Patients with epithelial ovarian cancer (EOC) have poor outcomes; most tumors will relapse within several years and develop resistance to platinum-based therapy [1]. Platinum-resistant ovarian cancer (PROC) is traditionally defined as cancer that relapses within 6 months of last platinum-based treatment [1], though a recent consensus recommendation suggests that 12 weeks may be a more appropriate cutoff for determining relapse [2].

Standard of care treatment consists of single-agent, non‑platinum chemotherapy with or without bevacizumab [3,4]. Single-agent, non‑platinum chemotherapy in PROC demonstrates response rates of 4 %–13 %, median progression-free survival (PFS) of 3–4 months, and median overall survival (OS) of 11–12 months [[5], [6], [7], [8]]. The addition of bevacizumab improves PFS but has not demonstrated a survival benefit versus single-agent chemotherapy [9]. Standard of care therapies are also associated with hematologic and gastrointestinal toxicity, as well as cumulative neuropathy, which makes continuation of treatment after multiple lines of therapy difficult for patients [[5], [6], [7],9]. Therefore, novel treatment regimens are needed to improve these efficacy outcomes and provide more tolerable safety.

Mirvetuximab soravtansine-gynx (MIRV) is a first-in-class antibody-drug conjugate (ADC) that targets folate receptor alpha (FRα), which is a biomarker minimally expressed on normal tissues but overexpressed in up to about 95 % of ovarian carcinomas, with 1 in 3 cases of PROC exhibiting high FRα expression (≥75 % of cells with ≥2+ membrane staining intensity by immunohistochemistry) [[10], [11], [12], [13], [14], [15]]. MIRV binds to FRα-expressing tumor cells and is internalized via endocytosis, where the cytotoxic maytansinoid DM4 payload is released, which allows for both direct tumor targeting and bystander effects [11]. MIRV monotherapy received initial accelerated approval from the United States Food and Drug Administration (FDA) in November 2022 for the treatment of patients with FRα-positive PROC who have received 1–3 prior systemic treatment regimens [10]; this approval was based on the single-arm phase 2 SORAYA trial (NCT04296890) [16]. Full approval was received from the FDA in March 2024 and from the European Medicines Agency in November 2024 and was based on the confirmatory, randomized, phase 3 MIRASOL (GOG-3045/ENGOT-ov55) trial (NCT04209855) [17]. In the MIRASOL trial, MIRV demonstrated statistically significant and clinically meaningful differences against chemotherapy in PFS (5.62 versus 3.98 months; HR 0.65 [95 % CI, 0.52–0.81]; P P P = 0.0046), making it the first therapy to demonstrate a survival benefit against standard of care, single-agent chemotherapy [17,18]. The MIRASOL trial further confirmed MIRV's differentiated and tolerable safety profile compared to those of standard chemotherapies, consisting primarily of low-grade gastrointestinal, neurosensory, and resolvable ocular AEs. Additionally, MIRV has also demonstrated antitumor activity and tolerability as part of a combination regimen in recurrent ovarian cancer across a range of FRα expression, with bevacizumab, carboplatin, and bevacizumab plus carboplatin, making MIRV a potential combination agent of choice [[19], [20], [21]].

MIRV may also activate monocytes and promote phagocytosis of tumor cells via Fc-FcγR interactions [22]. Monocyte activation may trigger T cell responses that could be enhanced by an immune checkpoint inhibitor [22]. The programmed cell death-1 (PD-1) receptor is an immune checkpoint protein that binds its ligand, programmed death-ligand 1 (PD-L1), on various cell types to suppress the immune response for immune tolerance and prevention of autoimmune responses [23,24]. Upregulated PD-L1 expression has been observed on ovarian and endometrial cancer cells, which induces immune suppression in the tumor microenvironment and allows the tumor to evade normal immune surveillance and destruction of mutated cells [25]. In patients with ovarian cancer, higher PD-L1 expression has been associated with significantly worse PFS (P = 0.027) and OS (P = 0.011) [24]. Accordingly, it follows that therapeutic antibodies that inhibit PD-1/PD-L1 binding have been investigated in various types of cancers, including gynecologic cancers. PD-1/PD-L1 inhibitors, commonly referred to as immune checkpoint inhibitors, can activate tumor-infiltrating lymphocytes within a tumor microenvironment, which can lead to improved clinical outcomes [23].

The rationale for the combination of MIRV plus pembrolizumab was based on preclinical findings in a murine EOC model that showed that the combination exerted a promising antitumor effect that was dependent on cytotoxic CD8+ cells and induced immunogenic cell death as measured by upregulation of immunogenic cell death markers [26]. These data provided a rationale for using MIRV plus pembrolizumab to achieve concomitant activation of the immune system in later-line PROC patients.

The phase 1b/2 FORWARD II study (NCT02606305) was designed to evaluate MIRV in combination with various other therapies. Here, we report on the combination of MIRV plus pembrolizumab in heavily pretreated patients with PROC. Preliminary analyses of the dose escalation phase demonstrated favorable tolerability, promising early evidence of response, and durable antitumor activity [27,28]. Here, we report the final efficacy and safety analyses of the escalation and expansion cohorts of the MIRV plus pembrolizumab arm.