyes (25%, 0%), fatigue (24%, 1%), and diarrhea (22%, 2%). MIRV was granted accelerated approval by the United States Food and Drug Administration (FDA) in November 2022 based on the SORAYA clinical trial data.

5.3. Phase III studies

There have been two global randomized phase III trials investigating MIRV in platinum-resistant HGSOC, the results of which can be found in Table 2. In the MIRASOL study, patients with platinum-resistant HGSOC with high FRα expression by IHC with 2+ or 3+ staining intensity (PS2+ scoring) among ≥ 75% of viable tumor cells, were randomized to MIRV or investigators choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel or topotecan). MIRV showed improvement in mPFS of 5.6 vs 3.9 months and median OS of 16.5 vs. 12.8 months with a hazard ratio (HR) of 0.67 (95% CI: 0.50–0.89) [39]. This is the only agent in platinum-resistant HGSOC that has shown an overall survival benefit to date in phase III trials. Given the heterogeneity of the control arm, it is somewhat unclear whether MIRV is superior to weekly paclitaxel alone, the most effective agent in the control group. Compared to chemotherapy, MIRV had had lower serious AEs 23.9% vs 32.9%, lower grade 3 AEs occurring in 42% vs 54% of patients, and lower hematologic toxicity with anemia in 9.6% vs 34.3%. This trial led to MIRV’s official FDA approval in the platinum-resistant setting.

Table 2.

Summary of completed phase III results to date of mirvetuximab soravtansine for platinum-resistant ovarian cancer.

	MIRV monotherapy	MIRV monotherapy
Patient Population	Platinum-resistant HGSOC with ≥ 50% of tumor cells with any FRα membrane staining visible	Platinum-resistant HGSOC with high FRα expression (≥75%)
Trial	FORWARD-I [38] (n = 366, 243 MIRV)	MIRASOL [19] (n = 453, 226 MIRV)
ORR	22%	42.3%
PFS	4.1mts	5.6mts
DOR	NR	6.7mts
AEs: total % (Grade 3/4%)
Blurry vision	42% (2.5%)	41% (8%)
Diarrhea	31% (5%)	29% (1%)
Nausea	45% (1%)	27% (2%)
Neuropathy	26% (2.5%)	22% (1%)
Dry eye	26% (1%)	28% (3%)
Neutropenia	6% (0%)	11% (1%)
Keratopathy	33% (1%)	32% (9%)
Anemia	10% (1%)	10% (1%)

MIRV, mirvetuximab soravtansine; HGSOC, high grade serous ovarian cancer; FRα, folate receptor alpha; ORR, objective response rate; NR, not reported; PFS, progression free survival; DOR, duration of response; AE, adverse events.

The MIRASOL trial was conducted after the phase III FORWARD I trial failed to meet its primary endpoint of improving PFS following MIRV treatment when compared to standard of care. In this study, patients were thought to be FRα positive by IHC if at least 50% of tumor cells had any FRα membrane staining visible via 10× scoring [38]. MIRV did not result in a significant improvement in PFS compared with chemotherapy although in the folate receptor high patients (≥75% of tumor cells positive for FRα), MIRV was consistently favored and showed a more manageable safety profile than chemotherapy. In the later in-depth analysis of the FORWARD I study, data revealed that the method of determining FRα positivity using the observable membranous staining at x10 microscope objection for enrollment of the study was not a reliable method to detect patients whose tumors have high expression of FRα. In the preceding phase I program patients were considered eligible not only by proportion of the tumor cells staining for any FRα expression but also by the intensity of FRα staining, and only samples with 2+ or 3+ staining intensity (PS2+ scoring) were deemed positive. In rescoring of the samples used in FORWARD-I, 34% of patients would have fallen below the PS2+ cutoff which could have diluted the treatment effect of MIRV in this study [40]. The contrasting findings between these two studies emphasize the need to determine an appropriate cutoff to establish a reliable and reproducible biomarker for predicting response to MIRV.

