Intracranial activity of mirvetuximab soravtansine in platinum-resistant high-grade serous ovarian cancer: Insights from a patient with central nervous system metastasis

Graphical abstract

Highlights

• •Mirvetuximab soravtansine is a new therapeutic option for FRα-high, platinum-resistant high-grade serous ovarian cancer.
• •Other antibody-drug conjugates have demonstrated intracranial activity in solid tumours.
• •In this case, marked intracranial response was observed after 2 cycles of mirvetuximab soravtansine.
• •This case highlights a potential new therapeutic role for mirvetuximab soravtansine in patients with brain metastasis.

Abstract

Background

Ovarian cancer is the most lethal gynaecologic malignancy, often diagnosed at advanced stages due to nonspecific early symptoms. Although most patients initially respond to platinum-based chemotherapy, recurrence and resistance occur in the majority, leading to poor prognosis and limited treatment options. Recently, a novel antibody–drug conjugate has demonstrated significant clinical benefit in platinum-resistant high-grade serous ovarian cancer, offering a promising new therapeutic strategy in this historically challenging disease setting.

Methods

We report a case of a 66-year-old woman with platinum-resistant high-grade serous ovarian cancer and a central nervous system metastasis who was started on fourth-line palliative treatment with mirvetuximab soravtansine, an antibody-drug conjugate targeting folate receptor-alpha. Following the second cycle, a significant reduction of the left parasagittal subcortical lesion was observed, from 19 × 15 mm to 11 × 6 mm, with complete resolution of vasogenic edema and mass effect, demonstrating intracranial activity of mirvetuximab soravtansine.

Conclusion

To our knowledge, no published studies or case reports have yet documented central nervous system activity of mirvetuximab soravtansine in ovarian cancer. This case highlights a potential new therapeutic role for this agent in patients with ovarian cancer and central nervous system involvement and underscores the need for prospective clinical trials to rigorously assess its central nervous system penetration and efficacy in larger patient cohorts.

1. Introduction

High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecologic malignancy, with approximately 324,600 new cases and 206,900 deaths in 2022 [Bray et al., 2024]. Due to the lack of specific symptoms and an effective screening method, up to 80% of cases are diagnosed at advanced stages, with high mortality. This underscores the need for more effective therapies [Tekalign and Teshome, 2022]. Most patients respond to first-line platinum chemotherapy (CT), with objective response rates (ORR) of 75–80%. Nevertheless, disease progression is frequent, with an approximately 70% recurrence rate. Although most patients remain platinum-sensitive at first recurrence, resistance to platinum-based therapy commonly develops over time [Caruso et al., 2025, Pujade-Lauraine et al., 2014].

Platinum-resistance ovarian cancer (PROC) is defined by a platinum-free interval (PFI) of less than six months and has distinct characteristics, such as aggressive behaviour and limited therapeutic options [Caruso et al., 2025, Pujade-Lauraine et al., 2014]. Until recently, single-agent non-platinum CT such as weekly paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan, represented the standard of care, yielding modest response rates of 10–15% and median progression-free survival (PFS) of 3–9 months [Caruso et al, 2025]. The AURELIA trial, published over a decade ago, demonstrated that adding bevacizumab to CT improved PFS (6.7 versus 3.4 months; hazard ratio [HR] 0.48; P < 0.001), although without an improvement in overall survival (OS) (16.6 versus 13.3 months; HR 0.85, 95% confidence interval [CI] 0.66–1.08) [Pujade-Lauraine et al., 2014].

Preclinical and translational research has identified folate receptor alpha (FRα) as a promising therapeutic target. FRα, a glycosylphosphatidylinositol-anchored glycoprotein encoded by the FOLR1 gene, plays a crucial role in folate transport during cell growth and development [Ab et al., 2015]. While minimally expressed in most normal adult tissues, 30–40% of patients with PROC exhibit FRα-high expression [Caruso et al., 2025, Matulonis et al., 2023, Zannoni et al., 2025].

