TY - JOUR
T1 - Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma
AU - Gao, Jianjun
AU - Navai, Neema
AU - Alhalabi, Omar
AU - Siefker-Radtke, Arlene
AU - Campbell, Matthew T.
AU - Tidwell, Rebecca Slack
AU - Guo, Charles C.
AU - Kamat, Ashish M.
AU - Matin, Surena F.
AU - Araujo, John C.
AU - Shah, Amishi Y.
AU - Msaouel, Pavlos
AU - Corn, Paul
AU - Wang, Jianbo
AU - Papadopoulos, John N.
AU - Yadav, Shalini S.
AU - Blando, Jorge M.
AU - Duan, Fei
AU - Basu, Sreyashi
AU - Liu, Wenbin
AU - Shen, Yu
AU - Zhang, Yuwei
AU - Macaluso, Marc Daniel
AU - Wang, Ying
AU - Chen, Jianfeng
AU - Zhang, Jianhua
AU - Futreal, Andrew
AU - Dinney, Colin
AU - Allison, James P.
AU - Goswami, Sangeeta
AU - Sharma, Padmanee
N1 - Funding Information:
This research is supported in part through an alliance between AstraZeneca/ MedImmune and the MDACC Immunotherapy Platform, the MD Anderson Physician Scientist Award (J.G.), Khalifa Physician Scientist Award (J.G.), Andrew Sabin Family Foundation Fellows Award (J.G.) and Wendy and Leslie Irvin Barnhart Fund (J.G.). We thank the genomic medicine, CGL core team for WES. In addition, we thank Ashura Khan (Program Director) and the Immunotherapy Platform team for technical support. P.S. and J.P.A. are members of the Parker Institute for Cancer Immunotherapy, which supports their research work at MDACC.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41591-020-1086-y
DO - 10.1038/s41591-020-1086-y
M3 - Article
C2 - 33046869
AN - SCOPUS:85092369845
SN - 1078-8956
VL - 26
SP - 1845
EP - 1851
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -