ADCs were developed to combat chemotherapy resistance and mitigate systemic toxicity by capitalizing on the interaction between antibodies and tumor antigens to deliver cytotoxic drugs more precisely to cancer cells [27]. The constructs of ADC are engineered by a monoclonal antibody which directly towards a specific antigen on tumor cells, a stable and clearable linker molecule, and a cytotoxic substance, often referred to as the payload [28] (see Fig. 2).

Fig. 2

Structure and characteristics of antibody–drug conjugates

The target antigen serves as a biomarker found on the cell surface, exclusively expressed in cancer cells compared to normal tissues. This characteristic allows ADCs to minimize off-target and systemic toxicities. The ideal scenario is where the antigen is not only present across all cancer cells but also minimally found in normal tissue. This ensures that the ADC is firmly anchored at the tumor site, reducing platinum resistance by preventing the ADC from combining with other molecules. This, in turn, enhances the intracellular accumulation of platinum. Some studies have also revealed that biomarker expression is associated with clinical responses in other solid tumors [29]. In the context of ovarian cancer, targets such as FRα and Mesothelin, among others, have been under investigation for ADC therapy.

Traditionally, the payloads like monomethyl auristatin E (MMAE) have been restricted in their use due to severe side effects and a lack of selectivity. However, in ADCs, these payloads exhibit a formidable anti-tumor capability [30]. Another critical mechanism of platinum resistance in ovarian cancer involves diminishing the cytotoxic effects of platinum on DNA by upregulating genes in the DNA repair pathway. In theory, ADCs can be employed to counter the impact of platinum resistance in ovarian cancer, particularly when PROC patients have a pro-apoptotic mechanism for the cytotoxic payload through DNA repair pathway damage.

The linker in an ADC is a critical component that bridges the monoclonal antibody and its payload. This chemical linker serves to connect the cytotoxic payload to the monoclonal antibody while ensuring the stability of the ADC during its circulation in the bloodstream. The choice of linker chemistries and the site of conjugation significantly influences ADC performance, impacting stability, pharmacokinetic and pharmacodynamic properties, as well as the therapeutic window [31]. These advancements in linker technology including Lysosomal-Cleavable Linker, Peroxide-Cleavable Linkers and Linkers Cleaved by Other Enzymes aim to enhance the therapeutic index of ADCs by improving their specificity and reducing off-target effects. Each of these developments contributes to the broader goal of creating more effective and safer ADC therapies for cancer treatment [32, 33].

To enhance bioavailability and prevent degradation by digestive enzymes, ADCs are administered intravenously. Early endosomes contain ATP-dependent proton pumps that create an acidic environment, which assists in the binding of the mAb (monoclonal antibody) component of the ADC to the Fc receptors (FcRn), primarily found on the endosomal membrane [34]. This binding helps in the recycling of the ADC to the tumor cell surface. In lysosomes, the acidic environment and proteolytic enzymes facilitate the degradation of the ADC and the release of its toxic payload. The payload is then transported from the lysosome lumen to the cytosol, where it induces apoptosis or other forms of cell death through mechanisms such as DNA intercalation or inhibition of microtubule polymerization. Additionally, ADCs have a 'bystander killing' effect, which allows them to eliminate neighboring tumor cells that do not express the target antigen [35]. (Refer to Fig. 3).

Fig. 3

Mechanism of ADC action in tumor cell destruction through microtubule disruption and DNA damage

Target and its relative ADC

Various ADCs are actively being studied in clinical trials for PROC. The following sections will describe several targets expressed in ovarian cancer and the corresponding ADCs being tested in clinical trials for patients with PROC.

MUC16

MUC16 is a substantial transmembrane protein, predominantly overexpressed in around 80% of epithelial ovarian cancer(EOC) patients, but not present in the epithelial cells of normal ovaries. Additionally, MUC16 exhibits overexpression in pancreatic cancer, with percentages of 55% in moderately differentiated tumors and 91% in well-differentiated tumors [36, 37].

