Mirvetuximab soravtansine-gynx: mechanism of action

Folate is essential for DNA replication, methylation, and the synthesis of nucleotide precursors. Interestingly, folate and FRα have an important role in the process of cancer progression. Growing evidence shows that various solid tumors (including ovarian cancer) are characterized by FRα overexpression. Moreover, high FRα expression represents a risk factor for developing resistance to chemotherapy. Hence, targeting FRα represents an opportunity for managing ovarian cancer and other solid tumors.

Several medications targeting FRα have been developed including farletuzumab (MORAb-003), MORAb-002, vintafolide (BMS-748285), luveltamab tazevibulin (STRO-002), and MIRV (IMGN853).10–13 Table 1 shows emerging ADCs in managing ovarian cancer and other solid tumors (most expressing FRα).12 MIRV is an ADC formed by a monoclonal antibody (M9346A) that selectively targets FRα, covalently joined by a cleavable disulfide linker to the genotoxic payload DM4 (ravtansine/soravtansine/N2′-deacetyl-N2′-(4-mercapto-4-methyl-1-oxopentyl)-maytansine). DM4 is a potent tubulin-targeting agent that is conjugated to the antibody with a drug-to-antibody ratio of 3.5:1.13 14 The drug-to-antibody ratio represents the average number of drug molecules conjugated to an antibody, possibly impacting both the efficacy and safety of an ADC. DM4 is a second-generation maytansine derivative discovered in the 1970s.13 14 The complex structures of maytansinoids coupled with their potent cytotoxicity and potential for cancer treatment has stimulated great interest since its identification. DM4 disrupts tubulin resulting in mitotic arrest and apoptosis. Its effect is estimated to be about 100–1000-fold more potent than vinca alkaloids.13 14

The antibody component of MIRV binds to FRα. This receptor is overexpressed on the surface of epithelial tumor cells, characteristic of ovarian, endometrial, triple negative breast, mesothelioma, and non-small cell lung cancers.13 14 When the ADC binds the receptor, MIRV is internalized and DM4 is released into the cell under lysosomal action. DM4 leads to cell-cycle arrest and apoptosis and is also able to diffuse into neighboring cells and induce further cell death (bystander effect).12–15

Data obtained from pre-clinical models supported the anti-tumor activity of MIRV. In particular, the association between MIRV with other agents (carboplatin, doxorubicin, bevacizumab) resulted in synergistic anti-proliferative effects in an ovarian cancer cell line (IGROV-1) in vitro.12–14 Histological analysis of ovarian xenograft tumors showed that MIRV in combination with other agents provides rapid (within 30 days) and extensive necrosis (more than 50%) of tumor tissue.12–15

Mirvetuximab soravtansine-gynx in platinum-resistant ovarian cancer

Several studies have investigated the role of MIRV in patients with platinum-resistant ovarian cancer.16–20 In 2017, the phase I expansion study (ClinicalTrials.gov Identifier: NCT01609556) reported the first experience regarding the administration of MIRV in a population of patients with FRα-positive and platinum-resistant ovarian cancer. This study included 46 heavily pre-treated patients (23 (50%) received ≥4 lines). FRα positivity (≥25% of tumor cells with at least 2+ staining intensity) was assessed by immunohistochemistry with a validated assay using FOLR1 2.1 (a murine monoclonal antibody which recognizes FRα in formalin-fixed paraffin-embedded tissues). One complete and 11 partial responses were achieved. The objective response rate was 26.1% (95% CI 14.3% to 41.1%) and the median progression-free survival was 4.8 (95% CI 3.9 to 5.7) months. Patients who had <4 prior and ≥4 lines of therapy achieved a progression-free survival of 6.7 (95% CI 3.9 to 8.7) months and 3.9 (95% CI 2.6 to 5.4) months, respectively. No significant differences were observed between patients with low (25–49% of tumor cells), medium (50–74% of tumor cells), and high (≥75% of tumor cells) FRα expression.16