5.4. MIRV combinations for platinum-resistant ovarian cancer

MIRV has been under investigation in the platinum-resistant setting when combined with bevacizumab and pembrolizumab, as part of the Phase Ib/II FORWARD II study. Table 1 summarizes the results to date of these trials. Patients with platinum-resistant HGSOC with FRα expression of at least ≥25% of tumor cells at ≥2+ intensity received MIRV in combination with bevacizumab. Following a November 2017 amendment, the threshold was raised from ≥25% to ≥50% for continuing enrollment [41]. The final results of 94 patients demonstrated an ORR of 44% with 5 complete responses, mDOR of 9.7 months, and mPFS of 8.2 months [36]. Patients with high FRα expression (≥75%) had a higher ORR of 48% and longer mPFS of 9.7 months and those that were bevacizumab-naïve had an ORR of 56% and mDOR of 10.4 months. Most patients experienced at least one treatment-related adverse event (TRAE), the most common of which included blurry vision (57%), diarrhea (54%), nausea (51%) and fatigue (43%) most of which were grade 1 or 2. The most common grade 3 AE was hypertension in 15% of patients. The absolute benefit for the addition of bevacizumab is still unclear, but the safety profile was acceptable and more data is needed. Only preliminary data are available currently on 14 patients with MIRV and pembrolizumab, and demonstrated an ORR of 43% and mPFS of 5.2 months [37].

5.5. Mirvetuximab for platinum-sensitive ovarian cancer

While MIRV is currently FDA and EMA approved in the platinum-resistant setting, there have been studies evaluating the efficacy of MIRV in patients with platinum-sensitive ovarian cancer (PSOC) that have been completed or are ongoing as outlined in Table 3. In 2018, the FORWARD II trial evaluated MIRV in combination with carboplatin in patients with FRα positive (≥25% of tumor cells with ≥2+ staining intensity) PSOC. This trial enrolled 18 patients and demonstrated an ORR of 71%, with three complete responses and a mPFS of 15 mts [34]. On a separate arm of the FORWARD II study, 31 patients with PSOC were treated with MIRV and bevacizumab and were found to have an ORR of 48%, mDOR 12.7 months and mPFS of 9.6 months [36]. A third arm was treated with the triplet combination of carboplatin, MIRV and bevacizumab followed by MIRV and bevacizumab maintenance at the discretion of the investigator. Forty-one patients with PSOC were treated with this triplet and the ORR was 83%, mDOR of 10.9 months and mPFS of 13.5 months [44]. The toxicities observed were as expected based on the side effect profile of each individual agent and included diarrhea (83% all grade, grade 3/4 10%), nausea (72% all grade, grade 3/4 2%), fatigue (76%, 5%), blurred vision (68%, 0%), thrombocytopenia (71%, 51%), neutropenia (44%, 44%), and hypertension (32%, 10%).

Table 3.

Summary of trials for mirvetuximab soravtansine in platinum-sensitive ovarian cancer.