Mirvetuximab soravtansine (MIRV) is a first-in-class antibody-drug conjugate (ADC) targeting FRα, comprising a humanised FRα-binding monoclonal antibody linked via a cleavable disulphide linker to the maytansinoid DM4 payload, a tubulin-targeting cytotoxic agent. Following binding to the FRα receptor, it undergoes receptor-mediated internalisation, lysosomal degradation, and release of DM4-containing cytotoxic metabolites that induce cell death [Matulonis et al., 2023].

Its clinical efficacy was first demonstrated in the single-arm, phase 2 SORAYA trial (NCT04296890), which enrolled 106 patients with FRα-high PROC who had received 1–3 prior therapies, including pior mandatory bevacizumab. The trial achieved its primary endpoint with an ORR of 32.4% (95% CI 23.6–42.2%) with a median duration of response of 6.9 months (95% CI 5.6–9.7). The safety profile was characterised primarily by low-grade, reversible ocular and gastrointestinal adverse events (AE) [Matulonis et al., 2023].

Building on these findings, the phase 3 MIRASOL trial (NCT04209855) randomised patients with PROC and fallopian tube or primary peritoneal cancer to MIRV or CT (paclitaxel, PLD, or topotecan). Eligible patients had received 1–3 prior lines of therapy and had high FRα tumour expression (≥75% of cells with ≥ 2 + staining intensity as determined by VENTANA FOLR1 RxDx Assay). [Moore et al, 2023].

453 patients were randomized 1:1 to receive MIRV (6 mg/kg adjusted ideal body weight [AIBW] intravenously every 3 weeks [Q3W]) or CT. At a median follow-up of 13.1 months, the trial met its primary endpoint, with a benefit in PFS (5.62 versus 3.98 months, HR 0.65, 95% CI 0.52–0.81; P < 0.001). The trial also met key secondary endpoints, with significantly higher ORR (42.3% vs 15.9%, odds ratio 3.81, 95% CI 2.44–5.94; P < 0.001). Importantly, there was a statistically significant OS benefit (16.46 versus 12.75 months, HR 0.67, 95% CI 0.50–0.89; P = 0.005). The most notable toxicity was ocular toxicity, characterised by blurred vision and keratopathy as off-target effects on the corneal epithelium that are dose-dependent and reversible. Ocular AEs occurred in 56% of patients, with a median time to onset of 5.4 weeks, and nearly all resolved to grade 0 or 1 [Moore et al., 2023].

2. Case report

A 66-year-old nulliparous postmenopausal woman, without a relevant medical history, presented in August 2021 with abdominal discomfort, distension, and early satiety. She underwent a computed tomography of the thorax, abdomen, and pelvis (CT-TAP) in October 2021 which revealed a complex ovarian mass measuring 12 × 10 cm, associated with disseminated peritoneal implants and ascites. Laboratory evaluation showed a markedly elevated CA-125 level of 811U/mL.

A laparoscopy performed in November 2021 drained five liters of ascites and showed evidence of unresectable extensive peritoneal carcinomatosis. Histopathological examination of biopsies confirmed the diagnosis of HGSOC. The disease was classified as a stage IIIC (2014 FIGO classification system).

The patient was subsequently referred for medical oncology evaluation and was considered fit for systemic therapy, with an ECOG PS of 0. She received three cycles of neoadjuvant CT with carboplatin (AUC5) and paclitaxel (175 mg/m²) Q3W, until February 2022. The CT showed a partial response, with reduction in the extent of peritoneal carcinomatosis and the primary ovarian lesion.

In March 2022, the patient had interval debulking surgery with hyperthermic intraperitoneal CT, achieving complete macroscopic resection and CA-125 normalisation. She completed three additional cycles of adjuvant CT. Both somatic and germline BRCA mutation testing were negative. Maintenance therapy with niraparib 200 mg once daily was initiated in July 2022, which was well tolerated, without any toxicities leading to dose reductions or treatment interruption.

Disease progression (DP) was diagnosed in November 2023. This was further characterized by whole-body positron emission tomography–computed tomography (PET-CT) in December that confirmed DP with extensive lymph node (LN) involvement. A right cervical LN biopsy confirmed recurrence of HGSOC.

