The recent approvals for antibody-drug conjugates (ADCs) in multiple malignancies in recent years have fuelled the ongoing development of this class of drugs. These novel agents combine the benefits of high specific targeting of oncogenic cell surface antigens with the additional cell kill from high potency cytotoxic payloads, thus achieving wider therapeutic windows. This review will summarise the clinical activity of ADCs in tumour types not covered elsewhere in this issue, such as gastrointestinal (GI) and genitourinary (GU) cancers and glioblastoma (GBM). In addition to the ongoing clinical testing of existing ADCs, there is substantial preclinical and early phase testing of newer ADCs or ADC incorporating strategies. This review will provide selected insights into such future development, focusing on the development of novel ADCs against new antigen targets in the tumour microenvironment (TME) and combination of ADCs with immuno-oncology (IO) agents.

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Antibody-drug conjugates: beyond current approvals and potential future strategies

There is limited evidence regarding the tumor expression of nectins and their clinical implications in muscle invasive bladder cancer. Herein, we evaluated expression of Nectins 1-4 in 64 patients with muscle invasive bladder cancer who underwent radical cystectomy using a histochemical scoring method (H-score; immunohistochemical staining intensity multiplied by the percentage of positive-staining cells). The cutoff values were defined based on the median H-scores. Of the 64 patients, 45 (70%) had residual tumors in radical cystectomy specimens, while 13 (20%) had lymph node metastasis. The median (interquartile range) H-scores of Nectin-1, - 2, - 3, and - 4 expression were 0 (0-10), 80 (30-180), 5 (0-30), and 100 (33-160), respectively. The Nectin-4 H-score of the neuroendocrine variant was significantly lower than that of pure urothelial carcinoma (P = 0.015). Post-neoadjuvant chemotherapy pathological response (<ypT2N0 residual disease and pN-negative) was achieved in 18 (49%) of the 37 patients who received neoadjuvant chemotherapy. Clinical stage II, not Nectin expression, was an independent factor associated with pathological response (P = 0.019, adjusted odds ratio 6.9, vs stage III/IV). There was no correlation in Nectin-4 tumor expression between transurethral resection and matched radical cystectomy specimens and between radical cystectomy specimens and matched lymph node metastatic lesions. However, there was a significant decrease in Nectin-4 expression in post-neoadjuvant chemotherapy radical cystectomy specimens compared to pre-neoadjuvant chemotherapy transurethral resection specimens (P = 0.008). Given the downregulation of Nectin-4 by chemotherapy and the significant discrepancy between radical cystectomy and matched lymph node metastasis specimens, baseline primary tumors may not be a suitable material for evaluating Nectin-4 expression and its potential as a predictive biomarker for enfortumab vedotin treatment. 

Tumor expression of Nectin-1-4 and its clinical implication in muscle invasive bladder cancer: An intra-patient variability of Nectin-4 expression.

Antibody Drug Conjugates in Bladder Cancer: Current Milestones and Future Perspectives.

Immune checkpoint inhibitors (ICIs) are widely used in the management of patients with advanced urothelial carcinoma (aUC). However, its performance in aUC patients with poor performance status (PS) remains unknown.We aimed to assess the impact of patients' performance status on the oncologic outcomes in patients with aUC treated with ICIs.We searched PubMed, Web of Science, and Scopus from inception until July 2022 to identify studies assessing the association between the Eastern Cooperative Oncology Group (ECOG) PS and the oncologic outcomes in patients with aUC treated with ICIs in randomised (RCTs) and nonrandomised (NRCTs) control studies according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The outcomes of our interests were overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and objective response rate (ORR).Overall, six RCTs comprising 5428 patients and 32 NRCTs comprising 6069 patients were included. The meta-analysis of the RCTs revealed that patients with ECOG PS = 0 and PS ≥1 had a trend towards better OS with ICIs compared with those treated with chemotherapy (pooled hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.71-1.04, and HR: 0.74, 95% CI: 0.53-1.03, respectively). There was no significant difference in terms of response to ICIs between patients with poor and good PS (I2 = 0%, p = 0.46). The meta-analysis of the NRCTs revealed that patients with PS ≥2 had significantly worse OS than those with PS <2 (pooled HR: 2.52, 95% CI: 2.00-3.17), as well as worse CSS (pooled HR: 3.35, 95% CI: 1.90-5.91), PFS (pooled HR: 2.89, 95% CI: 1.67-5.01), and ORR (pooled odds ratio: 0.47, 95% CI: 0.27-0.82). Similarly, patients with PS ≥1 had significantly worse oncologic outcomes than those with PS = 0.In the NRCTs, poor PS was correlated with worse oncologic outcomes in aUC patients treated with ICIs. In the RCTs, ICIs performed better than chemotherapy across all PS categories. These findings should be interpreted with caution due to the high heterogeneity across the studies and patient populations. More RCTs including poor PS are needed to assess the impact of PS on ICI therapy outcomes.Immune therapy for patients with urothelial carcinoma should not be restricted on the grounds of performance status. However, patients with poor performance status should be considered for other factors such as life expectancy and comorbidities. 

Impact of Performance Status on Oncologic Outcomes in Patients with Advanced Urothelial Carcinoma Treated with Immune Checkpoint Inhibitor: A Systematic Review and Meta-analysis.

Recently, the standard of care for advanced urothelial cancer (UC) has been changed by developing immune-checkpoint inhibitors (ICIs). However, its response rate is limited to 20–30%. The identification of biomarkers to predict the therapeutic effects of ICIs is urgently needed. The present study explored the association between immunohistochemical biomarkers and clinical outcomes in UC patients treated with pembrolizumab. A total of 85 patients with UC who received pembrolizumab after chemotherapy from January 2018 to May 2020 were retrospectively reviewed. Tumor tissues were obtained for immunohistochemical study from 47 out of 85 patients. The protein expressions of PD-L1, WT1, Nectin-4, CD4, CD8, Foxp3, and CD68 in tumor cells and/or tumor infiltrating lymphocytes were immunohistochemically examined. The associations between protein expressions and overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) were statistically analyzed. Patients with positive PD-L1 in tumor cells showed significantly worse OS (Log-rank test: HR 5.146, p = 0.001, Cox regression analysis: HR 4.331, p = 0.014) and PFS (Log-rank test: HR 3.31. p = 0.022), along with significantly lower DCR (14.3%) compared to the PD-L1 negative patients (67.5%). In addition, patients with strong expression of Nectin-4 in tumor cells showed significantly higher DCR (100%) than the other patients (50%). PD-L1 expression in tumor cells was associated with poor prognosis (OS and PFS) and low DCR. Interestingly, the strong expression of Nectin-4 was correlated with high DCR. PD-L1 and Nectin-4 expression in tumor cells could be prognostic biomarkers useful for pembrolizumab in patients with advanced UC.

M. Komatsu

Papers

Expressions of PD-L1 and Nectin-4 in urothelial cancer patients treated with pembrolizumab.