INTRODUCTION

Endometrial cancer represents the sixth most commonly diagnosed cancer in women worldwide, predominantly affecting post-menopausal women.1 2 The global incidence of endometrial cancer has been steadily increasing, attributed to factors such as longer life expectancy, obesity, and lifestyle changes.1 Currently, in patients with metastatic endometrial cancer, treatment options are determined by considering the clinical characteristics of the patient, the type of any prior therapy, and molecular characterization. The last of these should include testing for mismatch repair deficiency, human epidermal growth factor receptor 2 (HER2, especially in serous histology), and estrogen/progesterone receptors. Additionally, evaluation of tumor mutational burden and testing for POLE and TP53 mutational status may be used to guide investigational treatment strategies.3

Despite advances in treatment, outcomes for advanced or recurrent endometrial cancer remain suboptimal, mainly due to the heterogeneity in tumor response and the development of resistance to standard therapies (including carboplatin-based chemotherapy alone or in combination with trastuzumab, non-platinum chemotherapy, immunotherapy alone or in combination with chemotherapy or tyrosin-kinase inhibitors, hormone therapy).3 Antibody-drug conjugates represent an emerging approach in cancer therapy, combining the specificity of monoclonal antibodies with the anti-tumor activity of potent cytotoxic drugs.4 For endometrial cancer, antibody-drug conjugates offer a promising therapeutic option, especially for patients with advanced disease and limited treatment options (Figure 1).

Figure 1

Mechanism of action of antibody-drug conjugates and promising targets in endometrial cancer. FRα, folate receptor alpha; HER2, human epidermal growth factor receptor 2; TROP2, trophoblast cell-surface antigen-2.

Early data about the efficacy and safety of various antibody-drug conjugates in endometrial cancer are encouraging. Given the increasing number of antibody-drug conjugates reaching the clinic, there is a need for researchers and physicians with a special interest in gynecological oncology for a concise examination of the existing trial data to better understand antibody-drug conjugates in treating endometrial cancer. This review article aims to fill this knowledge gap by providing an exhaustive overview of antibody-drug conjugates currently in clinical development for endometrial cancer.

ANTIBODY-DRUG CONJUGATES AT A GLANCE

Antibody-drug conjugates are formed by a high-affinity antibody and a highly cytotoxic payload connected by a stable linker.5 The antibody component in antibody-drug conjugates is pivotal for selective targeting, drug internalization, and bloodstream stability. Advanced protein engineering techniques are employed to enhance the antibody’s stability, reduce immunogenicity, and improve its pharmacokinetic and pharmacodynamic properties.6 IgG isotype is the most commonly used antibody backbone. Notably, distinct IgG subclasses exhibit differences in their constant regions and hinge motifs, which influence the solubility and half-life of monoclonal antibodies as well as their binding affinity to various fragment crystallizable gamma receptors present on immune effector cells. Most antibody-drug conjugates use the IgG1 framework to optimize these characteristics.4

The ideal linker is stable in the bloodstream to avoid premature drug release, which could cause systemic toxicity, but labile enough within the tumor cells to release the cytotoxic agent effectively. Linkers are generally classified as cleavable or non-cleavable, each of them having specific characteristics suited for different intracellular conditions of tumor cells.5 Cleavable linkers are designed to release the drug in response to specific tumor microenvironment conditions and include (a) hydrazone, pH-sensitive linkers susceptible to acidic conditions in cancer cell endosomes and lysosomes; (b) disulfide linkers that exploit the high intracellular glutathione levels in cancer cells for payload release; (c) peptide linkers that are stable and controlled and release the drug on specific enzyme cleavage by proteases (eg, cathepsin-B); (d) β-glucuronide linkers that are sensitive to β-glucuronidase, an enzyme overexpressed in some tumors.5

Non-cleavable linkers require the enzymatic degradation of the entire antibody-drug conjugate into the lysosomes to release the payload, often resulting in charged amino acids retained on the payload.4 5 The payloads are highly potent cytotoxic drugs that act on critical cellular processes. Commonly used payload classes include microtubule inhibitors (eg, maytansine derivatives DM1/DM4 and auristatins monomethyl auristatin E/F), DNA damaging agents (eg, calicheamicin, pyrrolobenzodiazepine analogs), topoisomerase I inhibitors, and RNA polymerase II inhibitors (eg, α-amanitin).

