Immune-related adverse events in urothelial cancer patients: Adjustment for immortal time bias

Cancer Sci. 2022 Nov;113(11):3912-3921. doi: 10.1111/cas.15539. Epub 2022 Sep 2.

Abstract

To investigate the association between the onset, severity, and type of immune-related adverse events (irAEs) and the efficacy of pembrolizumab in patients with platinum-pretreated advanced urothelial carcinoma (UC), we retrospectively collected clinical datasets of 755 patients and conducted landmark analysis. Patients who survived for fewer than 3 months were excluded from the evaluation to reduce the immortal time bias. In total, 620 patients were evaluated, of whom 220 patients (35.5%) experienced grade ≥2 irAEs, including 134 patients with grade 2 irAEs and 86 with grade ≥3 irAEs. Propensity score matching extracted 198 patients with and without grade ≥2 irAEs. The onset of grade ≥2 irAEs was associated with longer median progression-free survival (PFS) (8.3 months vs. 4.5 months, p = 0.003) and overall survival (OS) (20.4 months vs. 14.3 months, p = 0.031) and a higher objective response rate (ORR) (44.8% vs. 30.2%, p = 0.004). Patients with grade 2 irAEs had significantly better oncological outcomes (PFS, OS, and ORR) than grade ≤1 and ≥3 irAEs. Patients with grade ≥3 irAEs had worse outcomes than grade 2 irAEs. Endocrine and skin irAEs were related with better survival outcomes, and the rate of severities was lower in these categories. In conclusion, the occurrence of irAEs, particularly low-grade irAEs, was predictive of pembrolizumab efficacy in patients with platinum-pretreated advanced UC.

Keywords: immortal time bias; immune-related adverse events; pembrolizumab; therapeutic efficacy; urothelial carcinoma.

MeSH terms

  • Antineoplastic Agents, Immunological* / adverse effects
  • Carcinoma, Transitional Cell* / drug therapy
  • Humans
  • Nivolumab / adverse effects
  • Platinum
  • Retrospective Studies
  • Urinary Bladder Neoplasms* / drug therapy

Substances

  • Nivolumab
  • Antineoplastic Agents, Immunological
  • Platinum