Neoadjuvant Durvalumab Plus Tremelimumab Achieves 37.5% Pathological Complete Response in High-Risk Urothelial Carcinoma
This first pilot trial of neoadjuvant dual checkpoint blockade (anti-PD-L1 plus anti-CTLA-4) enrolled 28 cisplatin-ineligible patients with high-risk urothelial carcinoma features. Pathological complete response reached 37.5% with 58% downstaged to pT1 or less, while grade 3+ immune-related adverse events occurred in 21%. The biomarker correlative data support further development of predictive companion diagnostics for immunotherapy patient selection in the neoadjuvant bladder cancer setting.
The original study
Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma.
- Authors
- Gao J, Navai N, Alhalabi O, Siefker-Radtke A, Campbell MT, Tidwell RS, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't
- PMID
- 33046869
Original 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.