Given a PFI of 17 months, treatment with carboplatin (AUC5, D1), gemcitabine (900 mg/m², D1 and D8), and bevacizumab (7.5 mg/kg, D1) Q3W was proposed. She completed three cycles until March 2024, with dose reductions and interruption due to mucositis. She maintained bevacizumab monotherapy until June 2024, at which time the PET-CT demonstrated DP in cervical and de novo mediastinal LN.

Treatment with weekly paclitaxel (80 mg/m²) was initiated, with a partial response after three cycles. She received three additional cycles, with interruption after documentation of DP in supra- and infra-diaphragmatic LN in a PET-CT from November 2024.

At this time, she reported a two-month history of lumbar and cervical pain. Following multidisciplinary team discussion (MTD), these symptoms were attributed to bulky LN metastases. Given the limited benefits from CT and suboptimal pain control, she received antalgic radiotherapy in January 2025, 25 Gy in 5 fractions, over cervical and supraclavicular LN, with boost up to 25–30 Gy in mediastinal, pelvic and lumbar LN. In April 2025, PET-CT demonstrated DP, with new lesions in the celiac trunk, mesentery, right common iliac vessel and psoas muscle.

FRα immunohistochemistry testing demonstrated high expression (>75%). Due to delays in testing and in the regulatory approval of MIRV, treatment approval was obtained in June 2025. Re-staging PET-CT revealed new lesions involving the liver parenchyma and vertebral bodies, and a suspicious central nervous system (CNS) lesion in the left parasagittal subcortical area, measuring 19 × 15 mm, with vasogenic edema and mass effect. Given that the patient was asymptomatic, corticosteroid therapy was not initiated.

MIRV was initiated in July 2025 (6 mg/kg AIBW Q3W), with marked reduction in cervical lymphadenopathy after the first cycle, accompanied by a decrease in CA-125 levels from 65 to 27U/mL.

After the second cycle, she experienced a transient episode of right-sided hemiparesis, which resolved spontaneously. Follow-up brain magnetic resonance imaging demonstrated a significant lesion reduction to 11 × 6 mm and complete resolution of vasogenic edema and mass effect [Fig. 1]. Similar symptoms did not recur during subsequent follow-up. Following MTD, local treatment was not proposed given the lesion's small size and improvement in edema with treatment.

Fig. 1.

PET-CT demonstrating central nervous system progression Description: PET-CT performed in July 2025 demonstrating a metabolically active brain metastasis (right), compared with a prior PET-CT showing no evidence of metabolically active intracranial disease (left).

Following the third cycle, a PET-CT performed in September 2025 revealed marked regression of hepatic, bone, and abdominal LN metastases, with isolated progression in bilateral inguino-femoral and right external iliac LN. No abnormal metabolic uptake was observed in the CNS [Fig. 2].

Fig. 2.

PET-CT demonstrating metabolically complete response in the brain Description: PET-CT performed in September 2025 demonstrating a dissociated response, characterized by marked regression of hepatic, bone, cerebral, and abdominal nodal metastasis, with isolated progression in bilateral inguino-femoral and right external iliac lymph nodes (right), compared with the previous PET-CT, before treatment initiation (left).

At MTD, continuation of MIRV was recommended in light of the favorable clinical response and excellent tolerability. As of November 2025, the patient remains in treatment, with preserved performance status, no significant treatment-related AEs, and no neurological deficits.

3. Discussion

CNS metastases in HGSOC are rare, historically reported in 1–3% of cases, occurring predominantly as a late manifestation in heavily pretreated patients with longer survivals [Eryılmaz et al., 2025, Limon et al., 2022]. As systemic therapies continue to improve patients’ survival, the incidence of CNS metastases may increase [Limon et al., 2022]. Optimal management typically involves multimodal therapy [Eryılmaz et al., 2025]. This case reflects the clinical challenges associated with PROC and highlights the critical unmet need for systemic therapies with intracranial activity in ovarian cancer.

