Predicting the Pathologic Complete Response After Neoadjuvant Pembrolizumab in Muscle-Invasive Bladder Cancer

Abstract

Background: In the PURE-01 study (NCT02736266), we aimed to evaluate the ability to predict the pathologic complete response (pT0N0) after pembrolizumab by using clinical and tumor biomarkers.

Methods: In an open-label, single-arm, phase 2 study, 3 courses of 200 mg pembrolizumab preceding radical cystectomy were administered in patients with T2-4aN0M0 muscle-invasive bladder cancer. The analyses included a comprehensive genomic profiling and programmed cell-death-ligand-1 (PD-L1)-combined positive score assessment (CPS; Dako 22C3 antibody) of pre- and posttherapy samples. Multivariable logistic regression analyses evaluated baseline clinical T stage and tumor biomarkers in association with pT0N0 response. Corresponding coefficients were used to develop a calculator of pT0N0 response based on the tumor mutational burden (TMB), CPS, and the clinical T stage. Decision-curve analysis was also performed. All statistical tests were 2-sided.

Results: From February 2017 to June 2019, 112 patients with biomarker data were enrolled (105 with complete TMB and CPS data). Increasing TMB and CPS values featured a linear association with logistic pT0N0 probabilities (P = .02 and P = .004, respectively). For low TMB values (≤11 mut/Mb, median value, n = 53), pT0N0 probability was not associated with increasing CPS. Conversely, for high TMB values (>11 mut/Mb, n = 52), pT0N0 was statistically significantly associated with higher CPS (P = .004). The C index of the pT0N0 probability calculator was 0.77. On decision-curve analysis, the net benefit of the model was higher than the "treat-all" option within the clinically meaningful threshold probabilities of 40%-50%.

Conclusions: The study presents a composite biomarker-based pT0N0 probability calculator that reveals the complex interplay between TMB and CPS, added to the clinical T stage.

Figure 1.

Decision curve analysis exploring the net benefit related to the use of our risk calculator in comparison with the treat-all and treat-none options. Net benefit was achieved for threshold probabilities higher than 10%.

Figure 2.

Three-dimensional plot exploiting the correlation between TMB and CPS score according to pretreatment probability of pathologic complete response (pT0N0). The plot is based on the actual biomarker data obtained from the PURE-01 study (n = 112). The x- and y-axes reported continuous values of TMB (0–45 mutations/Mb) and CPS (0%-99%), respectively. The z-axis reported the logistic probability of pT0N0 derived from interaction between TMB and CPS. Colors represent the pT0N0 probability tertile: <26% (first tertile), 26%-40% (second tertile), >40% (third tertile). CPS = combined positive score; TMB = tumor mutational burden.