Journal Article

Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma

Macaluso, Marc Daniel, Blando, Jorge M., Araujo, John C., Allison, James P., Wang, Ying, Shen, Yu, Liu, Wenbin, Shah, Amishi Y., Guo, Charles C., Navai, Neema, Alhalabi, Omar, Basu, Sreyashi, Duan, Fei, Gao, Jianjun, Tidwell, Rebecca Slack, Papadopoulos, John N., Sharma, Padmanee, Matin, Surena F., Futreal, Andrew, Zhang, Yuwei, Wang, Jianbo, Dinney, Colin, Zhang, Jianhua, Yadav, Shalini S., Goswami, Sangeeta, Msaouel, Pavlos, Corn, Paul, Kamat, Ashish M., Campbell, Matthew T., Siefker-Radtke, Arlene, Chen, Jianfeng

2020

Overview

Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma 1 , 2 , with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy 2 . The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17% 2 . Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features ( n  = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease 3 – 5 . The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities ( n  = 4), hepatitis and colitis ( n  = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery ( n  = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment. Neoadjuvant combination of immune checkpoint therapy in patients with cisplatin-ineligible bladder cancer achieves clinical efficacy and uncovers immune features as potential predictive biomarkers of treatment response.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1059/2325 / 631/67/589/1336 / 692/308/575 / Abnormalities / Adult / Aged / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - adverse effects / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - adverse effects / Antineoplastic Agents, Immunological - administration & dosage / Antineoplastic Agents, Immunological - adverse effects / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Biomarkers / Biomedical and Life Sciences / Biomedicine / Bladder / Bladder cancer / Cancer / Cancer Research / Carcinoma - drug therapy / Carcinoma - immunology / Carcinoma - pathology / Chemotherapy / Cisplatin / Cisplatin - adverse effects / Colitis / CTLA-4 Antigen - antagonists & inhibitors / CTLA-4 Antigen - immunology / CTLA-4 protein / Drug therapy / Drug therapy, Combination / Female / Health services / Hepatitis / Histology / Humans / Immune checkpoint / Immunotherapy / Infectious Diseases / Letter / Male / Metabolic Diseases / Middle Aged / Molecular Medicine / Monoclonal antibodies / Neoadjuvant therapy / Neoplasm Staging / Neurosciences / Patient outcomes / Patients / PD-L1 protein / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - immunology / Risk / Risk Factors / Safety / Surgery / Targeted cancer therapy / Tumors / Urothelial carcinoma / Urothelium - drug effects / Urothelium - immunology / Urothelium - pathology