DMUC5754A

DMUC5754A is composed of a humanized IgG1 monoclonal antibody targeting the MUC16 protein and is combined with MMAE, a potent agent that disrupts cell division. This therapeutic pair is linked via a specialized linker, maleimidocaproic acid-valine-citrulline-p-aminobenzyloxycarbonyl, known for its ability to release the drug inside the targeted cells. In research involving mice with human ovarian and pancreatic cancer cells, DMUC5754A has demonstrated a propensity for specifically binding to MUC16, showing promise as a targeted treatment due to its selectivity and effectiveness in attacking tumor cells.

The phase I study NCT01335958 involved 77 patients including 66 ovarian cancer patients and established the recommended phase II dose (RP2D) of DMUC5754A. According to the study results, the RP2D for a dosing schedule every three weeks (Q3W) was determined to be 2.4 mg/kg, while for a dosing schedule every week (Q1W), it was set at 1.4 mg/kg. The Q3W schedule demonstrated better outcomes than the Q1W [37]. Additionally, observations from the study indicated that DMUC5754A, generally showed an acceptable tolerance profile in patients with PROC. Most treatment-related adverse events (TRAEs) attributed to DMUC5754A treatment were manageable and reversible with dose adjustments. The study also suggested that the biomarker HE4 might serve as an indicator of treatment response to DMUC5754A, in addition to MUC16 expression. Nevertheless, a larger clinical trial is required to validate this finding. Additionally, the observation of objective responses in MUC16-high patients indicated the potential significance of MUC16 target expression for clinical benefit from DMUC5754A treatment, although current data may be insufficient to firmly support this conclusion.

In summary, DMUC5754A exhibits a favorable safety profile and significant anti-tumor activity in ovarian cancers expressing MUC16. However, DMUC4046A was discontinued due to the development of THIOMAB technology, a novel technique aimed at enhancing stability and anti-tumor activity [38].

DMUC4064A

DMUC4064A is a humanized monoclonal antibody to target MUC16, and it is conjugated with the cytotoxic agent MMAE, which disrupts microtubules. This conjugation utilizes a state-of-the-art technique that ensures precise attachment of the linker-drug, resulting in a consistent drug-to-antibody ratio(DAR). This is achieved through the synthesis of 'THIOMAB™ drug conjugates' [38].

Findings from the initial Phase I trial (NCT02146313) indicate that DMUC4064A has a generally acceptable safety profile when delivered through intravenous infusion in doses ranging from 1.0 to 5.6 mg/kg every three weeks to patients with PROC. The RP2D for DMUC4064A was determined to be 5.2 mg/kg Q3W for DMUC4064A. Blurred vision and peripheral neuropathy were the primary side effects necessitating dosage adjustments. Most side effects observed during the study were clinically manageable and non-serious [39].

Despite the promising activity and safety profile, there is currently no registered clinical trial involving this agent. The reasons for this situation remain unclear. Nonetheless, the clinical application of DMUC4064A in treating PROC patients highlights the promise of MUC16 as a viable therapeutic target for these patients. Further studies are necessary to establish the efficacy and safety of DMUC4046A. Additionally, the introduction of the THIOMAB technique notably increased efficacy in PROC patients when compared to DMUC5754A. Therefore, the application of this technique to other ADCs for the benefit of patients remains a promising avenue of research.

NaPi2b

NaPi2b, also referred to as SLC34A2, functions as a sodium-dependent phosphate transporter across multiple transmembrane domains [40]. Research on patients with PROC and non-small cell lung cancer (NSCLC) has revealed a significant prevalence of NaPi2b expression [41].

Lifastuzumab vedotin

Lifastuzumab vedotin (DNIB0600A, LIFA) is an ADC comprising a humanized IgG1 anti-NaPi2b monoclonal antibody (MNIB2126A) and a potent antimitotic agent, MMAE. The antibody is linked to the drug via a protease-labile linker, specifically maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl.