Based on these data, the FORWARD I (ClinicalTrials.gov Identifier: NCT02631876) study was designed.17 The FORWARD I is an open-label randomized controlled phase III trial including patients (n=366) with 1–3 prior lines and FRα-positive tumors (medium and high expression). Patients were randomized 2:1 to receive MIRV at 6 mg/kg adjusted ideal body weight or investigator’s choice chemotherapy (including paclitaxel, pegylated liposomal doxorubicin, or topotecan, n=109 patients). In the intention-to-treat population, MIRV did not significantly improve progression-free survival (the primary endpoint measure of the study). Median progression-free survival was 4.1 and 4.4 months in the MIRV and chemotherapy groups, respectively. However, in contrast with the phase I/II studies that were performed before, FORWARD I used the 10× scoring system instead of the positive stating 2+ (PS2) scoring system to score FRα on immunohistochemistry. The 10× scoring system was felt to be easier to use but ultimately was found not to correlate as vigorously with the PS2 scoring method as was seen in the bridging study. In fact, only 35% of FORWARD I participants would have been FRα high expressors if the PS2 scoring system was used while, with the 10× scoring system, FORWARD I classified 58% as FRα high expressors. Looking at patients expressing high levels of FRα (expression level 75% or more determined by central testing using the anti-FOLR1 2.1 antibody (Ventana Medical Systems, Roche Tissue Diagnostics)), median progression-free survival was longer in patients treated with MIRV than in patients having chemotherapy (4.8 months vs 3.3 months; HR 0.69, 95% CI 0.48 to 1.00; p=0.049). However, these results were not considered statistically significant due to the Benjamini–Hochberg procedure used to control for false discovery when multiple hypothesis testing is performed.17 MIRV showed a significant improvement in comparison to chemotherapy in all secondary endpoints (including objective response rate (22% vs 12%), CA125 response (51% vs 27%), post-progression-free survival (median 10.0 vs 8.4 months), and quality of life (32% vs 14%, assessed by the EORTC QLQ-OV28 abdominal/GI sub-scale).17 In the high FRα cohort, the HRs for progression-free and overall survival supported the possible beneficial effect of MIRV (although not statistically significant).17

Considering the lessons learned by the FORWARD I study, it became clear that the maximal benefit of MIRV was seen in patients with high FRα expression, so two new studies focusing on MIRV in platinum-resistant disease were designed (the SORAYA and the MIRASOL trials) in patients with high FRα levels.17 18 21 The SORAYA trial (Study-0417 (ClinicalTrials.gov Identifier: NCT04296890)) is a prospective phase II single-arm regulatory study focusing only on FRα-high patients using the PS2 scoring system.18 Overall, data from 105 patients who had received 1–3 prior lines of treatment were evaluated. Prior use of bevacizumab was mandatory, and PARP inhibitors were previously administered in 48% of patients. The objective response rate was 32.4% (95% CI 23.6% to 42.2%), including five complete and 29 partial responses. The median duration of response was 6.9 (95% CI 5.6 to 9.7) months. Sub-group analyses showed that the objective response rate was 38.0% and 27.5% in patients with and without prior PARP inhibitor exposure, respectively.18 The observed objective response rate represented a substantial improvement in historical response to available single-agent chemotherapy in a similar population.

The MIRASOL (GOG 3045/ENGOT-ov55; ClinicalTrials.gov Identifier: NCT04209855) trial is a phase III trial evaluating MIRV versus investigator’s choice (paclitaxel, pegylated liposomal doxorubicin, or topotecan) in advanced high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancers with high FRα expression (high expression ≥75% of cells with PS2+ staining intensity).21 The MIRASOL trial enrolled 453 patients with high FRα expression according to the PS2 scoring system; 14% had one prior line of therapy, 39% had two prior lines of therapy, and 47% had three prior lines of therapy. In total, 62% of patients received prior bevacizumab; 55% received a prior PARP inhibitor. At data cut-off (March 6, 2023), the median follow-up time for overall survival was 13.1 months and 14% of patients in the MIRV arm remained on the study drug compared with 3% in the chemotherapy arm.21 Median progression-free survival assessed by the investigator (primary endpoint) was 5.62 (95% CI 4.34 to 5.95) months versus 3.98 (95% CI 2.86 to 4.47) months in the MIRV and chemotherapy arms, respectively (HR 0.65 (95% CI 0.52 to 0.81); p<0.001). The objective response rate was 42% and 16% in the MIRV and chemotherapy arms, respectively. The investigators noted tumor reduction in 80% and 55% of patients receiving MIRV and chemotherapy, respectively. The median overall survival was 16.4 and 12.7 months in the MIRV and chemotherapy groups, respectively (HR 0.67 (95% CI 0.50 to 0.89), p=0.0046), which represents a 33% reduction in the risk of death with MIRV. These data were confirmed by blinded independent central review. Accordingly, the objective response rate was 36% and 15% in the MIRV and chemotherapy arms, respectively.21 Although the study is not powered for sub-set analyses, preliminary data reported at ASCO 2023 suggested important results with both bevacizumab-naïve and bevacizumab-pretreated groups showing a consistent benefit with MIRV in patients with platinum-resistant ovarian cancer. Unfortunately, no data regarding the progress of the patients during or after PARP inhibitor have yet been reported. The MIRASOL trial is still ongoing, with an estimated study completion date of April 2024.21

