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Advancing Ovarian Cancer Therapy: Emerging ADCs Targeting Cadherin-6 

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Released: November 06, 2026

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CDH6-directed therapy is rapidly evolving from a translational concept toward potential clinical relevance as emerging data from clinical trials of CDH6-targeted antibody–drug conjugates become available. To integrate new advances, healthcare professionals must be prepared to interpret the data, understand biomarker strategies, and anticipate how new agents may be included in existing treatment paradigms. This short commentary will equip them with the clinical insight, decision-making skills, and confidence needed to improve outcomes for patients with ovarian cancer by learning about the advances of CDH6-targeted agents. 

David M. O'Malley
David M. O'Malley, MD
Debra L. Richardson
Debra L. Richardson, MD
Shannon N. Westin
Shannon N. Westin, MD, MPH, FASCO
CDH6 Agents in Ovarian Cancer

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Recent therapeutic advances in ovarian cancer treatment have accelerated the development of investigational antibody–drug conjugates (ADCs), with several agents currently undergoing clinical evaluation for efficacy and safety. ADCs consist of monoclonal antibodies directed against antigens preferentially expressed on tumor cells, linked to cytotoxic chemotherapy payloads that are released following cellular internalization. Although cadherin-6 (CDH6)–targeted ADCs are not yet FDA approved, understanding their emerging clinical evidence and potential integration into clinical practice is increasingly important. This commentary focuses on CDH6-directed ADCs in platinum-resistant ovarian cancer.

Biological Role of CDH6 and Its Potential as a Therapeutic Target

David M. O’Malley, MD:
Cadherins are transmembrane proteins that play a critical role in cell–cell adhesion and maintenance of epithelial and endothelial barrier integrity. Cadherins interact with intracellular proteins, including catenins, to form adherens junctions that maintain tissue architecture and regulate cell–cell adhesion and vascular permeability. Dysregulation of cadherin expression or function can disrupt these interactions, contributing to increased tumor cell motility, invasion, and metastatic dissemination.

CDH6 is highly expressed in ovarian cancer cells, especially in high‑grade ovarian serous carcinoma, where CDH6 mRNA expression is elevated, and its expression is regulated by the transcription factor PAX8. Altered CDH6 expression may contribute to tumor invasion and metastatic dissemination, and increased expression has been associated with adverse clinical features, including advanced-stage disease and potentially shorter progression-free and overall survival.

CDH6-targeted ADCs are designed to deliver cytotoxic payloads selectively to CDH6-expressing tumor cells. Following antibody binding and internalization, the payload is released intracellularly, inducing tumor cell death. Depending on the properties of the payload and linker, the released cytotoxic agent may also affect neighboring tumor cells through a bystander effect.

Treatment Landscape for Advanced Ovarian Cancer

Shannon N. Westin, MD, MPH, FASCO:
Patients diagnosed with advanced epithelial ovarian cancer typically undergo cytoreductive surgery and platinum-based chemotherapy, either through primary surgery followed by chemotherapy or neoadjuvant chemotherapy followed by interval surgery. Traditionally, disease progression or recurrence within 6 months after the last platinum-based regimen has been classified as platinum-resistant disease. However, the treatment paradigm is evolving toward identifying patients for whom further platinum-based therapy is not an appropriate option, considering factors such as disease progression during treatment, early symptomatic relapse, prior platinum exposure, and platinum hypersensitivity when desensitization is not feasible.

Historically, treatment for platinum-resistant ovarian cancer has relied on single-agent nonplatinum chemotherapy with or without bevacizumab, generally yielding modest response rates. However, biomarker-directed therapies and novel combinations have expanded treatment options. In 2026, the FDA supported new approvals in this area. For example, relacorilant was approved in combination with nab-paclitaxel to treat patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1-3 prior systemic treatments, with one of those including bevacizumab in the regimen. In addition, the FDA approved IV or SQ pembrolizumab in combination with paclitaxel, with or without bevacizumab, for patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (combined positive score ≥1) and received 1-2 prior regimens.

Emerging Data for CDH6 ADCs in Development for Ovarian Cancer

Debra L. Richardson, MD:
Several CDH6-targeted ADCs are in clinical development, including CUSP06, HS-20124, raludotatug deruxtecan (R-DXd), SIM0505, and TJ102. Most are being evaluated in early-phase trials, though R-DXd has advanced to phase III evaluation. TJ102 is a bispecific ADC targeting both CDH6 and FRα. Another CDH6-targeted ADC, HKT288, was discontinued because of neurologic toxicity.

Among ADCs available for patients with ovarian cancer, mirvetuximab soravtansine is FDA approved specifically for FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer following 1-3 prior systemic regimens. In contrast, trastuzumab deruxtecan has received tumor-agnostic accelerated approval for previously treated, unresectable or metastatic HER2-positive (IHC 3+) solid tumors when no satisfactory alternative treatment options are available.