Current clinical development focuses on payloads active against drug-resistant tumors, seeking to improve solubility, stability, and tolerability. Innovative strategies also involve the employment of prodrugs and payloads with mechanisms different from those of traditional cytotoxic drugs, like targeting mutant proteins for higher tumor specificity.4 7 The drug-to-antibody ratio is another critical factor in antibody-drug conjugate design. An optimized drug-to-antibody ratio balances efficacy with safety, as too many or too few drug molecules can lead to toxicity or reduced effectiveness, respectively. Moreover, a high drug-to-antibody ratio can result in reduced efficacy caused by increased hydrophobicity, which leads to greater aggregation and altered pharmacokinetic properties.6

On binding with the target antigen through the antibody component, antibody-drug conjugates are internalized into the target cells via receptor-mediated endocytosis.4 Once inside the cell, the antibody-drug conjugates encounter different intracellular environments that trigger the release of the cytotoxic payload from the antibody. A critical aspect of the antibody-drug conjugate mechanism of action is the ‘bystander killing’ effect, which is particularly beneficial in treating heterogeneous tumors with varying antigen expression. This off-target effect occurs when the released cytotoxic payload diffuses from the targeted tumor cells to neighboring cells, including cancer cells that might not express the target antigen and cells from the surrounding tumor microenvironment.8

Additional mechanisms like antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis contribute to the anti-cancer effects of an antibody-drug conjugate.9 In certain cases, antibody-drug conjugates may be intentionally engineered to eliminate these immunogenic properties if deemed too toxic when combined with certain payloads.10

PROMISING TARGETS AND RELATIVE ANTIBODY-DRUG CONJUGATES IN CLINICAL DEVELOPMENT

The ideal target antigen for antibody-drug conjugates should be highly expressed in tumor cells, rapidly internalized via endocytosis on antibody binding, and low in abundance in normal tissues.4 Pre-clinical and translational research efforts have identified several antibody-drug conjugate targets in endometrial cancer currently investigated in clinical trials, including HER2, folate receptor alpha (FRα), trophoblast cell-surface antigen-2 (TROP2), and B7-H4 (Table 1).

Table 1

Antibody-drug conjugates in clinical development in endometrial cancer

Human Epidermal Growth Factor Receptor 2

HER2 promotes tumor cell growth and division, especially when overexpressed or amplified. Studies have shown that about 35% of serous endometrial cancer and 16% of uterine carcinosarcomas overexpress HER2, which can be identified through standardized staining methods and scoring criteria.11 In serous endometrial cancer, HER2 overexpression has been linked to more aggressive disease behavior and poorer outcomes.11 This observation has suggested a potential therapeutic benefit from HER2-targeted therapies in endometrial cancer. Indeed, trastuzumab, a monoclonal antibody targeting HER2, has been shown to improve progression-free survival in patients with HER2-positive (ie, immunohistochemistry score 3+ according to 2007 American Society of Clinical Oncology/College of American Pathology (ASCO/CAP) guidelines for breast cancer or 2+ with gene amplification) serous endometrial cancer when used in combination with chemotherapy.12

Trastuzumab Deruxtecan (DS-8201a)

Trastuzumab deruxtecan is an antibody-drug conjugate composed of the humanized IgG1/κ monoclonal antibody trastuzumab targeting HER2, combined with the topoisomerase I inhibitor deruxtecan payload via a cleavable tetrapeptide-based linker.13 14 Recently, the Food and Drug Administration (FDA) granted accelerated approval to trastuzumab deruxtecan for the tissue-agnostic treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry 3+) solid tumors who have received prior systemic treatment and who have no satisfactory alternative treatment options, making it the first antibody-drug conjugate available for the treatment of patients with endometrial cancer (whose tumors have an immunohistochemistry 3+ HER2 expression).15 Trastuzumab deruxtecan is also currently approved by the FDA and European Medicines Agency (EMA) for the treatment of patients with advanced, pre-treated HER2-positive breast and gastric cancer, HER2-low breast cancer, and HER2-mutated non-small cell lung cancer.16