In the study referenced as NCT01363947, LIFA was shown to possess an acceptable safety profile when given via intravenous infusion to patients with NSCLC or PROC on a tri-weekly schedule. The RP2D of LIFA was observed at 2.4 mg/kg, informed by its overall safety and tolerability. The most common side effects across doses included fatigue, nausea, diminished appetite, peripheral sensory neuropathy, vomiting, and alopecia. Neutropenia emerged as the most common severe adverse event of grade 3 or higher. Objective responses were predominantly seen in patients with high NaPi2b expression, indicating a potential link between the expression of the NaPi2b target and LIFA's clinical efficacy [41]. Nonetheless, to corroborate these findings, more extensive clinical trials are required to yield statistically robust evidence. This study preliminarily demonstrated LIFA's safety and anti-tumor efficacy, laying the groundwork for the dosage recommended for the ensuing phase II trial.

The phase II study (NCT01991210) marks the first randomized phase II trial comparing an ADC with standard-of-care chemotherapy for patients with PROC. Within the intent-to-treat(ITT) cohort, LIFA led to a median progression-free survival (PFS) span of 5.3 months, compared to 3.1 months for those treated with pegylated liposomal doxorubicin (PLD). It is noteworthy that patients with high NaPi2b expression undergoing LIFA treatment observed a median PFS of 5.3 months, contrasted with 3.4 months for those on PLD. In this population, the objective response rate (ORR) for LIFA was 34% (95% CI, 22–49%), which stands against 15% for PLD (95% CI, 7–28%) with a statistical significance (p = 0.03). Specifically, NaPi2b-high patients had an ORR of 36% with LIFA (95% CI, 22–52%) versus 14% with PLD (95% CI, 6–27%) (p = 0.02) [42].

As the first randomized phase II trial assessing the ADC format of a potent drug for patients with PROC, this study confirmed the clinical activity of ADCs in PROC. LIFA exhibited an improved ORR compared to PLD, along with an enhancement in PFS. However, the superiority of LIFA over PLD in this small trial was not statistically significant. The study also noted substantial differences between the LIFA and PLD arms in patients experiencing over a 50 percent decline in CA-125 or HE4. This suggests that circulating CA-125 and HE4 might predict response benefits, potentially serving as surrogates for clinical response, warranting further attention and validation for novel clinical applications. Despite its promise, LIFA did not show a significant benefit for patients with PROC when compared to chemotherapy, leading to the discontinuation of this ADC. However, preliminary results have been obtained for another ADC targeting NaPi2b, called XMT-1536, with final results still pending.

Upifitamab rilsodotin (XMT-1536, UpRi)

UpRi is another ADC targeting NaPi2b, comprised of a humanized IgG1 anti-NaPi2b monoclonal antibody and the antimitotic agent monomethyl auristatin F (MMAF). An ongoing study, NCT03319628, has enrolled patients with PROC and NSCLC of the adenocarcinoma subtype. In this trial, individuals expressing NaPi2b have been included in the dose-escalation phase, whereas those with PROC and NSCLC have joined the expansion cohort. Furthermore, the UPLIFT segment of the trial is actively recruiting individuals with PROC totaling 270 patients to date. The primary endpoint of the UPLIFT study was the ORR in NaPi2b-positive PROC patients [43]. However, the result of the UPLIFT preliminary study indicate that UpRi failed to meet the primary endpoint, leading to the discontinuation of its development. This decision was prompted by five patient deaths due to grade 5 adverse events during treatment with XMT-1536. Currently, there are no ongoing clinical trials in PROC patients with NaPi2b expression. Nevertheless, NaPi2b remains a potential target for ADCs due to its high frequency of expression in PROC, suggesting a need for the development of new ADCs targeting NaPi2b.

Mesothelin

Mesothelin, initially identified through its interaction with antibodies generated against ovarian cancer cells, serves as a notable target for tumor antigen. Mesothelin is a cell-surface glycosylphosphatidylinositol-linked protein that is predominantly membrane-bound and exhibits high expression particularly in pancreatic ductal adenocarcinomas, ovarian adenocarcinomas, and mesotheliomas. Given its prevalent expression in both pancreatic and ovarian malignancies, mesothelin presents a promising candidate for monoclonal antibody therapies, especially when used in conjunction with cytotoxic agents [44, 45].