ADCs have recently demonstrated remarkable intracranial activity across multiple solid tumours, most robustly in HER2-positive breast cancer with trastuzumab deruxtecan showing substantial intracranial efficacy in patients with stable or active brain metastases, with 12-month PFS and CNS-PFS of 61.6% and 58.9%, respectively [Harbeck et al., 2024]. The prospective phase 2 TUXEDO-1 study in patients with active HER2-positive breast cancer brain metastases reported an intracranial ORR of 73%, with a median PFS of 21 months and an OS not reached at final analysis [Bartsch et al., 2024].

Beyond breast cancer, in HER2-mutant lung cancer, pooled analyses from DESTINY-Lung01/02 demonstrated an intracranial ORR of 30–50% [Jänne et al., 2025]. For TROP2-directed therapy, datopotamab deruxtecan showed intracranial activity in post-hoc analyses from TROPION-Lung01/05, with improved CNS-PFS and measurable intracranial responses in patients with baseline brain metastases [Lisberg et al., 2024].

Although data remain preliminary, these findings converge on the observation that ADCs can achieve CNS efficacy, likely mediated by blood–brain barrier disruption and favorable payload properties [Mair et al., 2023].

MIRV is a new treatment option for FRα-high PROC, but its CNS efficacy remains uncharacterized. The MIRASOL and SORAYA trials excluded patients with CNS metastases and did not report intracranial outcomes. The observed CNS response in our patient provides the first clinical evidence suggesting intracranial activity of this drug.

The biological plausibility for CNS penetration is supported by high FRα expression and the DM4 payload, a microtubule inhibitor known for robust cytotoxic activity. Like other ADCs, MIRV may exploit disruptions in the blood–brain barrier present in patients with CNS metastatic lesions, where the normal barrier is replaced by a more permeable one, with increased endothelial fenestration [Mair et al., 2023].

In our case, radiologic shrinkage of a left parasagittal subcortical lesion from 19 × 15 mm to 11 × 6 mm, with complete resolution of vasogenic edema and mass effect after two cycles of MIRV, suggests the existence of CNS activity of MIRV. While causality cannot be definitively established in a single case, and confounders such as blood–brain barrier variability, steroid use, and systemic disease control cannot be excluded, these findings provide compelling rationale for prospective evaluation.

Further investigation is warranted to determine the CNS penetration and efficacy of MIRV in larger patient cohorts. Prospective clinical trials are needed to rigorously assess its CNS activity in FRα-high PROC patients with brain metastases. Such trials should include patients with untreated or progressing brain metastases, incorporate predefined CNS-specific endpoints, utilize standardized neuroimaging protocols, and integrate correlative biomarker studies, including FRα expression in CNS lesions. This approach will be essential to address the unmet need for effective systemic therapies in this population and to optimize the use of MIRV in clinical practice.

4. Conclusion

MIRV is a first-in-class ADC approved for the treatment of FRα-high PROC, demonstrating significant improvements in PFS and OS with a favorable safety profile. However, patients with CNS metastases were excluded from pivotal trials and none have reported CNS-specific efficacy or outcomes; therefore, evidence for intracranial efficacy is lacking. To date, and to the best of our knowledge, there are no published studies or case reports documenting intracranial activity of MIRV in HGSOC brain metastases. The management of these patients remains an unmet clinical need, as other available systemic therapies have limited CNS activity. The observed clinical response in this individual case suggests that MIRV may have potential intracranial activity, but robust data are lacking. There is a need for prospective clinical trials to rigorously assess its CNS penetration and efficacy in prospective cohorts of patients.

6. Consent for publication

Consent for publication was obtained from the participant and from all authors involved in the study.

CRediT authorship contribution statement

S Ramalho: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. T Martins: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Formal analysis, Conceptualization. I Pinho: Writing – review & editing, Visualization, Validation, Supervision, Conceptualization. F Silva: Writing – review & editing, Visualization, Validation, Supervision. M Pantarotto: Writing – review & editing, Visualization, Validation, Supervision. M Vitorino: Writing – review & editing, Visualization, Validation, Supervision. MVaz Batista: Writing – review & editing, Visualization, Validation, Supervision. ML Batarda: Writing – review & editing, Visualization, Validation, Supervision, Conceptualization.

Ethics approval and consent to participate

Written informed consent was obtained from the patient who participated in this case report.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.