The safety profile of trastuzumab deruxtecan mainly consists of hematological toxicities, fatigue, nausea and vomiting, alopecia, left-ventricular ejection fraction decrease, and interstitial lung disease/pneumonitis.17 Approximately 15% of patients treated with trastuzumab deruxtecan develop interstitial lung disease/pneumonitis. Even if most events are low grade and can be managed safely, about 2–3% of patients develop a fatal event.18 Careful monitoring, prompt diagnosis (including patient education for early identification), and appropriate multidisciplinary management are key mitigation strategies to reduce the incidence and seriousness of such events.18

In the phase I study NCT02564900 for HER2-expressing tumors and in the phase II HERALD/EPOC1806 basket trial for advanced solid tumors with HER2 amplification, signals of trastuzumab deruxtecan antitumor activity were observed in endometrial cancer, among other histologies.13 14 In the HER2-overexpressing endometrial cancer cohort of 40 patients enrolled in the DESTINY-PanTumor02 phase II trial (NCT04482309), the overall response rate regardless of HER2 expression intensity was 57.5%, whereas a remarkable 84.6% overall response rate was observed in patients with HER2 immunohistochemistry 3+ tumors (n=13). Of note, HER2 overexpression was defined as an immunohistochemistry score for HER2 of 3+ or 2+ scored using ASCO/CAP guidelines for gastric cancer. The median duration of response was not reached in the entire endometrial cancer cohort, whereas progression-free survival was 11.1 months in the whole endometrial cancer cohort and was not reached in patients with HER2 3+ disease.19

The rate of drug-related adverse events leading to discontinuation in all patients enrolled in DESTINY-PanTumor02 was 8.6%. Trastuzumab deruxtecan was investigated in Japanese patients with HER2-expressing advanced or recurrent uterine carcinosarcoma in the phase II STATICE (NCCH1615) trial. The trial enrolled 34 patients, of whom 32 were evaluable for efficacy (22 in the HER2-high and 10 in the HER2-low groups). In the HER2-high group, the overall response rate by central review was 54.5%, for a median duration of response of 6.9 months. The overall response rate in the HER2-low group was 70% for a median duration of response of 8.1 months. Regardless of HER2 expression intensity, the disease control rate was 100%, and the median progression-free survival was 6.7 months. The median overall survival was 13.3 months in the HER2-high group and not reached in the HER2-low group.

Trastuzumab deruxtecan is also active in HER-2 mutated endometrial cancer, as suggested by the primary results of the phase II DESTINY-PanTumor01 study (NCT04639219) in patients with solid tumors harboring specific HER2-activating mutations, showing an overall response rate of 100% in the two patients with endometrial cancer enrolled.20 In endometrial cancer, trastuzumab deruxtecan is being evaluated in combination with ceralasertib (an ATR inhibitor) in the dose-escalation part of the phase I/IB DASH trial (NCT04704661), and in combination with olaparib, a poly-(ADP-ribose)-polymerase (PARP) inhibitor, in the phase I NCT04585958 trial.

DB-1303 (BNT323)

DB-1303 is structured with a humanized anti-HER2 IgG1 monoclonal antibody linked to the topoisomerase I inhibitor P1003 through a maleimide tetrapeptide-based cleavable linker.21 In the dose escalation part of the phase I/IIA study NCT05150691 with DB-1303, one out of three treated patients with endometrial cancer experienced a partial response.21 Further preliminary results in 17 patients with HER2-expressing endometrial cancer evaluable for response showed a partial response rate of 58.8% and a disease control rate of 94.1%.22 The most common treatment-emergent adverse events in the safety population of endometrial cancer (n=32) were nausea, fatigue, and vomiting, whereas the most common grade ≥3 treatment-emergent adverse events were hypokalemia, anemia, and syncope. No interstitial lung disease occurred, and no treatment-emergent adverse events led to drug discontinuation or death.22

Trastuzumab Duocarmazine (SYD985)