Recently, the final results of the cohort of patients treated with MIRV plus bevacizumab included in the multi-cohort FORWARD II (ClinicalTrials.gov Identifier: NCT02606305) study were published.19 This cohort included 94 heavily pre-treated FRα-positive patients, of which 52% received ≥3 previous lines; 55 (59%) and 25 (27%) had prior bevacizumab and PARP inhibitor exposure, respectively. The objective response rate was 44% (95% CI 33% to 54%), including five complete and 36 partial responses. The median duration of response was 9.7 months (95% CI 6.9 to 14.1) and median progression-free survival was 8.2 months (95% CI 6.8 to 10.0).19 Promising activity was observed for patients regardless of the level of FRα expression or prior bevacizumab. No specific data on anti-tumor activity of PARP inhibitor-pretreated groups were presented. Table 2 shows the main studies testing MIRV in platinum-resistant ovarian cancer.

According to the available evidence, MIRV seems a reasonable option for all patients (even those heavily pre-treated) with platinum-resistant ovarian cancer with high FRα expression. Previous exposure to bevacizumab and PARP inhibitors should not be a contraindication for receiving MIRV.

Mirvetuximab soravtansine-gynx in platinum-sensitive ovarian cancer

In 2018 Moore et al reported data from a phase Ib escalation study testing MIRV in platinum-sensitive ovarian cancer included in the FORWARD II trial (ClinicalTrials.gov Identifier: NCT02606305).20 Eighteen women with relapsed FRα-positive (≥25% of cells with ≥2+ staining intensity) ovarian cancer were treated with carboplatin plus MIRV.20 Thirteen patients continued with MIRV maintenance after carboplatin discontinuation. The objective response rate was 71%. Three complete and nine partial responses were achieved. Median progression-free survival was 15 months.20 Recently, Gilbert et al reported an update of the FORWARD II trial (ClinicalTrials.gov Identifier: NCT02606305). Although the study focused on platinum-resistant disease, they reported data on 31 patients treated with MIRV plus bevacizumab.19 In this latter group, the objective response rate, median duration of response, and progression-free survival were 48%, 12.7 months, and 9.6 months, respectively.19 Table 3 shows details regarding published data on the adoption of MIRV in platinum-sensitive ovarian cancer.

The triplet of carboplatin, MIRV, and bevacizumab as a cohort from FORWARD II was presented by O’Malley et al in 41 patients with FRα expression (51% medium and 49% high) with platinum-sensitive disease. Seventy-three percent of patients had received one prior platinum-based therapy and 27% had ≥2 prior platinum regimens. The patients could continue therapy with MIRV and bevacizumab as maintenance therapy after six cycles at the discretion of the investigator. The objective response rate was 83%, with 98% of patients having disease regression in the entire cohort with a duration of response of 10.9 months and progression-free survival of 12.8 months. These benefits were nearly the same in patients with medium and high expression. No new safety signals were identified; the toxicities observed were as expected based on the side effect profiles of each agent and duration of therapy, with thrombocytopenia as the most common cause of drug-related discontinuation.22

