Outcomes of Patients with Advanced Urothelial Carcinoma after Anti-programmed Death-(ligand) 1 Therapy by Fibroblast Growth Factor Receptor Gene Alteration Status: An Observational Study

Abstract

Background: Clinical outcomes of anti-programmed death‑(ligand) 1 (anti-PD-[L]1) therapy in patients with locally advanced or metastatic urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (FGFRa+) remain unclear; recent studies have reported either comparable or poorer outcomes versus patients without FGFR alterations (FGFRa-).

Objective: To analyze the outcomes of patients with mUC and any FGFRa (mutations or fusions) who received anti-PD-(L)1 therapy.

Design setting and participants: In this noninterventional, retrospective, multicenter study, clinical practice data were collected from FGFRa+/- patients who received prior immunotherapy between May 2018 and July 2019.

Outcome measurements and statistical analysis: Investigator‑determined overall response rate (ORR), disease control rate (DCR), and overall survival (OS) were assessed in multivariate and unadjusted analyses.

Results and limitations: Ninety-four patients (66% men; median age, 63 yr) with mUC and known FGFR status were included; 38 (40%) were FGFRa+ and 56 (60%) were FGFRa-. In FGFRa+ versus FGFRa- patients who received any line of anti-PD-(L)1 therapy (n = 92), ORR, DCR, and OS were 16% versus 26%, 29% versus 52% (relative risk: 1.14 [95% confidence interval {CI}, 0.92-1.40]; p = 0.3), and 8.57 versus 13.2 mo (hazard ratio [HR]: 1.33 [95% CI, 0.77-2.30]; p = 0.3), respectively. A multivariate analysis provided some evidence supporting shorter OS in FGFRa+ versus FGFRa- (any line of anti-PD-L[1] therapy; HR: 1.81 [95% CI, 0.99-3.31]; p = 0.054). Limitations include this study's retrospective nature and a potential selection bias from small sample size.

Conclusions: Some evidence of lower response rates and shortened OS following anti-PD-(L)1 therapy was observed in FGFRa+ patients. The phase 3 THOR study (NCT03390504) will prospectively compare FGFRa+ patients with advanced mUC treated with erdafitinib versus pembrolizumab.

Patient summary: Patients with metastatic urothelial carcinoma and prespecified fibroblast growth factor receptor alterations (FGFRa) potentially have worse clinical outcomes when treated with anti-PD-(L)1 therapy than those without FGFRa.

Keywords: Anti–programmed death-(ligand) 1 therapy; FGFR alteration; Fibroblast growth factor receptor; Programmed cell death protein 1; Programmed death-(ligand) 1; Urothelial carcinoma.

Fig. 1

BLC0001 study design. Acceptable FGFR alterations included any FGFR mutation or gene fusion; copy number alterations/gene amplifications were not eligible in the absence of co-occurring FGFR mutations or fusions. FGFR = fibroblast growth factor receptor; FGFRa+/– = fibroblast growth factor receptor alteration positive/negative; mUC = metastatic urothelial carcinoma; PD-(L)1 = programmed death‑(ligand) 1.

Fig. 2

Kaplan–Meier curves of overall survival. Overall survival measured to the date of the patient’s death from any cause from the date of starting: (A) any line of anti–PD-(L)1 therapy, (B) first line of anti–PD-(L)1 therapy, (C) second line of anti–PD-(L)1 therapy, and (D) any subsequent line of anti–PD-(L)1 therapy following platinum-based chemotherapy. Patients who terminated study participation or were lost to follow-up were censored at the date they were last known to be alive. CI = confidence interval; FGFRa+/– = fibroblast growth factor receptor alteration positive/negative; HR = hazard ratio; PD-(L)1 = programmed death‑(ligand) 1.

Fig. 3

Multivariate analysis of overall survival in patients treated with (A) any line of prior anti–PD-(L)1 therapy, (B) first-line anti–PD-(L)1 therapy, and (C) second-line anti–PD-(L)1 therapy. CI = confidence interval; FGFRa+/– = fibroblast growth factor receptor alteration positive/negative; HR = hazard ratio; NE = not evaluable; PD-(L)1 = programmed death‑(ligand) 1; PH = proportional hazard.

Fig. 3

Multivariate analysis of overall survival in patients treated with (A) any line of prior anti–PD-(L)1 therapy, (B) first-line anti–PD-(L)1 therapy, and (C) second-line anti–PD-(L)1 therapy. CI = confidence interval; FGFRa+/– = fibroblast growth factor receptor alteration positive/negative; HR = hazard ratio; NE = not evaluable; PD-(L)1 = programmed death‑(ligand) 1; PH = proportional hazard.