Trastuzumab duocarmazine is composed of trastuzumab and a DNA-alkylating, duocarmycin-based payload conjugated via a cleavable linker.23 Pre-clinically, trastuzumab duocarmazine showed anti-tumor activity in HER2-expressing uterine serous cancer models.23 Preliminary results of the phase I study NCT02277717 showed partial responses in 5 (39%) of 13 patients with endometrial cancer enrolled.24 The most common grade 3–4 treatment-related adverse events were keratitis, fatigue, conjunctivitis, and dry eye.24 In the dose-escalation cohort, 28% of patients discontinued the drug because of treatment-related toxicity (most commonly ocular adverse events or pneumonitis). In the dose-expansion cohorts, 19% of patients discontinued the study because of treatment-related adverse events (mainly ocular events). Trastuzumab duocarmazine was also evaluated in the phase II NCT04205630 trial in patients with HER2-expressing, advanced endometrial cancer and in the phase I study NCT04235101 in combination with the PARP inhibitor niraparib in patients with solid tumors, including endometrial cancer. The trials have completed the enrollment, and results are awaited.

Disitamab Vedotin (RC48)

Disitamab vedotin is composed of the humanized IgG1/κ anti-HER2 monoclonal antibody disitamab linked to monomethyl auristatin E (a tubulin polymerization inhibitor) via a cleavable, lysosomal proteolytic enzyme-sensitive linker.25 In early trials with disitamab vedotin in patients with advanced solid tumors, the most common grade ≥3 adverse events comprised neutropenia, leukopenia, hypesthesia, and increased conjugated blood bilirubin.25 Fatal events related to disitamab vedotin (infection and febrile neutropenia) were observed in the phase I NCT02881190 trial, and 9.1–31.6% of patients discontinued the drug across dose levels because of treatment-related adverse events.25 Disitamab vedotin is under investigation in the phase II basket study NCT06003231 in patients with pre-treated, HER2-expressing solid tumors, including endometrial cancer.

Folate Receptor α

FRα is a cell-surface protein with a high affinity for binding and transporting physiological levels of folate. FRα overexpression may enhance folate uptake through receptor-mediated endocytosis, allowing the internalization of folate/folate conjugates, important factors for DNA synthesis/repair and cancer cell growth. The expression of FRα in normal tissues is restricted, but it is often overexpressed in various epithelial tumors, including endometrial cancer. The peculiar high expression of FRα in endometrial cancer, particularly in uterine carcinosarcoma, has led to its consideration as a potential target for diagnostics and therapeutics.10 FRα expression is not significantly altered by chemotherapy, suggesting that immunohistochemical FRα staining at diagnosis can guide the selection for FRα-targeted treatment in subsequent lines of therapy (avoiding the need for tumor rebiopsy on progression).10

Mirvetuximab Soravtansine (IMGN853)

Mirvetuximab soravtansine is composed of mirvetuximab (a humanized IgG1/κ anti-FRα monoclonal antibody) and the maytansinoid DM4 (a tubulin inhibitor) linked by a glutathione-sensitive cleavable linker.26 Mirvetuximab soravtansine is currently approved by the FDA for the treatment of adult patients with pre-treated, FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.27 Pre-clinical experiments showed that mirvetuximab soravtansine has anti-tumor activity in models of FRα-expressing endometrial cancer, with a notable bystander-killing effect on low/negative FRα-expressing cells (due to the diffusion of DM4 metabolites).26

Among the 11 women with endometrial cancer enrolled in the phase I NCT01609556 study, two patients experienced a clinical benefit (ie, stabilization of disease ≥4 months or CA 125 response).28 In the 44 patients included in the safety analysis, the most frequent treatment-emergent adverse events were fatigue, blurred vision, diarrhea, peripheral neuropathy, keratopathy, AST/ALT increase, and headache. As confirmed in larger phase II and III clinical trials in ovarian cancer, the mirvetuximab soravtansine safety profile consists mainly of ocular and gastrointestinal adverse events.29 The rates of serious adverse events and treatment discontinuation for adverse events with mirvetuximab soravtansine were 23.9% and 9.2%, respectively.29 Ocular events, observed in approximately 50% of patients, are generally reversible with supportive care or dose modifications, and rarely result in treatment discontinuation. Moreover, the ocular events observed with mirvetuximab soravtansine seem not to be related to FRα expression in corneal epithelial tissue but rather a result of an off-target effect of the DM4 payload, as highlighted by the observation of similar ocular events with other antibody-drug conjugates using DM4 but binding to different targets (eg, tusamitamab ravtansine targeting CEACAM5) and the absence of ocular events with other FRα-targeting antibody-drug conjugates. Mirvetuximab soravtansine was also investigated in combination with the PARP inhibitor rucaparib in patients with FRα-positive, recurrent endometrial and ovarian cancer in the NCT03552471 phase I study.30 Notably, two out of three evaluable patients with endometrial cancer experienced a tumor response. The most frequent grade ≥3 adverse events observed with the combination were fatigue, pneumonitis, and anemia.30