CUSP06 is an investigational CDH6-targeted ADC composed of a monoclonal antibody linked to an 8-exatecan–based topoisomerase I inhibitor payload through a protease-cleavable linker. The phase Ia/Ib CUSP06-1001 trial is evaluating its safety, tolerability, pharmacokinetics, and efficacy in patients with platinum-refractory or -resistant advanced ovarian cancer, advanced renal cell cancer, and other CDH6-expressing solid tumors. The phase Ib dose-expansion study included patients with platinum-resistant high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer who had received 1-4 prior lines of therapy. Tumor shrinkage was observed in the majority of patients across the 4 dose cohorts, with overall response rates (ORRs) of 50.0% at 3.6 mg/kg CUSP06 (n = 22), 40.0% at 4.4 mg/kg CUSP06 plus prophylactic G-CSF (n = 23), 61.9% at 4.0 mg/kg CUSP06 (n = 21), and 45.0% at 4.0 mg/kg CUSP06 plus prophylactic G-CSF (n = 20). Overall, 5 participants across the 4 cohorts achieved a complete response, and CUSP06 demonstrated an ORR of 53.3% among patients previously treated with mirvetuximab soravtansine.

R-DXd is the furthest along CDH6-targeted ADC in clinical development and is currently being evaluated in multiple clinical trials, including the phase II/III REJOICE-Ovarian01 and phase Ib/II REJOICE-Ovarian02 studies. R-DXd consists of a CDH6-targeting antibody connected to a topoisomerase I inhibitor payload through a cleavable tetrapeptide-based linker, with a drug-to-antibody ratio of approximately 8.

REJOICE-Ovarian01 enrolled patients with platinum-resistant high-grade serous or high-grade endometrioid ovarian, primary peritoneal, or fallopian tube cancer and excluded patients with platinum-refractory disease. In the phase II dose-optimization portion, patients received 1-3 prior lines of therapy, with additional eligibility requirements related to prior treatments. The confirmed ORRs were 44.4% at R-DXd 4.8 mg/kg (n = 36), 50.0% at R-DXd 5.6 mg/kg (n = 36), and 57.1% at R-DXd 6.4 mg/kg (n = 35). Based on its overall benefit–risk profile, the 5.6 mg/kg dose was selected for the phase III portion, which is evaluating R-DXd against physicians' choice of chemotherapy (weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan) to further assess its efficacy and safety. In an updated analysis of the phase II portion reported at ESMO in October, with longer follow-up and an expanded population, R-DXd demonstrated a confirmed ORR of 50.0% (99/198) across all dose levels. Among patients with CDH6-positive tumors (defined by CDH6 ≥1% tumor cell membrane expression) receiving the selected phase III dose of 5.6 mg/kg, the ORR was 49.2% (31/63).

In the phase Ib/II REJOICE-Ovarian02 trial, preliminary data from 30 patients with platinum-resistant high-grade serous ovarian, fallopian tube, or primary peritoneal cancer who had received 1-3 prior lines of systemic therapy demonstrated promising activity with R-DXd in combination with bevacizumab. Confirmed ORRs were 80% (8/10) at R-DXd 4.8 mg/kg and 53% (8/15) at R-DXd 5.6 mg/kg. Across both cohorts, there were 15 partial responses and 1 complete response. All patients achieved disease control and experienced tumor shrinkage. However, the small cohorts and short follow-up warrant cautious interpretation.

Managing Adverse Events of CDH6-Targeting ADCs

Shannon N. Westin, MD, MPH, FASCO:
Treatment-emergent adverse events, including gastrointestinal toxicities, cytopenias, and fatigue, are common with investigational CDH6-targeted ADCs. In the first-in-human phase I study of CUSP06, all patients experienced a treatment-emergent adverse event, with approximately 60% experiencing grade 3 or higher events. Interstitial lung disease (ILD)/pneumonitis is an important potential adverse event associated with R-DXd. In REJOICE-Ovarian01, treatment-related ILD/pneumonitis occurred in 3.7% of patients, including 1 grade 3 event (0.9%). In the subsequent REJOICE-Ovarian02 study, 2 fatal cases of treatment-related ILD were reported in a patient receiving R-DXd 5.6 mg/kg in combination with bevacizumab, highlighting the importance of monitoring for pulmonary toxicity.

Nausea is among the most common adverse events associated with CDH6-targeted ADCs and can often be managed with appropriate prophylactic antiemetics and supportive care. Other common adverse events include fatigue, asthenia, and hematologic toxicities such as anemia, neutropenia, and thrombocytopenia. Healthcare professionals will need to monitor complete blood counts and assess patients for fatigue, shortness of breath, fever, and signs of infection. Management may include treatment of reversible causes of anemia, red blood cell transfusions or iron supplementation when indicated, and dose interruptions or reductions according to toxicity severity and study protocols. Finally, G-CSF may be considered for neutropenia, and platelet transfusions or other supportive interventions may be appropriate for selected patients with thrombocytopenia. Early identification and management of adverse events are essential to maintaining treatment tolerability.

Conclusions

Shannon N. Westin, MD, MPH, FASCO:
As clinical development of CDH6-targeted ADCs progresses, important questions remain regarding optimal patient selection, biomarker requirements, sequencing after other ADCs, and potential combinations with existing therapies. Although preliminary efficacy results are encouraging, randomized trials and longer-term safety data will be essential to define the role of these investigational agents in platinum-resistant ovarian cancer and determine whether they may eventually have applications in earlier treatment settings.

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