Optimal PD-L1-high cutoff for association with overall survival in patients with urothelial cancer treated with durvalumab monotherapy

Abstract

Background: Studies have indicated that programmed death ligand 1 (PD-L1) expression may have utility as a predictive biomarker in patients with advanced/metastatic urothelial carcinoma (UC). Different immunohistochemical (IHC) assays are in development to assess PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs).

Methods: In this post hoc analysis of the single-arm, phase 1/2 Study 1108 (NCT01693562), PD-L1 expression was evaluated from tumor samples obtained prior to second-line treatment with durvalumab in patients with advanced/metastatic UC using the VENTANA (SP263) IHC Assay. The primary objective was to determine whether the TC ≥ 25%/IC ≥ 25% algorithm (i.e., cutoff of ≥ 25% TC or ≥ 25% IC with PD-L1 staining at any intensity above background) was optimal for predicting response to durvalumab. PD-L1 expression data were available from 188 patients.

Results: After a median follow-up of 15.8 and 14.6 months, higher PD-L1 expression was associated with longer overall survival (OS) and progression-free survival (PFS), respectively, with significant separation in survival curves for PD-L1-high and-low expressing patients for the TC ≥ 25%/IC ≥ 25% cutoff (median OS: 19.8 vs 4.8 months; hazard ratio: 0.46; 90% confidence interval: 0.33, 0.639). OS was also prolonged for PD-L1-high compared with-low patients when samples were categorized using TC/IC combined positive score ≥ 10 and IC≥ 5% cutoffs. In multivariate analysis, IC but not TC PD-L1 expression was significantly associated with OS, PFS, and objective response rate (P < 0.001 for each), although interaction analysis showed similar directionality of benefit for ICs and TCs.

Conclusions: These findings support the utility of a combined TC/IC algorithm for predicting response to durvalumab in patients with UC, with the TC≥ 25%/IC≥ 25% cutoff optimal when used with the VENTANA (SP263) IHC Assay.

Conflict of interest statement

J. Ye, P. Mukhopadhyay, J. Walker, A. K. Gupta, M. C. Rebelatto, J. A. Williams are employees of AstraZeneca. M. Zajac, Y. Ben, X. Jin, J. Antal were employees of MedImmune/AstraZeneca at the time of manuscript development. These commercial affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Prevalence of PD-L1–high patients at different TC and IC cutoffs for defining positive PD-L1 expression in study 1108.

IC, tumor-infiltrating immune cells; PD-L1, programmed death ligand-1; TC, tumor cells. Highlighted bar indicates the PD-L1 cutoff previously used to investigate response to durvalumab.

Fig 2. Overall survival in Study 1108 at different cutoffs for PD-L1 expression in tumor cells (TC) with cutoffs of ≥ 1% (A), ≥ 10% (B), ≥ 25% (C), and ≥ 50% (D).

CI, confidence interval; HR, hazard ratio; NA, not applicable; OS, overall survival; PD-L1, programmed death ligand-1; TC, tumor cell.

Fig 3. Overall survival in Study 1108 at different cutoffs for PD-L1 expression in tumor-infiltrating immune cells (IC) with cutoffs of ≥ 1% (A), ≥ 10% (B), ≥ 25% (C), and ≥ 50% (D).

CI, confidence interval; IC, tumor-infiltrating immune cell; HR, hazard ratio; NA, not applicable; OS, overall survival; PD-L1, programmed death ligand-1.

Fig 4. Overall survival in Study 1108 at different cutoffs for PD-L1 expression in tumor cells (TC) or tumor-infiltrating immune cells (IC) with cutoffs of ≥ 1%/≥ 1% (A), ≥ 10%/≥ 25% (B), ≥ 25%/≥ 25% (C), and ≥ 50%/≥ 25% (D).

CI, confidence interval; IC, tumor-infiltrating immune cell; HR, hazard ratio; NA, not applicable; OS, overall survival; PD-L1, programmed death ligand-1; TC, tumor cell.

Fig 5. Median overall survival in Study 1108 at different TC and IC cutoffs for defining positive (PD-L1–high) and negative (PD-L1–low) expression.

IC, tumor-infiltrating immune cells; PD-L1, programmed death ligand-1; TC, tumor cells. Highlighted bar indicates the PD-L1 cutoff previously used to investigate response to durvalumab.

Fig 6. Objective response rates in study 1108 at different TC and IC cutoffs for defining positive (PD-L1–high) and negative (PD-L1–low) expression.

IC, tumor-infiltrating immune cells; PD-L1, programmed death ligand-1; TC, tumor cells. Highlighted bar indicates the PD-L1 cutoff previously used to investigate response to durvalumab.