In the phase I study NCT02996825, mirvetuximab soravtansine was investigated in combination with gemcitabine in selected FRα-positive tumors. Of the four evaluable patients with endometrial cancer treated at the recommended phase II dose, two experienced a partial response, and one achieved stabilization of disease.31 In the endometrial cancer cohort, grade ≥3 adverse events included lymphopenia/neutropenia/thrombocytopenia and hypertension.31 Recently, results of the phase II study (NCT03835819) of mirvetuximab soravtansine in combination with pembrolizumab in patients with microsatellite-stable, advanced, FRα-positive (≥50% of tumor cells with ≥2+ staining on immunohistochemistry) serous endometrial cancer were reported at the 2024 American Association for Cancer Research meeting.32 Of 16 patients treated with the combination, one experienced a complete response, five a partial response, and five a stabilization of disease, for an overall response rate of 37.5% and a disease control rate of 68.8%. The study met the co-primary endpoints (objective response and 6- month progression-free survival rate). The most common treatment-related adverse events observed were AST elevation, blurred vision, fatigue, and diarrhea. Mirvetuximab soravtansine is under investigation as a monotherapy in a phase II trial in patients with FRα-positive persistent or recurrent endometrial cancer (NCT03832361).

Farletuzumab Ecteribulin (MORAb-202)

Farletuzumab ecteribulin combines farletuzumab (an FRα-targeting, humanized IgG1/κ monoclonal antibody) with eribulin mesylate (a microtubule inhibitor) through a cathepsin-cleavable linker.33 Farletuzumab ecteribulin was evaluated in the phase I NCT03386942 study in patients with advanced, FRα-positive tumors, including three patients with endometrial cancer, of whom one experienced a partial response and two experienced a stabilization of disease.33 Grade 3–4 treatment-emergent adverse events included ileus and ALT, γ-glutamyl transferase (GGT), and lipase increase. The maximum tolerated dose was not reached at the tested doses. Four patients discontinued the study drug owing to treatment-related adverse events, including grade 1 interstitial lung disease in one case and pneumonitis in two cases. Farletuzumab ecteribulin is currently under investigation in patients with endometrial cancer and other solid tumors in a phase I/II study (NCT04300556).

Luveltamab Tazevibulin (SΤRO-002, SP8193)

Luveltamab tazevibulin combines the anti-FRα human IgG1 monoclonal antibody SP8166 with SC209 (a 3-aminophenyl-hemiasterlin cytotoxic payload and inhibitor of microtubule polymerization) through a cathepsin-cleavable linker.34

In the dose expansion part of the phase I trial STRO-002-GM1 (NCT03748186), luveltamab tazevibulin showed preliminary anti-tumor activity in patients with advanced FRα-expressing endometrial cancer. In 16 patients evaluable for tumor response (out of the 17 treated), the investigators observed a tumor response (partial response+unconfirmed partial response) in six patients and a stabilization of disease in five patients for a response rate of 37.5% and a disease control rate (partial response+unconfirmed partial response+stabilization of disease) of 68.8%. Notably, the response rate and disease control rate were 50% and 87.5%, respectively, in patients with FRα expression ≥25%.34 The most common any-grade treatment-emergent adverse events were neutropenia, anemia, and arthralgia. Grade ≥3 treatment-emergent adverse events included anemia, arthralgia, neutropenia, nausea, asthenia, fatigue, and thrombocytopenia. One patient discontinued the treatment because of a treatment-emergent adverse event (grade 3 arthralgia). Luveltamab tazevibulin is currently under investigation in Chinese patients with endometrial cancer and other solid tumors in the phase I/IIA study NCT06238687.

