e16608 Background: The occurrence PD-1 ICIs brings a new era of treatment for bladder cancer (BC). Although the safety and efficacy of most PD-1 ICIs have been certified progressively, whether they can be used in patients (pts) with renal impairment is always a concern for clinicians. Consequently, we intend to investigate the variation of renal function and efficacy of PD-1 ICIs based immunochemotherapy for pts with muscle invasive bladder cancer (MIBC) and renal insufficiency in short term. Methods: Our study relied on population of the TRUCE-01 trial (NCT04730219), an open-label, single-arm phase II study of tislelizumab based immunochemotherapy in pts with MIBC. Data of pts, including demographic information, imaging and pathological assessment of efficacy, and serum creatinine (SCr) level in baseline, after the first, second and third cycle (C1, C2 and C3) of treatment was collected and analyzed retrospectively. We calculated at estimated glomerular filtration rate (eGFR) according to CKD-EPI formula 2009, and divided pts into different groups according to baseline eGFR, in reference to CKD categories in the K-DIGO 2012 guidelines. Results: 74 pts have been included in our research in total. The median age was 69.5 years (IQR 61.7-75.0) and 56 (75.7%) were male. Median SCr in baseline was 77.4umol/L (IQR 67.8-96.6), while median eGFR was 84.6 (IQR 63.6-94.0) (the unit of eGFR is mL/min/1.73 m 2 ). At baseline, 25 pts were classified as G1 (eGFR≥90), 36 as G2(eGFR <90 and≥60), 12 as G3 (eGFR <60 and ≥30), and 1 as G4 (eGFR <30 and≥15). No significant difference was found in eGFR between pts with CKD G1-2 in comparison to baseline and after C1, C2, C3 of treatment (All p>0.05). In pts with CKD G3-4, it is notable that eGFR may improve when the C1, C2 and C3 completed, in comparison to the baseline (p=0.087, p=0.046, p=0.114 in Wilcoxson test, p=0.082 in Repeated Measures ANOVA). 48 (64.9%) pts received 3 cycles of ICIs and underwent an operation. 24 of 48 (50%) pts received radical cystectomy (RC) and others were treated by maximal TURBT. All of them have conducted efficacy evaluation by both radiographic test and pathology. It is noted that no statistical difference in outcomes between Group G1-2 and G3-4 (p=0.772). Conclusions: Despite renal impairment is common in pts with MIBC, PD-1 immunotherapy is generally safe for kidney of MIBC patients with renal insufficiency and have no influence on efficacy in the short term. The potential improvement in eGFR of patients with worse renal function and its mechanism is essential to be revealed and verified. [Table: see text]
e16609 Background: Urothelial carcinomas (UCs) are the sixth most common tumor. Among them, UTUCs are uncommon, accounting for only 5-10% of UCs. Currently, radical nephroureterectomy (RNU) remains the gold standard of treatment for UTUC. Neoadjuvant chemotherapy treatment can be used for specific UTUC patients, especially for highly staged and/or grade tumors, such as kidneys with potentially decreased renal function after RNU. Neoadjuvant therapy is a series of treatments administered preoperatively for UTUC, mainly chemotherapy, and in recent years, novel therapies of immunotherapy have emerged. Since conventional cisplatin neoadjuvant regimens also require high preoperative renal function, neoadjuvant chemotherapy regimens such as immunotherapy provide more effective and feasible treatments for patients who are intolerant to current cisplatin chemotherapy regimens. However, there is a lack of valuable studies worldwide on novel regimens such as immunotherapy for UTUC. The aim of this study was to explore a novel preoperative neoadjuvant regimen of immunotherapy combined with chemotherapy for UTUC. To further observe the feasibility and effectiveness of this regimen in the field. Methods: 9 high-risk UTUC patients were included in this study. Among them, 7 had unilateral ureteral tumors. 1 had a unilateral renal pelvic tumor. 1 had unilateral pelvic ureteral tumor. Among them, 2 were combined with bladder tumor. All patients were given 3 cycles of tislelizumab 200 mg combined with albumin paclitaxel 200 mg after a thorough evaluation. The treatment cycles were 21 days. Imaging evaluation and surgical resection were given within 15-20 days after the end of the last treatment cycle. Results: 3 patients underwent radical nephroureterectomy with postoperative pathology suggesting SD status of the tumor. 1 patient underwent ureteral reimplantation with tumor-negative postoperative pathology (cCR) and 2 patients underwent ureteroscopic biopsy, 1 of whom had tumor-negative pathology (cCR). 2 patients declined surgical treatment with RNU, one patient had imaging confirmation that the tumor was in SD, and the other showed no evidence of tumor presence on imaging and cytology (cCR). 1 patient was treated intermittently for grade 2 myocardial adverse effects (the remaining patients had adverse effects mostly limited to grade 1, with alopecia and malaise as common symptoms). Conclusions: The characteristics of epithelial carcinoma of the upper urinary tract have led to a reduced intention of some patients to undergo RNU treatment after the completion of NAC treatment. Although the present study failed to obtain ideal pathological information after RNU, the clinical treatment effect (cCR 30%) presented in combination with imaging and cytological results reveals to some extent the promising prospect of future UTUC patients treated with NAC.
