Introduction
April 23, 2022 From June to 24th, the Chinese Society of Clinical Oncology (CSCO) Guidelines Conference was officially held in Beijing. During the meeting, Professor Cui Chuanliang from Peking University Cancer Hospital explained the medical treatment part of CSCO guidelines for urothelial carcinoma. After the meeting, Yimaitong invited Professor Cui Chuanliang to further share the updated content of the guidelines for urothelial cancer, which are organized as follows.
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Professor Cui Chuanliang M.D. Chief PhysicianPeking University Cancer Hospital Renal Cancer and Melanoma Department2010 Visiting Scholar, University of Pittsburgh Medical Center Young Member of CSCO Melanoma Professional CommitteeMember of CSCO Young Expert CommitteeSecretary of CSCO Urothelial Cancer Professional CommitteeBeijing Anti-Cancer Association Urogenital Oncology Committee Youth Member 
Recommendation for postoperative adjuvant therapymuscle-invasive bladder cancer Postoperative adjuvant therapyMedical therapy begins with postoperative adjuvant therapy. Based on the evidence from many trials of postoperative adjuvant therapy for PD-1, the 2021 guidelines include PD-1 therapy in the postoperative adjuvant therapy for urothelial carcinoma. The 2022 edition of the CSCO Guidelines for Urothelial Carcinoma still retains the recommendations for postoperative adjuvant therapy after PD-1 and gemcitabine+platinum adjuvant therapy. Data from the CheckMate-274 study confirmed that adjuvant therapy after PD-1 in patients with stage ypT2-ypT4, with or without lymph node metastasis (received neoadjuvant chemotherapy with preoperative platinum regimen), can reduce the overall risk of disease. The risk of recurrence and metastasis of the population is about 30%; the risk of recurrence and metastasis of PD-L1-positive patients is reduced by 47%. Therefore, patients who have received gemcitabine + platinum-based preoperative neoadjuvant therapy or who are not suitable for platinum-based chemotherapy after surgery can choose PD-1 therapy as the postoperative adjuvant therapy. The results of the subgroup analysis of this study showed that patients with upper urothelial carcinoma (UTUC), which are common in China, had limited benefit from PD-1 therapy. Data from the POUT study to be published in 2021 confirms that adjuvant chemotherapy remains an effective treatment option for patients with UTUC. The study selected patients with pT2-pT4 stage, with or without lymph node metastasis. The primary endpoint of the study was disease-free survival and distant metastasis-free survival. The patient’s 5-year disease-free survival (HR=0.54, 95%Cl 0.36-0.79, p=0.002) and distant metastasis-free survival (HR=0.55, 95%Cl 0.37-0.82, p=0.003) were both 63 %, significantly better than the placebo group; but the OS results were not statistically different (HR=0.77, 95%Cl 0.50-1.17, p=0.21). It can improve the patient’s PFS, but the patient’s OS has no significant benefit, which is also the problem faced by most of the current adjuvant therapy in urothelial carcinoma. Therefore, the guidelines recommend both PD-1 therapy and chemotherapy as adjuvant therapy for urothelial carcinoma. 
Fig.1 Recommendations for postoperative adjuvant therapy for muscle-invasive bladder cancerRecommendations for advanced patientsAt the 2021 ASCO meeting, it was mentioned that platinum-based chemotherapy is still recommended for the first-line treatment of urothelial carcinoma. For second-line therapy after disease progression, PD-1-based therapy or PD-1 maintenance therapy is recommended. After the disease progresses again, the guidelines recommend the use of antibody-drug conjugate (ADC) drugs or FGFR-targeted drugs for subsequent treatment. Figure 2 2021 ASCO first-line treatment regimen for metastatic urothelial carcinomaFirst-line treatment for metastatic bladder cancer >In general, chemotherapy is still the cornerstone of first-line treatment. Chemotherapy in first-line treatment includes the most recommended regimen of gemcitabine + cisplatin/carboplatin; class II recommendations include paclitaxel-containing regimens. In addition, clinicians need to judge whether the patient can tolerate cisplatin according to the patient’s renal function and ECOG score. In the cisplatin-containing chemotherapy regimen, the objective response rate (ORR) of the patients was 50%-60%, the median overall survival (OS) was 14-15 months, and the 1-year OS rate was 60%; the carboplatin-containing chemotherapy regimen Among the patients, the ORR was 30%-40%, the OS was less than 10 months, and the 1-year OS rate was 37%. Class III recommendations for first-line treatment in the CSCO guidelines also retain pembrolizumab and atezolizumab as the first-line treatment for patients who are intolerant of cisplatin. Results of the KEYNOTE-052 study showed that pembrolizumab was used as first-line treatment of patients with platinum-intolerant metastatic bladder cancer, with an ORR of 29% and a median OS of 11.3 months. The results of the IMvigor210 study showed that atezolizumab was used for the first-line treatment of patients with metastatic bladder cancer intolerant to platinum, and the ORR of the patients was 24%; the median OS was 16.3 months. In addition, patients with positive PD-L1, the median OS of first-line treatment with pembrolizumab can reach 18.5 months. Therefore, patients with platinum intolerance or CPS ≥ 10 can also choose PD-1 as a first-line treatment. 