Drug combination	Trial	Study Design	Patient Population: PSOC	Trial status Estimated study completion date	ORR (%)	mPFS (mts)	mDOR (mts)
MIRV monotherapy	PICCOLO [42]	Phase II	High FRα (≥75%) after 2 lines of platinum- chemotherapy	Complete December 2024	52%	6.9	8.3
MIRV + Carboplatin	FORWARD II [34] NCT02606305	Phase 1b/II	Low-high (≥25%) FRα expression	Complete March 2021	71%	15	NR
MIRV + Bev	FORWARD II [36,43] NCT02606305	Phase 1b/II	High (≥75%) FRα expression		48%	9.6	12.7
MIRV + Carbo + Bev followed by MIRV/Bev maintenance	FORWARD II [44] NCT02606305	Phase 1b/II	Medium-high FRα expression (≥50%) after 1–2 lines of therapy		83%	13.5	10.9
Under investigation without published data
Neoadjuvant MIRV + carbo and adjuvant MIRV + carbo	NCT04606914 [45]	Phase II	1 L treatment with high (≥75%) FRα expression	Recruiting May 2028	Not reported
MIRV + carbo followed by MIRV maintenance	MIROVA [46] NCT04274426	Phase II	High (≥75%) FRα expression after one line of chemotherapy	Active, not recruiting December 2026
MIRV + carbo followed by MIRV maintenance	Study-0420 [47] NCT05456685	Phase II	Low-high (≥25%) FRα expression after one line of chemotherapy	Active, not recruiting December 2026
Maintenance MIRV + olaparib	NCT05887609 [48]	Phase II	Medium-high (≥50%) FRα expression	Recruiting December 2027
Maintenance MIRV + Bev	GLORIOSA [49] NCT05445778	Phase III	High (≥75%) FRα expression	Recruiting April 2029

Bev, bevacizumab; carbo, carboplatin; Chemo, chemotherapy; PSOC, platinum sensitive ovarian cancer; FRα, folate receptor alpha; 1 L, first line; ORR, objective response rate; NR, not reported; PFS, progression free survival; DOR, duration of response; MIRV, mirvetuximab soravtansine; mts, months.

Following the promising data in the FORWARD II study in the platinum-sensitive setting, additional studies including phase II trials (PICCOLO, MIROVA, Study-420) and phase III trials (GLORIOSA) were designed. The PICCOLO trial, a single-arm phase II trial evaluated MIRV as third-line or greater in patients with FRα positive (≥75% of cells with 2+ staining intensity) PSOC was recently published and demonstrated in 79 patients, an ORR of 51.9% with 6 complete responses, median DOR of 8.3 months and mPFS of 6.9 months [42,50,51]. These findings support the use of MIRV following two prior lines of platinum-based therapy in patients with platinum-sensitive disease.

There are multiple trials in progress that are expected to complete over the next years. Study-420 (NCT05456685) is a phase II study of MIRV in combination with carboplatin followed by MIRV maintenance for patients with FRα positive (≥25% of cells with ≥2+ staining intensity) recurrent PSOC following one line of prior platinum-base chemotherapy [47]. The MIROVA trial (NCT04274426) is a multi-center, randomized, two-arm comparative trial of MIRV plus carboplatin versus platinum-based chemotherapy for patients with FRα high (≥75% of cells with 2+ staining intensity) ovarian cancer that are eligible for further platinum-based therapy [46]. This trial is expected to complete enrollment in late 2025.

The GLORIOSA trial (NCT05445778) is a phase III open-label study designed to evaluate the efficacy of MIRV plus bevacizumab as maintenance therapy in FRα high (≥75% of cells with ≥2+ staining intensity) PSOC after second-line platinum-therapy [49]. Another ongoing phase II study (NCT04606914) is evaluating MIRV in the first-line setting as neoadjuvant therapy [45]. In this study, patients receive one cycle of carboplatin followed by MIRV plus carboplatin in the perioperative setting. Lastly, a phase II study is evaluating MIRV in combination with olaparib as maintenance therapy for patients with moderate FRα expression (≥50%) after platinum-based chemotherapy [48] and those patients that are BRCA positive must have received a prior PARP inhibitor [48].

While not approved by the FDA, the National Comprehensive Cancer Network (NCCN) currently lists MIRV as monotherapy for patients PSOC with high FRα expression of ≥75% in light of the PICCOLO data and in combination with bevacizumab for patients with PSOC with moderate ≥50% FRα expression in light of the FORWARD II data (category 2B) [52].