DMOT4039A

DMOT4039A is a complex antibody–drug conjugate, comprising a humanized IgG1 anti-mesothelin monoclonal antibody, known as h7D9.v3, and MMAE, a powerful anti-mitotic agent. These two components are conjoined by a valine-citrulline linker that is susceptible to protease cleavage, yielding an approximate DAR of 3.5 [46].

During the Phase I clinical trial (NCT01469793), the optimal phase II dose was established at 2.4 mg/kg to be administered every three weeks. This dosage displayed promising efficacy and a favorable safety profile among ovarian cancer patients, including those previously treated with microtubule-inhibiting agents. The weekly dosing schedule was set at 1.0 mg/kg as the RP2D. However, two patients experienced dose-limiting toxicities under the tri-weekly regimen, specifically hyperglycemia and hypophosphatemia. Consequently, the maximum tolerated dose (MTD) of DMOT4039A was confirmed to be 2.4 mg/kg. At this dose, the median PFS for patients with ovarian cancer was noted to be 4.9 months [46].

DMOT4039A demonstrated evidence of anti-tumor activity with a tolerable safety profile and exhibited a benefit in PFS compared to chemotherapy in PROC patients (4.9 months vs. 3.4 months). However, its PFS is lower than that of chemotherapy combined with bevacizumab in PROC patients (4.9 months vs. 6.7 months) [47]. Hence, focusing therapeutic strategies on mesothelin is promising for the management of pancreatic and ovarian cancer. Nevertheless, further developments, such as the use of novel technologies like THIOMAB or novel linker, are needed to enhance its efficacy and anti-tumor activity to benefit PROC patients.

Anetumab ravtansine

Anetumab ravtansine is composed of a fully human IgG1 monoclonal antibody targeting mesothelin, linked to the cytotoxic agent maytansinoid DM4 [48]. This conjugate has demonstrated effective anti-tumor properties in the treatment of recurrent ovarian cancer and malignant mesothelioma.

In the phase Ib clinical trial registered as NCT02751918, a cohort of 65 patients received treatment with anetumab ravtansine in conjunction with PLD. The findings indicated that the combined treatment's MTD was established at 6.5 mg/kg every three weeks. The majority of adverse events were classified as grade 2 or milder. There were no fatalities ascribed to TRAEs related to anetumab ravtansine, although one death was associated with PLD (neutropenic sepsis). An objective response rate of 42.1% was observed. Specifically, patients expressing high levels of mesothelin and having received three or fewer prior systemic therapies experienced a median PFS of 8.5 months [49].

A phase II randomized trial (NCT03587311) is in progress to evaluate the combination of bevacizumab with either weekly anetumab ravtansine or weekly paclitaxel in treating platinum-resistant or refractory ovarian cancer [50]. Early results reveal median PFS of 5.3 months for the anetumab ravtansine combined with bevacizumab and 9.6 months for the bevacizumab combined with paclitaxel. This study implies a superior clinical advantage for patients with PROC when treated with a combination of bevacizumab and chemotherapy, as opposed to a combination of bevacizumab and ADC.

The results of these studies suggest that while anetumab ravtansine has shown some activity in patients with PROC, particularly those with high mesothelin expression, its efficacy appears less pronounced compared to paclitaxel. Therefore, further investigation is required to fully understand the therapeutic potential of anetumab ravtansine, either as a monotherapy or in combination with other agents such as chemotherapy. Additionally, the potential benefit of combining anetumab ravtansine with PARP inhibitors or immunotherapy, given the evolving landscape of ovarian cancer treatment, warrants additional clinical exploration.

Folate Receptor alpha (FRα)

FRα, encoded by the FOLR1b gene, is a glycosylphosphatidylinositol-anchored protein on the cell surface and represents a promising candidate for new therapeutic development [51]. It is not present in normal ovarian epithelium but is expressed in 80–96% of ovarian cancers. This distinct expression pattern makes FRα an exemplary candidate for ADC therapies [52].