e16594 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy show promise in the treatment of muscle-invasive bladder cancer (MIBC). However, not all patients benefit from the treatment. Urine can overcome shortcomings of tissue-based biomarkers to guide treatment decisions. Methods: Thirty-Three patients were recruited in this study and they received three cycles of tislelizumab 200 mg intravenously on day 1 plus nab-paclitaxel 200 mg intravenously on day 2 every three weeks, followed by surgical treatment. Acornmed 808 panel and shallow whole-genome sequencing were performed to predict the efficacy based on the urine DNA. Results: The urine ctDNA levels (highest variant allele fraction) were significantly lower in responder (CR and PR ) patients than this in non-responder (SD and PD) patients (p < 0.001). In addition, a decrease in chromosomal instability number (CIN) occurred in responding tumors (p = 0.028). Furthermore, ROC curves were used to compare the sensitivity and specificity of efficacy prediction, including the urine ctDNA level and CIN. In the ROC analysis, urine ctDNA level setting with an area under the ROC curve (AUROC) of 0.781 (95% CI 0.603 - 0.905, p = 0.005), achieving 100% sensitivity and 54.6% specificity in efficacy prediction. The ROC curve for CIN achieved a sensitivity of 68.2% and specificity of 72.7% (AUC = 0.731; 95% CI: 0.549-0.870, p = 0.013). Combination urine ctDNA level and CIN achieved a sensitivity of 100%, specificity of 63.6% (AUC = 0.806; 95% CI: 0.631-0.922, p = 0.002), positive predictive value (PPV) of 0.846, and negative predictive value (NPV) of 1.000. Conclusions: The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
e14549 Background: The platelet-to-lymphocyte ratio (PLR) has been used to predict therapeutic response in different tumors. However, no assessments of its usefulness have been performed in muscle-invasive bladder cancer (MIBC) patients receiving anti-PD-1 combined with neoadjuvant chemotherapy. Methods: The respective data of 62 MIBC patients receiving anti-PD-1 combined with neoadjuvant chemotherapy were analyzed. Whether PLR might predict treatment response to anti-PD-1 plus neoadjuvant chemotherapy and the cutoff value of the parameter were determined by ROC curve analysis. Moreover, 31 tumor mRNA sequencing data before the treatment were collected and analyzed using ESTIMATE R package. Results: PLR before the second period (PLR2, cut-off = 122.38, AUC = 0.667, 95% CI: 0.529-0.805, sensitivity = 0.935, specificity = 0.452) seemed to be useful predictors to determine patients who have a response or no response. The PLR2-low and PLR2-high groups were divided according to median score (154.9), and the estimate score and the immune score were significantly higher in the PLR2-low group. Conclusions: The PLR2 allowed for the accurate and efficient stratification of MIBC patients receiving anti-PD-1 plus chemotherapy and is easily applicable for clinical practice at no additional cost. Meanwhile, we identified that the diagnostic performance of PLR2 might reflect the tumor immune microenvironment, which plays an important role in immune therapy.
Abstract Purpose: Combinations of immune checkpoint inhibitors and nab-paclitaxel have improved outcomes in advanced urothelial carcinoma and muscle-invasive bladder cancer. This study evaluates the safety and efficacy of tislelizumab combined with low-dose nab-paclitaxel in extensive very high-risk (VHR) non-muscle-invasive bladder cancer (NMIBC). Patients and Methods: TRUCE-02 was a single-arm phase 2 trial that included 63 patients with visually incomplete resection and/or high-volume high-grade T1 tumors (with or without carcinoma in situ), who were ineligible for or declined radical cystectomy. Patients received intravenous tislelizumab (200 mg on day 1) and nab-paclitaxel (200 mg on day 2) every 3 weeks, with assessment approximately 3 months after initial administration. The primary endpoint was the complete response rate of high-risk disease. Main secondary endpoints included safety and duration of complete response. Results: The safety analysis included all 63 patients and the efficacy analysis included 59 patients. Thirty-seven patients [62.7%; 95% confidence interval (CI), 49.1-75.0%] achieved a complete response of high-risk disease, with a 24-month sustained response rate of 96.3% (95% CI, 89.4-100.0%). Grade 3-4 treatment-related adverse events occurred in nine patients (14%), with no fatal events reported. Conclusions: Tislelizumab plus low-dose nab-paclitaxel was well-tolerated and showed promising antitumor activity, making it a potential alternative for extensive VHR NMIBC patients who are ineligible for or decline radical cystectomy.
