Efficacy,Safety,Biomarker Analyses Of Immune Checkpoint Inhibitors In Advanced Urothelial Carcinoma

Background Urothelial carcinoma can occur in the renal pelvis,ureter,bladder,or urethra.Patients with locally advanced or distant metastases have a poor survival rate.Local treatment is difficult to cure,and the treatment method is mainly systemic treatment.Cisplatin-based chemotherapy is recommended for first-line treatment.However,about half of patients have limited treatment options because their bodies cannot tolerate chemotherapy drugs such as cisplatin.Immune checkpoint inhibitors play an anti-tumor immune response by blocking immune checkpoints,and have the advantages of long-tail effects and fewer adverse events.The common ones are anti-PD-1 antibody and anti-PD-L1 antibody.The proportion of its application population in the real world has increased significantly,bringing new treatment options for patients with advanced urothelial carcinoma.However,the heavy economic burden and serious lethal adverse reactions also limit its use.Therefore,it is also very important to find the dominant patients of advanced urothelial carcinoma who are effective for immune checkpoint inhibitors.Potential biomarkers need to be explored,common ones include PD-L1 expression,tumor infiltrating lymphocytes,tumor mutation burden,and gene mutations.There is heterogeneity in pathological specimens of primary tumors and metastases of urothelial carcinoma.It is not clear whether the results of biomarker detection between primary tumor and metastasis are different and whether this difference has influence on the effective prediction of ICIs.ObjectiveTo retrospectively analyze the efficacy and safety of immune checkpoint inhibitors or immune checkpoint inhibitors combined with other drugs in the treatment of patients with advanced urothelial carcinoma.Exploring biomarkers associated with immune checkpoint inhibitor therapy in advanced urothelial carcinoma and Influence of the difference of biomarkers between primary tumor and metastasis on predicting the efficacy of ICIs.MethodsPatients with advanced urothelial carcinoma treated with immune checkpoint inhibitors between January 1,2019 and August 31,2022 at the First Affiliated Hospital of Anhui Medical University were collected.Follow-up was conducted until the death of the patient,loss to follow-up,or until December 30,2022.66 patients with first-line treatment and 24 patients with second-line and above treatment were included.(1)Collect relevant medical history data;count the objective response rate and disease control rate as the short-term curative effect;count the progression-free survival and overall survival as the long-term curative effect;use CTCAE 5.0 to evaluate the adverse event and grades of patients.(2)Detection of biomarkers related with the tumor immune microenvironment in 27 patients treated with first-line immune checkpoint inhibitor whose pathological specimens were available: PD-L1 expression was detected by immunohistochemistry;the status of CD3+,CD4+,CD8+ T cell ratio was detected by immunohistochemistry.(3)Genome detection was performed in 5 patients treated with first-line immune checkpoint inhibitor whose pathological specimens of primary and metastatic lesions were available.High-depth targeted sequencing based on Circulating Single-Molecule Amplification and Resequencing Technology was used to detect gene mutation,TMB,microsatellite status.The results of genomic and tumor immune microenvironment biomarkers of primary tumor and metastatic tumor specimens from 5 patients were compared to explore the difference and correlation with the efficacy of immune checkpoint inhibitors.Results(1)For advanced urothelial carcinoma,the ORR and DCR of first-line immune checkpoint inhibitors or combination therapy with immune checkpoint inhibitors were19.7%(95%CI 10.9%～31.3%)and 81.8%(95%CI 70.4%～90.2%),respectively.The1-year progression-free survival rate was 31.8%(95%CI 20.9%～44.4%),1-year overall survival rate was 50.0%(95%CI 37.4%～62.6%).The ORR and DCR of the second-line and last-line immune checkpoint inhibitors or combination therapy with immune checkpoint inhibitors were 16.7%(95%CI 4.7%～37.4%)and 58.3%(95%CI36.6%～77.9%),respectively.Median PFS was 13 months(95%CI 7.5～18.5).Median OS was 13 months(95% CI could not be calculated).The 1-year progression-free survival rate was 25.0%(95%CI 为 9.8%～46.7%).The one-year overall survival rate was 37.5%(95%CI 18.8%～59.4%).The short-term curative effect of first-line treatment patients with ECOG score of 0 or 1 was different from that of patients with ECOG score of 2.Grade 3-4 adverse reactions occurred in 17 patients(18.9%). Hematological toxicity,elevated liver function indicators,and cardiotoxicity were the most common adverse reactions.(2)No correlation was found between PD-L1 expression and immune checkpoint inhibitor treatment.Compared with patients with CD4+ T cells ≥ 10% and < 10%,the distribution probability of disease progression is higher.There was no correlation between the expression difference of CD3/CD4/CD8 positive ratio and PFS or OS.53.8% of the patients were TLS-positive,and 46.2% of the patients were TLS-negative.No correlation was found between TLS and the efficacy of immune checkpoint inhibitor therapy.There are differences in the detection results of biomarkers between primary and metastases.At the gene level,the main genes different in primary with metastases were TSC1/2,MCL1 acquired by metastases and RAC1 lost by metastases.At the level of the immune microenvironment,there were differences in PD-L1,TMB,T cell ratio,and TLS in primary with metastases.In two cases of clinically effective patients,it was found that the ratio of CD3 and CD8 in the metastatic lesions increased compared with the primary lesions,and the expression of TLS changed from negative to positive.In one patient with disease progression,TLS expression in metastatic lesions changed from positive to negative.It is suggested that there are more lymphocyte infiltration in the metastatic lesions,and part of the tertiary lymphoid structure is formed,and this part of patients may be better treated with ICIs.Conclusion(1)Immune checkpoint inhibitors have a high disease control rate and survival time benefit in patients with advanced urothelial carcinoma,and their safety is acceptable.(2)The percentage of CD4 positive T cells may play a suggestive role in the evaluation of the therapeutic effect of immune checkpoint inhibitors.No correlation was found between the expression of PD-L1 and TLS and the therapeutic effect of immune checkpoint inhibitors.Several similarities and differences exist between primary and distant metastatic samples of advanced urothelial carcinoma in the detection of relevant biomarkers of the genome and immune microenvironment.Differences may affect assessment of response to immune checkpoint inhibitors in advanced urothelial carcinoma.It is necessary to use the relevant detection of the primary tumor with caution to determine the use of immune checkpoint inhibitor drugs,encourage clinical re-biopsy of metastatic lesions,and decide the choice of treatment plan based on the detection results of metastatic lesions.