Predictors of Pathologic Complete Response in Bladder Cancer After Pembrolizumab - Expert Commentary

Recent trials investigated the efficacy of immune checkpoint inhibitors (ICIs) in the neoadjuvant setting for cisplatin-ineligible patients. A recent single-arm trial of atezolizumab (two cycles) in cisplatin-ineligible patients showed a pathologic complete response (pCR) rate of 31%. Another study (PURE-01) of pembrolizumab (3 cycles) achieved a pT0 rate of 37%. Robust biomarkers that predict pCR are needed.

A recently published biomarker analysis of PURE-01 by Bandini et al. in the Journal of the National Cancer Institute investigated the utility of clinical and tumor biomarkers to predict pCR after pembrolizumab. PURE-01 was an open-label, single-arm, phase 2 study that enrolled patients scheduled for radical cystectomy (RC) and had a clinical T2-4aN0M0 stage. The pCR (pT0N0) was defined as the absence of viable tumor in examined tissue from RC and pelvic lymph node dissection. The study included 112 patients who underwent comprehensive genomic profiling and PD-L1 combined positive score (CPS) assessment.  The cohort included 19 (17%) patients with predominant variant histology. 

The authors conducted multivariable logistic regression analyses (MVA) to evaluate baseline clinical T-stage and tumor biomarkers associated with pCR. Only CPS was a statistically significant predictor of pCR (odds ratio [OR]: 1.02, 95% CI: 1.01-1.04, p=0.005). A calculator for pCR probability was developed using the coefficients of the multivariable model, including TMB, CPS, and cT-stage. The c-index of the pCR probability calculator was 0.77. The authors published this calculator as an online resource (The PURE-01 risk calculator).

The study evaluated the contribution of TMB and CPS in determining the probability of pCR. Interestingly, very high TMB levels were found to be a statistically significant predictor for pCR regardless of the PD-L1 expression. Only in tumors with high TMB (>11 Mut/Mb), the CPS values had a linear impact on pCR probability. This impact was not observed in low-TMB tumors.

The calculator has to be interpreted cautiously as it did not account for the impact of transurethral resection of the bladder tumor (TURBT) apart from using the clinical tumor stage. It is also important to note that the study used multiparametric MRI to assess the clinical stage. The definition of pCR and whether it predicts overall survival in a prospective manner need to be considered.  

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


  1. Bandini M, Ross JS, Raggi D, Gallina A, Colecchia M, Lucianò R, et al. Predicting the Pathologic Complete Response After Neoadjuvant Pembrolizumab in Muscle-Invasive Bladder Cancer. J Natl Cancer Inst. 2021 Jan 4;113(1):48–53. PMID: 32516377
  2. Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019;25(11):1706–14. PMID: 31686036
  3. Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Dec 1;36(34):3353–60. PMID: 30343614
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