e14563 Background: Bladder cancer is a molecularly diverse disease with heterogeneous clinical outcomes. Transcriptome-based molecular subtypes of muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC) have been shown to be both prognostic and predictive. However, its predictive role in Chinese bladder cancer remains unclear. The aim of this study was to identify the predictive role of molecular subtypes in China bladder cancer with neoadjuvant therapy. Methods: The study was conducted from May 2020 to August 2021. Patients who were age 18 years or older, were diagnosed with NMIBC or MIBC, and neoadjuvant tislelizumab combining nab-paclitaxel followed by surgery were included. Multigenomic sequencing was performed. Molecular subtypes were identified by published consensus. Results: We prospectively recruited 30 patients for neoadjuvant tislelizumab combining nab-paclitaxel, including 14 patients with NMIBC and 16 patients with MIBC. For bladder cancer, 73.3% (22/33) patients responded to neoadjuvant tislelizumab combining nab-paclitaxel. In NMIBC groups, 64.3% (9/14) patients were pCR. The objective remission rate ( ORR) was 71.4%. 4 molecular classes were identified in Chinese NMIBC, including class 1 (7.1%), class 2a (35.7%), class 2b (50%), class 3 (7.1%). Interesting, ORR was significantly higher for patients with class 2b (5/7, 71.4%) as compared to class 2a (3/5,60%) before neoadjuvant. Molecular classes changed in 35.7% (5/14) of patients before and after neoadjuvant. After neoadjuvant, 80% of class 2b patients responded to neoadjuvant, and all class 2a patients did not respond to neoadjuvant. In MIBC groups, a pPR was achieved by 37.5% patients (6/16). The ORR was 75%. We found 4 molecular classes in Chinese MIBC: basal/squamous (43.8%), luminal unstable (25%), luminal papillary (25%), and stroma-rich (6.2%). Patients with basal/squamous (85.7%) and luminal unstable (75%) had significantly higher ORR than luminal papillary (50%) before neoadjuvant. Molecular classes changed in 44.4% (4/9) of patients before and after neoadjuvant. After neoadjuvant, all patients with stroma-rich responded to neoadjuvant. Conclusions: Molecular classification could predict the efficacy of neoadjuvant tislelizumab combining nab-paclitaxel in Chinese bladder cancer, which may be preferable when studying biomarkers of bladder cancer in the future.
e16560 Background: Concordance between tumor DNA (tDNA) and urine tumor DNA (utDNA) profiles using paired samples was analyzed. Genomic analysis of utDNA and tDNA showed a high consistency, indicating that urine is an optional sample for noninvasive detection and response evaluation of bladder cancer (BC). Methods: Methods and results data were analyzed from an ongoing study, collecting all cases from Second Hospital Affiliated to Tianjin Medical University. Cases with pathologically confirmed BC and matching tissue/urine/whole blood before treatments were recruited. In 85 patients, 48 with paired samples were enrolled in this analysis after excluding 37 paired samples failed in sample QC or sample collection. WES (Whole Exome Sequence) was applied to tDNA and paired white blood cell (WBC) DNA. An Acornmed 808-Gene panel was applied to utDNA and paired WBC DNA. Somatic events, including SNV (single nucleotide variant), InDel (insertion and deletion) of hot genes were analyzed. Consistency of tDNA and utDNA were identified and analyzed in the intersection set between the two chips, and tDNA profiling was used as the“golden standard”. Results: Among 48 patients, 24(50.0%) were MIBC, 21(43.8%) were NMIBC and 41 (81.5%) were male. With neoadjuvant therapy, 23(47.9%) are identified as responders (CR or PR), 7(14.6%) identified as non-responders (SD or PD), 18(37.5%) are still following up. Overall, 75.4% (214/284) tDNA mutations were found in utDNA, and 75.1% (214/285) utDNA mutations were found in tDNA. The top20 genes’ mutation landscape of utDNA highly resembled that of tDNA. The top20 genes could cover 97.9% (47/48) tissue samples and 89.6% (43/48) urine samples. Also, top20 mutated genes showed a strong correlation between tDNA and utDNA(r = 0.7371, p = 0.0002). TP53, KMT2D, ARIDA1A, CREBBP, ERBB2, ERCC2 and KDM6A are the most frequent abnormalities captured in tDNA and utDNA. Interestingly, we also found that the consistency of top20 genes in responders (n = 23, r = 0.7015, p = 0.0006) are higher than non-responders (n = 7, r = 0.4118, p = 0.1853). As a consequence, 70.1% (157/224), 61.8% (21/34) tDNA mutations were found in utDNA, and 72.0% (157/218), 25.0% (21/84) utDNA mutations were found in tDNA in responders and in non-responders, respectively. Conclusions: In brief, utDNA was robustly consistent and highly associated with tDNA, with 61.8%̃75.4% tDNA variations detected in utDNA target sequecing by acornmed 808 panel. The consistency would be higher if TERT promoter included in WES panel. While in non-responders, only 25.0% utDNA mutations were found in tDNA, indicating a spatial and temporal tumor heterogeneity. Our data provided initial prospective evidence on further developing urine as an optional sample for noninvasive detection and response evaluation of BC. The large prospective cohort study is still ongoing.
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