6. Real world evidence

Since the FDA approval of MIRV in March 2024, studies are beginning to emerge about the use of this therapy in the real-world setting. Comparing the population enrolled in MIRASOL to those receiving MIRV in routine practice is an important distinction. MIRASOL included patients with an ECOG performance status of 0–1 and limited prior therapies to three or fewer lines [19]. In contrast, early real-world studies report up to 15% of patients with an ECOG performance score of 2 and approximately 35% with four or more prior lines of therapy [53]. This suggests that real-world patients may exhibit a lower performance status and may have received a greater number of prior treatments.

Despite these differences, real-world data indicates that patients receiving MIRV complete an average of seven cycles and remain on treatment for approximately 4.5 months with an average OS of 9 months [53]. These outcomes are comparable to those reported in the MIRASOL trial. Moreover, rates of treatment discontinuation remain consistent, with approximately 90% of patients discontinuing due to progression and only 10% due to toxicity. Toxicity profiles, including ocular events and neuropathy, are also similar to those observed in MIRASOL, with low overall rates of treatment-related dose delays, reductions, or discontinuation [19,53].

An important consideration for post-MIRV management is the potential for cumulative toxicity. Since most patients with platinum-resistant HGSOC have prior exposure to paclitaxel, a microtubule inhibitor with a mechanism of action similar to DM4, there are concerns regarding the risk of cumulative neuropathy. However, early data indicates that patients who received a taxane immediately prior to MIRV do not experience shorter treatment duration, shorter OS, or increased rates of dose modifications or discontinuation due to grade 3–4 neuropathy [53]. Additionally, prior taxane exposure does not appear to preclude the use of subsequent taxane therapy after MIRV. While the theoretical risk of worsened neuropathy remains, clinical studies to date suggest minimal impact on treatment tolerability or continuation.

7. Safety and tolerability

Overall, MIRV has a favorable safety profile, particularly compared to chemotherapy. Tables 1 and 2 summarize the treatment-related adverse events (TRAEs) from the phase II and III trials. In the SORAYA trial, 86% of patients experienced a TRAE with 29% being grade 3 or higher. The most common TRAEs (all grades) were blurred vision (41%), keratopathy (29%), and nausea (29%). TRAEs led to a dose delay in 33% of patients, dose reduction in 20% of patients, and discontinuation in 9% of patients [35]. In the FORWARD I study, 25.1% of patients on MIRV experienced grade 3 or higher TRAEs compared to 44% of patients on chemotherapy [38]. Dose reductions occurred in 19.8% of patients, and discontinuation occurred in 4.5% of patients. Like the SORAYA study, common TRAEs were blurred vision (42%), keratopathy (32.5%), and nausea (45.7%).

The most recent phase III MIRASOL study reported similar TRAEs. Again, the most common TRAEs were blurred vision (40.8%), keratopathy (32.1%), and abdominal pain (30.3%). Dose reduction occurred in 33.9% of patients and discontinuation occurred in 9.2% of patients (most often due to blurred vision or pneumonitis) [19]. Grade 3 or higher TRAEs occurred in 41.7% of patients on MIRV and 54.1% of patients on chemotherapy [19]. These trials in platinum-resistant HGSOC demonstrate that MIRV has a favorable and tolerable safety profile compared to chemotherapy.

In practice, we generally see lower rates of hematologic toxicities and some constitutional symptoms (like nausea, diarrhea, fatigue) in MIRV compared to chemotherapy. It is also important to note that alopecia is not a common TRAE with MIRV with <1% of patients experiencing alopecia [19,35,38]. This can be an important quality of life (QOL) consideration for patients who are heavily pretreated. However, MIRV treatment is associated with an increased rate of newer ADC-associated TRAEs, including ocular and pulmonary toxicities.

7.1. Ocular toxicities

Ocular toxicities on MIRV are likely due to off-target effects on the cornea. Corneal effects begin once MIRV reaches the cornea via the limbal region, where stem cells that accumulate DM4 are present [54]. These affected stem cells move inward and can cause the formation of cysts in the cornea. The cornea can regenerate new stem cells within 7–10 days and therefore, the corneal toxicities are generally reversible once MIRV treatment is delayed or stopped [28]. Ocular steroids can slow down the proliferation of limbal stem cells and therefore decrease the sensitivity to the effects of DM4 and reduce the side effects.