Mirvetuximab soravtansine (MIRV)

MIRV is an ADC that combines an FRα-targeting antibody with the cytotoxic maytansinoid DM4 via a cleavable linker. The binding of the antibody to the antigen prompts quick internalization of the FRα-ADC complex, which in turn triggers the release of DM4. The DM4 can disrupt microtubule dynamics, resulting in cell cycle arrest and apoptosis due to its potent antimitotic effects. Moreover, the cleavable linker enables active DM4 metabolites to permeate from the antigen-bearing tumor cells to adjacent cells, effectively eliminating them through a process known as "bystander" killing, which operates independently of antigen presence.

The FORWARD I, a phase III clinical trial, enrolled 366 patients, assigning them randomly to either a group receiving MIRV or a chemotherapy group. Kaplan–Meier estimates from the ITT population indicated no significant difference in PFS between the two cohorts. The median PFS was slightly lower in the MIRV group at 4.1 months, compared to 4.4 months in the chemotherapy group. However, a pre-defined subgroup with high levels of FRα exhibited more favorable outcomes in the MIRV group, including a longer median PFS of 4.8 months versus 3.3 months, a superior objective response rate of 24% versus 10%, and a higher CA-125 response of 53% versus 25%, relative to the chemotherapy group. Overall survival (OS) did not differ significantly in the ITT population. Within the subgroup expressing high FRα, the MIRV cohort experienced longer OS compared to chemotherapy, though this difference did not reach statistical significance. Serious TRAEs were comparably infrequent across both the MIRV and chemotherapy groups, occurring in 6.6% and 6.4% of patients, respectively [53].

MIRV demonstrated a favorable tolerability profile, and no new safety concerns were identified. The study's finding that PFS was not significantly improved with MIRV compared to chemotherapy may be attributed to the inappropriate method of evaluating FRα expression, which could have reduced MIRV's efficacy. Notwithstanding this, the data indicated that patients with high levels of FRα experienced a notable response to MIRV treatment. Based on this result, further studies are designed to evaluate the anti-tumor activity and safety of MIRV in patients with high-FRα expression, including studies like SORAYA and MIRASOL.

In the phase II SORAYA trial, the focus was on evaluating the efficacy and safety of MIRV among 106 patients with advanced HGSOC who displayed resistance to platinum-based therapies and exhibited high FRα expression levels. The ORR recorded was 32.4% (with a 95% confidence interval [CI] ranging from 23.6 to 42.2, and a significance level of P < 0.0001). The Blinded Independent Central Review (BICR) assessed efficacy in 96 participants and reported an ORR of 30.2% (95% CI, 21.3 to 40.4). Subgroup analyses indicated that MIRV was effective, regardless of the number of prior treatments or previous PARP inhibitors usage. The median PFS determined by the investigators was 4.3 months (95% CI, 3.7 to 5.2), while the median PFS determined by the BICR was slightly longer, at 5.5 months (95% CI, 3.8 to 6.9). The median overall survival was 13.8 months (95% CI, 12.0 to not reached). Throughout the study, no novel adverse events were identified [54].

In summary, the SORAYA trial revealed that MIRV monotherapy demonstrated a high ORR, lasting responses, and a well-tolerated safety profile in patients with high FRα expression in PROC. The ORR, median PFS, and median OS in the MIRV group outperformed doxorubicin liposomes monotherapy, as recommended by the NCCN guideline for these patients (30.2% vs. 11.7%, 4.3 months vs. 3.1 months, 13.8 months vs. 13.5 months). While it's important to note that these are results from separate clinical trials, they suggest that MIRV may have certain advantages over traditional non-platinum chemotherapy and combination therapy with bevacizumab. The study also indicated that MIRV exhibited anti-tumor activity, regardless of the number of prior treatments or prior PARP inhibitors usage in patients who had previously received bevacizumab. Additionally, the U.S. Food and Drug Administration (FDA) has requested the company to conduct a phase III study to compare the clinical effectiveness of MIRV with investigator's choice (IC) chemotherapy. Given the limited treatment options and poor prognosis for PROC patients, this study highlights the potential for MIRV to become a standard treatment option for this challenging population.