To confirm the value of these promising data in the setting of platinum-sensitive disease, phase II studies (PICCOLO trial (ClinicalTrials.gov Identifier: NCT05041257), MIROVA trial (ClinicalTrials.gov Identifier: NCT04274426), and Study-420 (ClinicalTrials.gov Identifier: NCT04606914)) and phase III studies (GLORIOSA trial (ClinicalTrials.gov Identifier: NCT05445778)) were designed (Table 4).23–26 The PICCOLO is a phase II single-arm study testing the value of MIRV alone in recurrent platinum-sensitive high-grade serous ovarian, peritoneal, and fallopian tube cancers with high FRα expression. The PICCOLO trial ended its accrual, enrolling 79 patients. The estimated study completion date is December 2024.23

The MIROVA trial is a multi-center, randomized, two-arm, open-label, comparative phase II trial of MIRV in FRα-high recurrent ovarian cancer eligible for platinum-based chemotherapy. Overall, 136 patients will be randomized between platinum-based chemotherapy versus carboplatin plus MIRV.24 The MIROVA trial introduces two important design features: (1) it adopts the new platinum-sensitive definition (GCIG consensus), including patients with a platinum-free interval of at least 3 months; and (2) it is evaluating all histologic sub-types of ovarian carcinoma (including carcinosarcoma and low-grade ovarian cancer).12 24 27

Study-420 (IMGN853-0420) is a phase II study evaluating the efficacy and safety of MIRV in combination with carboplatin followed by MIRV maintenance. The study aims to enroll 114 FRα-positive patients with recurrent platinum-sensitive high-grade serous ovarian cancer following one prior line of platinum-based chemotherapy. Somatic and germline BRCA-positive patients must have received prior treatment with a PARP inhibitor. The estimated study completion date is December 2026.25 This study would provide important data, especially in light of the updated results of the PAOLA 1 trial.28 This exploratory analysis and other emerging data from the ARIEL3 and SOLO2 trials suggested that progression under PARP inhibitors impaired the next sensitivity to platinum-based chemotherapy, thus exploring new options is of paramount importance.28–30

The GLORIOSA trial is a phase III open-label study designed to evaluate the safety and efficacy of MIRV plus bevacizumab as maintenance therapy in FRα-high (PS2+) platinum-sensitive high-grade serous ovarian, primary peritoneal, or fallopian tube cancers with high FRα expression. Somatic and germline BRCA-positive patients must have received prior treatment with a PARP inhibitor in maintenance following first-line treatment. The study aims to enroll 418 patients responding to second-line platinum-based chemotherapy. Patients are then randomized to receive MIRV plus bevacizumab as maintenance versus bevacizumab alone as maintenance. The estimated study completion date is April 2029.26 Interestingly, another ongoing study (ClinicalTrials.gov Identifier: NCT04606914) is testing MIRV in a first-line setting within neoadjuvant therapy. In this single-arm phase II study, 70 patients will receive one cycle of carboplatin followed by MIRV plus carboplatin (if FRα-positive) every 21 days. They will then be submitted to surgery followed by four cycles of MIRV plus carboplatin. It is up to the treating physician if they want to add bevacizumab to the last two cycles or use any type of maintenance therapy (PARP inhibitors in BRCA mutated patients). The estimated study completion date is May 2028.25

Although MIRV showed very encouraging anti-tumor activity in patients with platinum-sensitive ovarian cancer, the evidence supporting the adoption of MIRV in this setting is still limited. Potentially, MIRV might be adopted in addition to chemotherapy and/or bevacizumab in patients characterized by high FRα expression.

Mirvetuximab soravtansine-gynx: safety profile

Although published data on MIRV with chemotherapy are limited, MIRV as a single agent shows a manageable safety profile while, in combination regimens, the toxicities appear to reflect the side effect profiles of each agent.17–20 According to the data of published trials testing MIRV alone in patients with ovarian cancer, the most common adverse events included ocular events, diarrhea, fatigue, nausea, vomiting, and peripheral neuropathy. The ocular events and peripheral neuropathy are, together with pneumonitis, adverse events of special interest.