Rinatabart Sesutecan (PRO1184)

Rinatabart sesutecan is composed of an anti-FRα human monoclonal antibody linked to the topoisomerase I inhibitor exatecan via a cleavable hydrophilic linker.35 Preliminary results of the ongoing phase I/II study NCT05579366 of rinatabart sesutecan showed anti-tumor activity in patients with high, medium, and low FRα-expressing solid tumors, including a confirmed partial response in a patient with endometrial cancer.35 The most common treatment-related adverse events were nausea, leukopenia, fatigue, lymphopenia, and neutropenia.35

Other Antibody-Drug Conjugates Targeting FRα

Other FRα-targeting antibody-drug conjugates in clinical development in endometrial cancer include AMT-151 (NCT05498597) and IMGN151 (NCT05527184).

Trophoblast Cell-Surface Antigen-2

TROP2 is a 35 kDa transmembrane glycoprotein encoded by the TACSTD2 gene, playing a significant role in cellular signal transduction.36 TROP2 is overexpressed in endometrioid endometrial cancer compared with normal endometrial tissues and represents a marker for aggressive tumor phenotype: about 57% cases of endometrioid endometrial cancer have a TROP2 immunohistochemistry score >1+, and about 21% have a score of 3+.36 Clinical studies have shown that strong TROP2 immunostaining is significantly associated with higher tumor grade and is an independent prognostic factor for poor disease-free survival.36

Sacituzumb Govitecan (IMMU-132, hRS7-SN-38)

Sacituzumb govitecan comprises the humanized IgG1/κ monoclonal antibody hRS7 targeting TROP2 linked to the topoisomerase I inhibitor SN38 via a cleavable pH-sensitive linker.37 Sacituzumb govitecan is already approved by the FDA and EMA for the treatment of patients with pre-treated, advanced triple-negative breast cancer and hormone receptor-positive, HER2-negative breast cancer and received accelerated approval by the FDA for the treatment of patients with pre-treated, advanced urothelial cancer.38 39 The most common adverse events of grade ≥3 with sacituzumb govitecan are neutropenia, leukopenia, anemia, diarrhea, fatigue, and asthenia.40 Notably, in a recent meta-analysis, sacituzumab govitecan showed a higher mean incidence of all-grade adverse events compared with other antibody-drug conjugates, highlighting the need for careful monitoring of patients.41

The phase I/II IMMU-132–01 basket trial (NCT01631552) investigated sacituzumb govitecan in patients with advanced epithelial tumors.37 Of the 18 patients with advanced endometrial cancer included, four experienced a partial response and six a stabilization of disease, for an overall response rate of 22.2%.37 An overall response rate of 25% and a clinical benefit rate (complete response+partial response+stabilization of disease ≥6 months) were observed in an early analysis of 28 patients with endometrial cancer treated within the phase II TROPiCS-03 trial (NCT03964727).42 In the TROPiCS-03 trial grade ≥3 treatment-related adverse events were observed in 64% of patients (most commonly neutropenia (25%), febrile neutropenia (14%), and diarrhea (14%)), and the discontinuation rate due to treatment-related adverse events was 7%.42 In the phase II NCT04251416 trial designed for patients with advanced endometrial cancer with TROP2 overexpression, preliminary results showed an overall response rate and a clinical benefit rate of 35% and 39%, respectively.43 Sacituzumb govitecan is currently under investigation in combination with cisplatin in patients with platinum-sensitive, recurrent ovarian and endometrial cancer in the phase I NCT06040970 trial.

Datopotamab Deruxtecan (DS-1062)

Datopotamab deruxtecan is an antibody-drug conjugate composed of the humanized anti-TROP2 IG1 monoclonal antibody datopotamab linked to the topoisomerase I inhibitor deruxtecan via a cleavable linker.44 Datopotamab deruxtecan demonstrated encouraging and preliminary efficacy results in solid tumors in the phase I TROPION-PanTumor01 trial (NCT03401385).44 The most common any-grade treatment-emergent adverse events were nausea, stomatitis, and alopecia, whereas the most common grade ≥3 treatment-emergent adverse events were pneumonia, anemia, and a decreased lymphocyte count. Infusion-related reactions, ocular surface toxicities, and interstitial lung disease (an important risk with deruxtecan-containing antibody-drug conjugates) were other notable toxicities observed in the TROPION-PanTumor01 trial, and treatment-emergent adverse events leading to discontinuation occurred in 14.0–23.8% of patients.44 Datopotamab deruxtecan is under investigation in the phase II TROPION-PanTumor03 study (NCT05489211) alone and in combination with other anti-cancer agents in patients with advanced solid tumors, including endometrial cancer. Datopotamab deruxtecan is also under investigation in combination with the selective PARP1 inhibitor AZD9574 in patients with different solid tumors, including endometrial cancer, in module 5 of the phase I/IIA NCT05417594 study.