In the SORAYA study, 52% of patients experience any grade of blurry vision or keratopathy [35]. The average time to onset of symptoms was approximately 1.5 months. Eleven percent of ocular AEs resulted in dose reduction, while <1% resulted in treatment discontinuation [35]. A majority (>95%) of ocular AEs resolved to grade 0 or 1 with no permanent ocular damage noted. In the FORWARD I study, 42% of patients experiences blurred vision and 32.5% of patients experienced keratopathy. Grade 3 ocular toxicities occurred in less than 5% of patients [38]. In the MIRASOL trial, approximately 56% of patients experienced adverse ocular events, 7.8% with grade 3 blurred vision, 9.2% with grade 3 keratopathy, and 3.2% with grade 3 dry eyes [19]. Average time to onset of ocular events was 5.4 weeks and, again, nearly all ocular AEs resolved to grade 0 or 1. Ocular events only led to discontinuation of MIRV in 2% of patients.

Ocular toxicity and mitigation strategies in the United States include an eye exam prior to every other cycle, use of lubricating and steroid eye drops, and avoiding the use of contact lenses [55,56]. With these measures, no significant permanent ocular effects have been reported in any of the above trials. The FDA has issued a post-marketing approval commitment to prospectively analyze ophthalmologic assessments to further understand the ocular adverse events and additional risk mitigation strategies, which is pending [33].

7.2. Pulmonary toxicities

Significant pulmonary complications are overall relatively rare with MIRV. In SORAYA, only one lung-related complication was reported and thought not to be related to the study drug [35]. In FORWARD I, grade 1–3 pneumonitis was reported in approximately 3% of patients [38]. Finally, in MIRASOL, pneumonitis was rare and only led to discontinuation in 1.4% of patients [19]. An integrated analysis of all of these trials showed pneumonitis occurred in approximately 10% of patients but <2% were grade 3 or higher [57]. Average time to onset of pneumonitis was approximately 18.1 weeks with an overall discontinuation rate of approximately 3%. Approximately 44% had a dose delay or interruption, and 11% had a dose reduction [57]. Pneumonitis should be promptly recognized and managed with dose delay, dose modification, or, if grade 2 or higher, initiation of steroids and pulmonology consultation, similar to other ADC pneumonitis guidelines [58]. Outside of clinical trials there are only case-reports of mirvetuximab-induced interstitial lung disease, where for example a patient after six cycles had grade 1 asymptomatic pneumonitis found on chest imaging [59]. After her seventh cycle she had severe symptomatic pneumonitis requiring admission to the intensive care unit for oxygen support and high doses (2 mg/kg) of methylprednisolone with slow improvement. Two months after her hospital admission, her pulmonary function tests demonstrated severely reduced lung capacity, and she required 4 L of oxygen at rest. Clearly, further studies are needed to understand the real-world incidence of pulmonary toxicities and further work is necessary to create clear management guidelines to help mitigate the potential pulmonary toxicity.

7.3. Hematologic AEs

Hematologic TRAEs are relatively common on MIRV, although less frequent that traditional systemic chemotherapy. In the SORAYA trial, 13% experienced neutropenia, 9% experienced thrombocytopenia, and 8% experienced anemia [35]. In the FORWARD I study, hematologic TRAEs were overall low, including 6.6% neutropenia and 10.7% anemia [38]. On MIRASOL, 11% of patients experienced neutropenia and 9% experienced anemia [19]. All of these studies reported hematologic toxicities of MIRV at significantly lower rates compared to chemotherapy, which generally reports rates of neutropenia around 25–30% and anemia 30–35% [19,35,38].