In particular, ocular events are ADC-specific and reflect several features such as antigen expression on ocular surfaces, the fidelity of the linker, and the concentration of the molecule on the tissue and its elimination.31 Mitigation measures are implemented to reduce the burden of ocular events in patients receiving MIRV. As observed for another ADC (tisotumab vedotin), maintaining a healthy ocular surface is of paramount importance.31 Daily use of lubricating eye drops, periodic use of corticosteroid eye drops, and performing eye examinations at baseline and on a regular basis are all useful for preventing ocular toxicity.32 33 Figure 1 shows the cumulative incidence of adverse events of special interest occurring in patients receiving MIRV alone.16–18 Two published studies evaluated the safety profile of MIRV in combination with other medications.19 20 A phase Ib/II study reporting outcomes of treatment with MIRV plus bevacizumab highlighted the safety of this combination in a subset of 94 patients.19 Overall, 93 (99%) patients experienced at least one adverse event. The most common events were blurred vision (57%), diarrhea (54%), nausea (51%), fatigue (43%), neuropathy (37%), and keratopathy (34%). However, most cases were grade ≤2 and were managed with appropriate supportive care without sequelae.19

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Figure 1

Safety profile.

Similarly, the phase Ib trial of the combination of MIRV and carboplatin supported the safety of this combination. Among the 18 patients included, the most frequent adverse events included nausea (67%), diarrhea (61%), thrombocytopenia (61%), and blurred vision (61%). The majority of these events were mild-to-moderate (grade ≤2) and were managed with appropriate supportive care.20 Other adverse events of special interest were neuropathy (n=8, 44%), keratopathy (n=4, 22%), and pneumonia (n=4, 22%), all of which were grade 1 events.20 Table 5 shows details of the safety profile of the published trials focusing on MIRV monotherapy.

Mirvetuximab soravtansine-gynx: approval

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) granted orphan drug designation to MIRV for the treatment of ovarian cancer, fallopian tube cancer, and peritoneal cancer. In June 2018, the FDA granted MIRV fast-track designation for the treatment of patients with platinum-resistant ovarian cancer (with medium and high FRα expression) who had received at least one but no more than three prior systemic treatment regimens.13 In November 2022, based on the results of the SORAYA trial, the FDA granted accelerated approval to MIRV for FRα-positive platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer for those who have received 1–3 prior systemic treatment regimens.18 Moreover, the FDA also approved the VENTANA FOLR1 (FOLR-2.1) RxDx Assay (VENTANA Medical Systems, Roche Tissue Diagnostics) as a companion diagnostic device to select patients for receiving MIRV. VENTANA is a qualitative immunohistochemical assay using mouse monoclonal anti-folate receptor alpha (FOLR1) intended for use in the assessment of FOLR1 in formalin-fixed paraffin-embedded specimens. The cut-off for high intensity levels of FOLR1 is ≥75%.13

Other emerging agents targeting FR alpha

MIRV is not the only ADC targeting FRα.12 There are several new products under development. The majority of these products used topoisomerase I and microtubule inhibitors as payloads. Interestingly, preliminary data have shown very exciting activity of these emerging treatments (Table 1). MORAb-202, IMGN151, STRO-002, BAT8006, and PRO1184 are investigational ADCs targeting FRα.12 34 35 Farletuzumab (MORAb-202) showed encouraging clinical efficacy results in patients with platinum-resistant FRα-positive ovarian cancer treated in the phase I Study 101 in Japan.34 Although farletuzumab has an overall good safety profile, the occurrence of interstitial lung disease in about 5% of patients needs to be taken into account.25 Another interesting innovative treatment is ELU001. This is a ‘C’Dot’ drug conjugate (CDC) with an exatecan payload. The greater peculiarity is the ultra-small structure of the molecules allowing deep penetration into tumor tissue. Moreover, efficient renal elimination reduces the potential for off-target side effects. AZD5335 is going to be tested in the FONTANA trial (NCT05797168). This is a phase I/IIa study testing AZD5335 as monotherapy and in combination with an anti-cancer agent (AZD5305, a potent PARP1 inhibitor) in patients with solid tumors. Further evidence on these new ADCs is needed, especially for identification of the sub-set of patients having the highest benefit (all-comers vs FRα-positive).12