Sacituzumab Tirumotecan (MK-2870, SKB264)

Sacituzumab tirumotecan comprises the humanized IgG1/κ monoclonal antibody hRS7 linked to the topoisomerase I inhibitor tirumotecan (KL610023) via a cleavable, pH-sensitive linker.45 Preliminary investigation of sacituzumab tirumotecan showed antitumor activity in solid tumors in the NCT04152499 phase I/II trial.46 The most common grade ≥3 treatment-emergent adverse events were neutropenia, leukopenia, thrombocytopenia, anemia, and GGT increase.46 Sacituzumab tirumotecan is currently under evaluation in the phase III MK-2870–005/ENGOT-en23/GOG-3095 trial of sacituzumab tirumotecan monotherapy versus treatment of physician’s choice in participants with endometrial cancer who have received prior platinum-based chemotherapy and immunotherapy (NCT06132958).

Other antibody-drug conjugates targeting TROP2

LCB84 is another TROP2-targeting antibody-drug conjugate in early clinical development in endometrial cancer (NCT05941507).

B7-H4

B7-H4 is a member of the B7 family of immune checkpoint molecules, which inhibits T cell activation and proliferation and contributes to tumor immune evasion. B7-H4 is overexpressed in several solid tumors, and its overexpression correlates with tumor aggressiveness and poor prognosis.47 Of note, endometrial cancer is one of the solid tumors with the highest prevalence of B7-H4 expression (94%).48

SGN-B7H4V

SGN-B7H4V comprises the anti-B7-H4 fully-human IgG1 monoclonal antibody B7H41001, combined with monomethyl auristatin E via a protease-cleavable linker.49 In a preliminary analysis of the ongoing phase I SGNB7H4V-001 study (NCT05194072) with SGN-B7H4V, the most common treatment-emergent adverse events across doses were fatigue, peripheral sensory neuropathy, and neutropenia.49 However, severe neutropenia was observed in some patients and neutropenia was the most common grade ≥3 treatment-emergent adverse events with the schedule day 1 and day 8 of a 21-day cycle. Anemia, dyspnea, hypotension, and pneumonia were the most common grade ≥3 treatment-emergent adverse events with the schedule day 1 and day 15 of a 28-day cycle. The study reported a confirmed and durable response in a patient with endometrial cancer (one complete response out of 16 patients).

HS-20089

HS-20089 is composed of a humanized anti-B7-H4 IgG1 monoclonal antibody combined with a topoisomerase I inhibitor via a protease-cleavable linker.50 Preliminary results from 44 patients (including one patient with endometrial cancer) enrolled in the phase I NCT05263479 trial showed that HS-20089 has a promising activity (overall response rate: 24.2%, disease control rate: 63.6%), although details of the efficacy data specifically for the patient with endometrial cancer were not given.50 Most common grade 3–4 treatment-related adverse events were leukopenia, neutropenia, and thrombocytopenia.50 HS-20089 is also under investigation in combination with other anti-tumor agents in the phase I NCT06336707 trial in patients with advanced solid tumors, including endometrial cancer, and in the phase II trial NCT06014190 as a monotherapy in patients with recurrent or metastatic ovarian and endometrial cancer.

XMT-1660

XMT-1660 comprises the B7-H4-targeting human IgG1/κ monoclonal antibody XMT-1604 conjugated with auristatin F (a microtubule inhibitor) using a cleavable linker.51 XMT-1660 is currently under investigation in a phase I trial in patients with advanced solid tumors progressing to the standard of care, including endometrial cancer (NCT05377996).

AZD8205

AZD8205 consists of the human anti-B7-H4 monoclonal antibody INT016 combined with the topoisomerase I inhibitor AZ14170133 via a cleavable linker.48 A first-in-human, phase I/II study (NCT05123482) is currently evaluating the safety, tolerability, and initial activity of AZD8205 in patients with advanced solid tumors, including endometrial cancer.

