MIBC has a poor prognosis, and even with radical surgery, the 5-year survival rate is less than 60%. Although immune checkpoint inhibitors have made rapid progress in the treatment of advanced bladder and urinary tract epithelial cancer in the past year, many drugs have been approved for market both domestically and internationally.
Immunosuppressants targeting PD-1 or its ligand PD-L1, including Nivolumab, Pembrolizumab, Trastuzumab, and Triprolizumab, have been proven to be a promising approach for tumor immunotherapy. The Phase III clinical trial of Pembrolizumab compared with chemotherapy for the treatment of advanced bladder and urinary tract epithelial cancer has been successful. Nivolumab has an objective efficacy rate of 24.4% in patients with advanced bladder and urinary tract epithelial cancer who have previously failed treatment. Domestic trastuzumab (targeting high PD-L1 expression) and terilelizumab have significantly improved ORR and OS in patients who have failed platinum based chemotherapy, and the DoR of beneficiary patients has been significantly prolonged. Therefore, the efficacy of anti-PD-1 monoclonal antibody in advanced bladder and urinary tract epithelial cancer has been validated. In PURE-01, Pembrolizumab achieved a complete disease response rate of 42% in preoperative neoadjuvant therapy for MIBC, greatly changing the treatment status. Terriptylimab also achieved a pCR rate of 40% in neoadjuvant therapy for MIBC.
Whether the bladder can be preserved in patients with localized MIBC has always been a hot topic in clinical research. The ANZUP 1502 study is a phase II clinical trial evaluating the combination of Pembrolizumab and concurrent chemoradiotherapy for the treatment of MIBC, with 90% of patients achieving complete remission after 24 weeks. At the same time, TMT combined with immunotherapy achieved good bladder preservation effects in both the IMMUNOPRESSE-SOGUG study (electrocautery durvalumab+Treme radiotherapy, 12 week cCR rate of 81%) and the BTCR-GU15-023 study (durvalumab+radiotherapy, cCR rate of 54.5%). Therefore, based on the excellent results of phase II clinical studies, there are currently multiple phase III clinical studies underway, including KEYNOTE-992, SWOG1806, SunRISe-2, INTACT studies, etc.
Vidiximab for injection (product code: RC48, RC48-ADC) is an innovative new therapeutic biologic developed to meet the needs of patients with HER2 expressing malignant solid tumors. The injection of vediximab mainly exerts anti-tumor effects through two pathways: one is to inhibit the activation of HER2 downstream signaling pathways (such as PI3K/AKT) by binding to HER2 molecules on the surface of tumor cells, thereby interfering with cell transcription, growth, and proliferation; The second is through the action of small molecule MMAE on microtubule proteins during mitosis, which interferes with the formation of microtubules in cells, mainly manifested as depolymerization of microtubules and induction of cell cycle arrest in the G2/M phase. RC48-C005/C09 is a combined analysis of two clinical studies, C005 and C009. The trial enrolled a total of 107 patients with advanced urothelial carcinoma who had previously received first-line or above systemic therapy but failed. Among all 107 patients, the ORR evaluated by IRC was 50.5% (95% CI: 40.6, 60.3), and the BOR evaluation results showed that 2 patients achieved CR and 52 patients achieved PR.
From a biological perspective, the combination of targeted therapy and immunotherapy can simultaneously block the HER2 signaling pathway and PD-1/PD-L1 signaling pathway, bridge PD-1 expressing T lymphocytes and HER2 expressing tumor cells, and assist T cells in recognizing and killing tumor cells. In addition, the warhead of ADC drugs can cause tumor cell destruction through cytotoxic effects (especially the destruction of microtubules by MMAE), and the release of calcitonin, heat shock proteins, and other substances on the surface of apoptotic cells can induce immunogenic cell death (ICD), thereby activating T cells. MMAE and other microtubule protein stabilizers (MSA) can directly activate antigen-presenting cells (such as dendritic cells), promote DC maturation, enhance T cell recruitment, and reduce immune suppression in tumor tissues. Therefore, the combination of anti-HER2ADC and PD-1/L1 drugs has a synergistic effect, which can improve the immunosuppressive effect in the tumor microenvironment and enhance the infiltration of immune cells into the tumor. In the RC48-C014 study, the combination of vediximab (RC48) and terilelimab (JS001) was used for mUC with previous first-line treatment failure or intolerance/unwillingness to receive cisplatin chemotherapy. The study results showed an objective response rate of 73.2%, with an objective response rate of 76% in the first-line population, including HER2 IHC (2+/3+) and PD-L1 (+); The objective response rates of HER2 IHC (2+/3+) and PD-L1 (-) patients were 75% and 87.5%, respectively. Meanwhile, there was no significant increase in treatment-related adverse reactions compared to monotherapy.
In the first phase of this study, 6 patients did not experience any DLT events within 28 days after receiving the study drug and radiotherapy. According to the definition of the first phase study, this protocol is considered safe. In the first stage of patients, the CR rate reached 83% in March, which has preliminarily returned to normal for its effectiveness. Therefore, based on the results of the first stage, further research will be conducted in the second stage.
