Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma
Jianjun Gao, Neema Navai, Omar Alhalabi, Arlene Siefker-Radtke, Matthew T Campbell, Rebecca Slack Tidwell, Charles C Guo, Ashish M Kamat, Surena F Matin, John C Araujo, Amishi Y Shah, Pavlos Msaouel, Paul Corn, Jianbo Wang, John N Papadopoulos, Shalini S Yadav, Jorge M Blando, Fei Duan, Sreyashi Basu, Wenbin Liu, Yu Shen, Yuwei Zhang, Marc Daniel Macaluso, Ying Wang, Jianfeng Chen, Jianhua Zhang, Andrew Futreal, Colin Dinney, James P Allison, Sangeeta Goswami, Padmanee Sharma, Jianjun Gao, Neema Navai, Omar Alhalabi, Arlene Siefker-Radtke, Matthew T Campbell, Rebecca Slack Tidwell, Charles C Guo, Ashish M Kamat, Surena F Matin, John C Araujo, Amishi Y Shah, Pavlos Msaouel, Paul Corn, Jianbo Wang, John N Papadopoulos, Shalini S Yadav, Jorge M Blando, Fei Duan, Sreyashi Basu, Wenbin Liu, Yu Shen, Yuwei Zhang, Marc Daniel Macaluso, Ying Wang, Jianfeng Chen, Jianhua Zhang, Andrew Futreal, Colin Dinney, James P Allison, Sangeeta Goswami, Padmanee Sharma
Abstract
Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma1,2, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy2. 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 disease3-5. 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.
Conflict of interest statement
CONFLICT OF INTEREST
Dr. Sharma and Dr. Allison do not have any competing interest with this manuscript. However, they provided a list of all disclosures for transparency. Padmanee Sharma has ownership in Jounce, BioNTx, Constellation, Oncolytics, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Dragonfly, Lytix, Lava Therapeutics, Infinity Pharma, Adaptive Biotechnologies and Hummingbird. James P. Allison has ownership in Jounce, BioNTx, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Adaptive Biotechnologies, and Codiak. Padmanee Sharma serves as a consultant for Constellation, Jounce, Kite Pharma, Neon, BioAtla, Oncolytics Biotech, Forty-Seven, Polaris, Apricity, Marker Therapeutics, Codiak, ImaginAb, Dragonfly, Lava Therapeutics, Infinity Pharma, Lytix and Hummingbird. James P. Allison serves as a consultant for Jounce, Neon, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Lava Therapeutics, Dragonfly, Lytix, and Hummingbird.
Dr. Gao’s competing interest is listed below and here is a list of all his disclosures for transparency. Jianjun Gao serves as a consultant for ARMO Biosciences, CRISPR Therapeutics, Jounce, Nektar, Pfizer, Polaris, and Symphogen.
COMPETING INTEREST STATEMENTS
Jianjun Gao served as a consultant on a scientific advisory board for AstraZeneca and received compensation as an advisor. Ashish M. Kamat served on a scientific advisory board for AstraZeneca and received compensation as an advisor. Arlene Siefker-Radtke is on a scientific advisory board for AstraZeneca and receives compensation as an advisor. Jorge Blando became an AstraZeneca employee after the work on this manuscript was completed.
Figures
Source: PubMed