Other Targets

Enapotamab vedotin is an antibody-drug conjugate composed of a human IgG1 monoclonal antibody targeting AXL (a receptor tyrosine kinase) combined with monomethyl auristatin E via a protease-cleavable linker.52 Enapotamab vedotin was evaluated in the phase I/II trial NCT02988817 in patients with advanced solid tumors, including five patients with endometrial cancer, and showed preliminary antitumor activity.52

TORL-1–23 comprises a fully humanized IgG1 monoclonal antibody (TORL-1–23-MAb) targeting claudin 6 (an oncofetal cell-surface antigen) combined with monomethyl auristatin E via a cleavable cathepsin-sensitive linker.53 Initial results of the ongoing phase I study TORL123-001 (NCT05103683) in patients with advanced solid tumors, including endometrial cancer, demonstrated activity signals.53 Other antibody-drug conjugate targets with potential interest in endometrial cancer are B7-H3 (NCT06330064) and tissue factor (NCT02001623, NCT02552121, NCT03245736, NCT04925284).

FUTURE DEVELOPMENT OF ANTIBODY-DRUG CONJUGATES IN ENDOMETRIAL CANCER

One of the most challenging barriers to antibody-drug conjugate therapy development in endometrial cancer and solid tumors is the emergence of resistance. The mechanisms of resistance can potentially involve all the components of the molecule.54 Resistance can occur at the level of the antigen–antibody interaction, internalization, or intracellular release, mechanism of action, or effluxion of the payload. Resistance mechanisms involving the payload may be addressed by using an antibody-drug conjugate targeting the same antigen but with an alternative payload.54 Of note, the heterogeneity of tumor and microenvironment cells in endometrial cancer may jeopardize the efficacy of antibody-drug conjugates.54 In this regard, the optimization of antibody-drug conjugates design to improve the bystander-killing effect could overcome this issue.8

Looking to the future, combination strategies could significantly enhance the potential of antibody-drug conjugates in endometrial cancer, and combinatorial strategies are already being investigated in early clinical trials. In particular, antibody-drug conjugates may allow/potentiate the anti-tumor activity of immune checkpoint inhibitors, causing immunogenic cell death and increasing tumor immunogenicity, as suggested by the results of the combination of mirvetuximab soravtansine and pembrolizumab in FRα-expressing, microsatellite stable, serous endometrial cancer in the NCT03835819 phase II trial and by the clinical outcomes (nearly 30% of complete responses) of the combinatorial treatment with enfortumab vedotin (nectin-4-targeting antibody-drug conjugate with a monomethyl auristatin E payload) and pembrolizumab in advanced urothelial cancer.55 56 Additionally, integrating antibody-drug conjugates with other immunotherapeutic strategies (eg, cellular therapies and vaccines) might address tumor microenvironment-mediated resistance since these approaches could modify the tumor milieu to be more receptive to antibody-drug conjugates or synergize to enhance anti-tumor immunity.55

Bispecific/multispecific antibody-drug conjugates targeting multiple antigens that are co-expressed by tumor cells (eg, FRα and HER2 in serous endometrial cancer or uterine carcinosarcoma) represent an additional interesting strategy to expand the number of patients with endometrial cancer who could benefit from such agents.4 10 54 Adverse events are another relevant issue in antibody-drug conjugates. The type and incidence of toxicity with this class of drugs are quite heterogeneous and may vary based on payload, target, and linker type.41 Thus, choosing the right target/linker/payload combination is crucial from a safety point of view in future developmental strategies.41

In conclusion, as the treatment landscape of endometrial cancer evolves with the introduction of immunotherapy in combination with chemotherapy in the front-line setting of advanced and recurrent disease, it is expected that antibody-drug conjugates will play a central role in immune pre-treated patients or as an alternative when immunotherapy has limited benefit. The tailored, antigen-specific mechanism of action of antibody-drug conjugates, alone or in combination with other therapies, perfectly fit the emerging, more and more personalized approach to the treatment of endometrial cancer. Careful, proactive monitoring for treatment-emergent adverse events and selection of the best agent for the right patient based on a deep knowledge of the toxicity profile are key elements for mitigating adverse events.

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