7.4. Neuropathy

Peripheral neuropathy, attributed to the payload DM4 which is a potent tubulin-targeting antimitotic agent, is another common TRAE reported with MIRV. The SORAYA trial reported an overall 18% risk of peripheral neuropathy, with all being grade 1 (13%) or grade 2 (5%) [35]. However, only 9% of patients reported grade 1 peripheral neuropathy prior to treatment start. In the FORWARD I study, 26.7% of patients experienced peripheral neuropathy (11.9% grade 2 or higher) compared to 18.3% in the chemotherapy arm (although a majority occurred in the paclitaxel arm) [38]. Finally, in the most recent MIRASOL study, peripheral neuropathy was reported in 21.6% of patients on MIRV compared to 14.5% on chemotherapy [19]. On this trial, patients were excluded if they had preexisting peripheral neuropathy higher than grade 1. It is still unknown to what degree baseline peripheral neuropathy may preclude the use of MIRV as an additional treatment line in ovarian cancer.

7.5. Quality of life

For patients with advanced incurable cancers balancing quality of life with treatment efficacy is of utmost importance. Patients on the MIRASOL trial completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 instrument throughout treatment to measure the global health status, physical functioning, role functioning and fatigue symptoms. Compared to chemotherapy, a higher proportion had better quality of life across all categories and at all timepoints [60,61]. While these results are encouraging, real-world data on patient reported quality of life is needed outside of the clinical trial setting.

8. Regulatory affairs

In the United States, MIRV was initially granted orphan drug designation on 14 July 2014. Then on 18 June 2018, MIRV was granted fast track designation from the FDA [62]. The Biologics License Application was submitted on 28 March 2022 and granted priority review. On 14 November 2022 the FDA granted accelerated approval for MIRV as well as its companion diagnostic (VENTANA) with the requirement of clinical benefit proven in a confirmatory trial. On 22 March 2024 the FDA approved MIRV following the MIRASOL trial for adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens.

The European Medicine Agency (EMA) accepted the Marketing Authorization Application for MIRV on 27 October 2023 after support from the MIRASOL trial [63]. On 19 September 2024 the EMA Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending the marketing authorization of MIRV [64]. Following this decision, on 18 November 2024 the European Commission granted marketing authorization for MIRV for the treatment of adult patients with FRα-positive platinum-resistant high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who have received one to three prior systemic treatment regimens [65]. MIRV is now the first folate receptor alpha-targeted ADC approved in the European Union as well as in Iceland, Liechtenstein, Norway and Northern Ireland. Despite FDA and EU approval, MIRV is currently still pending approval in Canada.

9. Knowledge gaps and opportunities for further study

Despite recent successes of antibody-drug conjugates in the treatment of cancer, there remain challenges in optimizing their use in clinical practice. For MIRV, many unanswered questions remain, including understanding the optimal timing to utilize the drug and whether combination therapies can increase the probability of response. Future studies need to focus on optimizing linkers, antibodies, payloads, and target antigens with the ultimate goal to maximize ADC clinical efficacy while decreasing off-target toxicity. Additionally, it is still unclear where best to integrate novel ADCs in the treatment paradigm of ovarian cancer. Furthermore, it is unclear whether an ADC can cause cross-resistance to a different ADC with a similar payload.

Despite the growing clinical impact of ADCs in cancer treatment, a subset of patients does not respond to the initial ADC treatment, while other patients initially respond, but later develop resistance. The mechanisms of resistance are not well understood and may actually be related to the different components of the ADC, including altered target cell surface expression or gene mutations, upregulation of drug efflux transporters, changes in trafficking of ADC internalization, or simply payload resistance [66]. Since trastuzumab emtansine (T-DM1) and MIRV share a similar payload, they may also share resistance mechanisms. The most well-documented resistance mechanisms for T-DM1 involve dysfunctional intracellular processing of the ADC, as well as subversion of DM1-mediated microtubule disruption, pathways which could similarly contribute to the MIRV resistance [67]. Further research is needed to understand and help develop treatment strategies that overcome resistance mechanisms.