Fig.3 First-line treatment of metastatic bladder cancerMaintenance treatment after first-line treatment of metastatic bladder cancer Research data published abroad in the past two years show that the use of avelumab for maintenance therapy in patients with effective GC regimens significantly improved the patient’s OS (21.4 months vs 14.3 months, HR=0.69 , 95%Cl 0.56-0.86, p<0.001). Therefore, it is recommended as a level II maintenance therapy in the CSCO guidelines. Maintenance therapy with pembrolizumab following first-line platinum therapy improved PFS (5.4 months vs 3.0 months, HR=0.65, log-rank p=0.04). Therefore, the CSCO guideline regards it as a level III recommendation for maintenance therapy. 
Fig.4 Maintenance therapy after first-line therapy for metastatic bladder cancerSecond-line therapy for metastatic bladder cancer There is abundant research evidence on second-line treatment of metastatic bladder cancer in China. In addition to paclitaxel-based chemotherapy drugs, PD-1 monoclonal antibody was added to the second-line treatment regimen. The Polaris-03 study showed that the median OS of the whole population was 14.4 months in patients with urothelial carcinoma who had disease progression or intolerance after receiving at least first-line systemic chemotherapy and received toripalimab, PD-1 The median OS of positive patients can reach 35.6 months, and the benefit is very obvious. The phase II clinical trial of tislelizumab (BGB-A317-204) showed that PD-1-positive locally advanced or metastatic bladder urothelial carcinoma patients (second- and third-line treatment patients) received tislelizumab Zizumab treatment, ORR was 21%, median OS was 19.8 months. Therefore, the CSCO guidelines recommend toripalizumab and tislelizumab as second-line treatment options for class II. 
Fig.5 Second-line treatment of metastatic bladder cancerthird-line treatment of metastatic bladder cancer >Currently, new research focuses on third-line treatment options for advanced urothelial carcinoma. ADC drugs represented by Enfortumab Vedotin (EV), Sacituzumab Govitecan (SG) and Vidicitumab have achieved very good clinical results in the late-line treatment of patients with advanced urothelial carcinoma at home and abroad. Therefore, it was included in the guidelines as a recommended regimen for third-line therapy. EV-301 study showed that EV significantly prolonged the median OS of patients compared with chemotherapy (12.88 months vs 8.97 months, patient death HR=0.70, 95%Cl 0.56-0.89, p=0.001), ORR (17.9% vs. 40.6%, p < 0.001). In the TROPHY-U-01 study, SG was used as a third-line treatment regimen, and the ORR of patients was 27% (95%Cl 19.5-36.6), the median PFS was 5.4 months (95%Cl 3.5-7.2), and the median OS was 10.9 months (95%Cl 9.0-13.8). The RC48-C009 study showed that Her-2 positive patients received vedicitumab as a third-line treatment regimen with an ORR of 50%(95%Cl 37.2-62.8), median PFS was 5.1 months (95%Cl 4.0-6.9), median OS was 14.2 months (95%Cl 8.7-19.2). And the overall safety of these three ADC drugs in the treatment of urothelial carcinoma is basically good. The research on FGFR-targeted drugs in China is still in progress, and there are only some foreign data. Therefore, the guidelines only recommend it as a class III recommendation for the third-line treatment of metastatic bladder cancer. 
Figure 6 Third-line treatment of metastatic bladder cancerCurrent status of clinical research It can be seen from the layout of clinical studies of urothelial carcinoma that immune combined with ADC drug therapy is gradually moving from late-line therapy to first-line therapy, and then to perioperative therapy. In the EV-103 trial, EV was used as a first-line treatment for patients with cisplatin-intolerant advanced urothelial carcinoma, with ORR of 73.3% and median PFS of 12.3 months. The TROPHY-U-01 study presented new SG data at this year’s ASCO-GU meeting. The use of SG to treat metastatic urothelial carcinoma that failed platinum-based chemotherapy resulted in an ORR of 34% (95% Cl 20.1-50.6). . The data of the domestic RC48-C014 study published at the ASCO-GU meeting showed that PD-1 + vedicetumab treatment of patients with metastatic bladder cancer who had failed at least first-line therapy or were intolerant/unwilling to receive cisplatin chemotherapy, The patient’s ORR was 75% (95% Cl 50.9-91.3). Therefore, the expert group needs to further discuss whether to update the recommended scheme of ADC combined with PD-1 in the CSCO guidelines. Figure 7 Study layout of immunotherapy combined with ADCSummaryReviewer: Prof. Cui ChuanliangTypesetting: LRExecution: XY 