Gao et al. reported the safety and efficacy of neoadjuvant anti-PD-L1 plus anti-CTLA-4 in cisplatin-ineligible patients with high-risk muscle-invasive urothelial carcinoma. The safety profile was tolerable. Of the 24 patients who underwent cystectomy, 37.5% showed pathological complete response, 58% had downstaging to pT1 or less, and the one year RFS was 82.8%. Responders correlated with significant enrichment of tertiary lymphoid structures, B cells, and CD4+ and CD8+ T cells in pre-treatment tumor samples, but not with tumor mutational burden, DNA damage response genes, or an eight-gene signature predictive for anti-PD-L1 therapy.
Contributed by Shishir Pant
ABSTRACT: 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 ³3 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.
Author Info: (1) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. JGao1@mdanderson.org. (2) Department of Urology, The Universi
Author Info: (1) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. JGao1@mdanderson.org. (2) Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (24) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (29) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. PadSharma@mdanderson.org. The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. PadSharma@mdanderson.org. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. PadSharma@mdanderson.org.