The MIRASOL trial (NCT04209855) is a randomized phase III study that compared MIRV against IC of single-agent chemotherapy, including weekly paclitaxel, PLD, or topotecan. The study recruited 453 patients with high FRα expression and PROC who had received up to three previous treatment lines. The MIRV treatment arm reported a median OS of 16.46 months, superior to 12.75 months in the IC chemotherapy arm. Additionally, the median PFS was more favorable in the MIRV arm at 5.62 months, compared to 3.98 months in the IC chemotherapy arm. An ORR of 42.3% was observed in the MIRV arm, significantly higher than the 15.9% in the IC chemotherapy arm. This indicated a statistically significant and clinically meaningful PFS advantage for the MIRV arm over IC chemotherapy, as determined by investigators. The safety profile of MIRV was characterized mainly by low-grade ocular and gastrointestinal events, with no new TRAEs noted [55].

MIRV stands out as the first ADC therapy to show benefits in both PFS and OS for patients with PROC when compared to IC chemotherapy. In November 2022, the U.S. FDA issued an accelerated approval for MIRV in treating adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have undergone one to three previous systemic therapies, a decision influenced by results from the SORAYA trial. Simultaneously, the MIRVSOL study showed that MIRV exhibited superior clinical efficacy compared to chemotherapy monotherapy, and MRIV has been recommended as the preferred regimen for patients with FRα-positive, PROC. The progress of MIRV marks a considerable breakthrough for patients with FRα-positive PROC; while the development of MIRV is undoubtedly a significant advancement for patients with FRα-positive PROC, addressing treatment for patients with FRα-negative or low expression remains a challenging puzzle. New specific antigens and their respective ADCs still need development for these patients. Another concern regarding MIRV is the occurrence of low-grade ocular adverse events, necessitating more effective preventive measures.

MORAb-202(Eisai)

MORAb-202, an ADC combining farletuzumab with the chemotherapy drug eribulin mesylate, targets FRα–positive tumor cells. It utilizes a cathepsin-B cleavable linker for controlled drug release within the tumor cells [56].

The NCT03386942 study, representing the dose-escalation segment of a first-in-human phase I trial, investigated MORAb-202 in patients with FRα-positive solid tumors. The study established that MORAb-202 has a favorable safety profile, with doses ranging from 0.3 to 1.2 mg/kg administered every three weeks. This study did not determine the MTD for MORAb-202. Importantly, there were no instances of grade 3 bone-marrow suppression, suggesting the treatment's mild safety profile. The results from this study suggested antitumor activity in patients with FRα-positive solid tumors, including ovarian cancer. Out of 11 ovarian cancer patients evaluated, stable disease (SD) was noted in 2 patients, 5 patients experienced partial responses (PR), and 1 patient achieved a complete response (CR), culminating in a disease control rate of 75% [57].

These findings indicate that MORAb-202 has the potential to offer a new treatment modality for patients with PROC who have limited options due to resistance to platinum-based chemotherapies. Further investigations, including planned Phase 2 trials, aim to confirm the therapeutic benefits and safety profile of MORAb-202 for this patient population.

DPEP3

DPEP3 functions as a membrane-associated glycoprotein responsible for dipeptide hydrolysis. Findings from preclinical investigations indicate that DPEP3, normally present in low quantities or absent in most healthy tissues, shows increased expression in HGSOC [58]. Additionally, heightened levels of DPEP3 have been detected in the tumor-initiating cell subsets within patient-derived xenograft models of EOC [59, 60].

SC-003

SC-003 is an ADC consisting of SC-Mab003, a humanized IgG1 monoclonal antibody targeting dipeptidase 3, linked to a cytotoxic pyrrolobenzodiazepine (PBD) dimer via a stable valine-alanine dipeptide linker in plasma. Enhanced efficacy was observed when SC-003 was used in conjunction with an anti-PD-1 antibody in a syngeneic mouse model engineered to overexpress human DPEP3 [61]. This study revealed that the overexpression of DPEP3 enhanced the antitumor activity of SC-003. While initial findings on DPEP3 as a target for ADCs were promising, the clinical development of SC-003 was halted due to insufficient efficacy and tolerability, illustrating the challenges in ADC development and the need for continual discovery and validation of new targets.

HER-2

The HER2 is a transmembrane tyrosine kinase receptor that plays a critical role in cell proliferation, differentiation, and survival processes [62]. Overexpression of HER2 is observed in various solid tumors, such as those affecting the breast, stomach, biliary system, bladder, pancreas, and the gynecological tract [63]. A substantial number of patients with HER2-positive solid tumors exhibit progression following standard treatment, facing a grim prognosis and scarce treatment options [64, 65]. This represents an opportunity to enhance patient outcomes through the development of innovative therapeutics targeting HER2.

Trastuzumab deruxtecan (DS8201/T-DXd)

Trastuzumab deruxtecan (T-DXd), a HER2-targeting ADC, consists of a humanized IgG1 anti-HER2 monoclonal antibody linked to a potent topoisomerase I inhibitor through a tetrapeptide-based cleavable linker [66]. This drug is approved for use in both the United States and European Union for the treatment of HER2-positive breast cancer and HER2-positive gastric or gastroesophageal junction adenocarcinoma, as well as in the United States and Japan for HER2-mutated NSCLC [67].

The NCT04482309, a phase II study, aimed to determine the efficacy and safety of T-DXd for patients with select HER2-expressing solid tumors that were locally advanced, metastatic, or inoperable. T-DXd at a dosage of 5.4 mg/kg administered every three weeks was evaluated across seven patient cohorts with a history of treatment for HER2-expressing solid tumors. In the ovarian cancer cohort, the investigator-assessed ORR was 45.0% (95% CI, 29.3 to 61.5). Across all patient groups, the median OS reached 13.2 months, and in patients exhibiting HER2 IHC 3 + expression, the median OS was 20.0 months. The data from this research bolster the case for utilizing HER2-targeted ADC in the treatment of ovarian cancer, offering promising prospects for a patient subgroup typically associated with high mortality. Out of 267 treated patients, 226 (84.6%) experienced drug-related adverse events as assessed by investigators. Serious drug-related adverse events of grade 3 or above were reported in 109 (40.8%) patients [68]. The majority of drug-related interstitial lung disease (ILD) cases identified in this trial were of a lower grade, manageable, and the overall incidence was in line with findings from previous studies.

In this multicenter phase II trial, T-DXd has exhibited significant clinical activity, offering sustained benefits to patients with ovarian cancer who express HER2 and have undergone prior treatments. The safety profile identified aligns with the findings from prior research on T-DXd. The evidence from this study supports the anticancer efficacy of T-DXd in ovarian cancer and indicates its potential as a tumor-agnostic treatment for patients with HER2-expressing ovarian cancer.

Tissue factor

Tissue factor, a transmembrane glycoprotein, serves as the principal initiator of the tissue factor pathway, which is critical in blood coagulation and is also referred to as the extrinsic coagulation pathway [69, 70]. Its role in oncology is highlighted by its atypical expression across a spectrum of solid tumors. Notably, a significant proportion of tumor biopsies from ovarian cancer patients exhibit positivity for tissue factor, with immunohistochemical assessments revealing a range of 75–100%.

Tisotumab vedotin(TV)

Tisotumab vedotin consists of a fully human monoclonal antibody targeting tissue factor, linked to the microtubule-disrupting agent MMAE through a protease-cleavable valine-citrulline linker [71].

The innovaTV 208 trial is a multi-center, open-label, phase II study designed to assess the efficacy and safety of TV administered according to varied dosing schedules for patients with PROC. Enrolled participants are slated to receive TV on the first, eighth, and fifteenth days within every 28-day cycle (a weekly dosing regimen), at a dose level determined during the initial safety run-in phase, provided it is deemed safe and well-tolerated. A total of 98 participants were enrolled and of which 94 received study drug. The primary endpoint for the dose expansion phase of the innovaTV 208 trial is the confirmed ORR by RECIST v1.1 as assessed by the investigator [72]. The study has concluded, but its results have not yet been published. Further research is needed to fully establish the role of TV in the treatment of ovarian cancer, including its long-term efficacy and safety profile (Table 1).

Table 1 Clinical trials of ADCs in platinum-resistant ovarian cancer