RC48 in Combination With AK104 and Bevacizumab in OCCC

Ovarian clear cell carcinoma (OCCC) ranks as the second most common epithelial ovarian malignancy in Asian women, characterized by extremely poor prognosis, with a median overall survival (OS) of 25.3 months. OCCC demonstrates a dismal response rate to conventional chemotherapy, and once in a state of persistence or recurrence, treatments become severely limited, with a mere 5-year survival rate of 13.2%, with over two-thirds of patients succumbing within 1 year. Thus, there is an urgent need to explore new therapeutic approaches for recurrent and persistent OCCC patients. Evidence suggests that anti-angiogenesis therapy is effective against OCCC, which tends to exhibit a "hot tumor" phenotype. Hence, the combination of anti-angiogenesis therapy with immunotherapy holds promise for recurrent and persistent OCCC. Additionally, overexpression of human epidermal growth factor receptor 2 (HER2) plays a pivotal role in OCCC resistance formation. Antibody drug conjugates (ADCs) targeting HER2 have shown increasing efficacy in ovarian cancer treatment, with significant immunomodulatory effects enhancing the efficacy of immunotherapy. Based on this evidence, the investigators hypothesize that the combination of anti-angiogenesis therapy, immunotherapy, and HER2-targeted ADCs may improve the prognosis of OCCC patients. Therefore, the investigators are initiating this clinical study aimed at evaluating the efficacy and safety of disitamab vedotin (HER2-targeted ADC) in combination with AK104 (anti-PD-1 and CTLA4) and bevacizumab (anti-angiogenesis) in HER2 positive recurrent and persistent OCCC patients (disitamab vedotin 2.5 mg/kg + AK104 10 mg/kg + bevacizumab 15 mg/kg, every 3 weeks), with the aim of providing new treatment options for these refractory gynecologic malignancies.

During the initial stage of the study, patients with prior exposure to immunotherapy were excluded. Preliminary results from this stage showed antitumor activity and an acceptable safety profile of the combination regimen in patients who met the original eligibility criteria. Subsequently, selected patients with prior immunotherapy exposure and limited effective treatment options received the regimen on a compassionate-use basis after careful clinical assessment, and clinical benefit with manageable safety was observed. Based on these findings, the protocol was amended to remove prior immunotherapy exposure as an exclusion criterion, allowing such patients to be enrolled if they met all other protocol-defined eligibility criteria. The amendment was approved by the ethics committee, and the trial registration information was updated accordingly.