Furthermore, more accurate and reproducible predictive biomarkers may help improve treatment outcomes and facilitate optimal patient selection. Currently, the VENTANA FOLR1 immunohistochemistry (IHC) assay is FDA approved. In the platinum-resistant setting, patients must have FRα expression that is at least 2+ in ≥75% of tumor cells, however many of the clinical trials referenced in this review use different cutoff values for FRα positivity in indications that are likely to gain full FDA approval in the future. Additionally, there are many technical variables that may impact FRα test result including differences in laboratory tissue processing, but also known temporal and spatial heterogeneity of FRα expression in patients’ tumor tissue specimens. For example, test result obtained on tissue collected at initial diagnosis might not be representative of a patient’s tumor at recurrence. Only small studies have compared FRα expression between matched formalin fixed paraffin embedded (FFPE) archival tissue specimens and newly obtained FFPE tissue biopsies from a recurrence with discordance rates ranging from 11% to 44% [20,68,69]. Importantly, it is possible that tissue storage and processing techniques can interfere with the assessment of FRα expression and a specimen that has been paraffin embedded, and formalin fixed for many years may yield lower antigen expression simply due these tissue processing artifacts. A better understanding of the variables that can impact testing results and obscure the actual correct measurement FRα expression will allow a more accurate assessment of FRα expression in a patient’s tumor.

Improvements in the management of ocular toxicities will help optimize the use of MIRV in clinical practice. Close multidisciplinary collaborations with ophthalmologists who are familiar with the unique side effects from this novel ADC is imperative. Additionally, further research is necessary to help identify risk factors for pulmonary toxicity and help develop early mitigation strategies to minimize the risk of severe pulmonary toxicities.

Further clinical research will help expand the use of MIRV beyond ovarian cancers, and could include other cancers that have high expression of FRα such as endometrial cancer, low grade serous ovarian cancer non-small cell lung cancer and renal cell cancer.

10. Conclusions

Mirvetuximab soravtansine is a promising antibody–drug conjugate for the treatment of ovarian cancer. Following the positive results of the phase III MIRASOL study, which demonstrated an overall survival benefit over chemotherapy, MIRV is now approved in the United States for the treatment of a FRα -high – expressing, platinum-resistant epithelial ovarian cancer, and in the European Union for a FRα high-expressing platinum-resistant high-grade serous epithelial ovarian cancer. Multiple novel combinations of MIRV with anti-angiogenic agents and immunotherapy, as well as other chemotherapeutic agents, are currently being tested to further extend the utility of MIRV in the treatment of ovarian cancer with FRα expression. Further studies are also needed to improve our understanding of FRα as a predictive biomarker for the response to MIRV.

Funding Statement

This manuscript was funded by the National Institute of Health T32 fellowship titled Patient-Centered Outcomes Research Training in Urologic and Gynecologic Cancers (PCORT UroGynCan) [grant number T32CA251072].

Article highlights

• Mirvetuximab Soravtansine (MIRV), a folate receptor alpha targeted antibody drug conjugate (ADC) was the first ADC to be FDA and EMA approved for platinum resistant ovarian cancer.

• In the phase III MIRASOL trial MIRV improved overall survival compared to standard of care chemotherapy (16.5 vs. 12.8 months; HR 0.67).

• MIRV has unique ocular toxicities including blurry vision and keratitis, as well as rare but serious pulmonary toxicities.

• Ongoing trials are evaluating MIRV in the platinum sensitive setting and in combination with bevacizumab and chemotherapy.

Authors’ contributions

JS, AS, BJ, GK- compiling literature, writing manuscript, table creation, critically reviewed the article.

Disclosure statement

Dr. Gottfried Konecny is on the Ad board and speaker bureau for AbbVie. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.