Immune-related AEs tied to improved survival in bladder cancer patients on atezolizumab

In patients with locally advanced or metastatic urothelial cancer patients receiving atezolizumab treatment, immune-related adverse events (AEs) were associated with improved survival outcomes, according to an analysis of individual participant data from the IMvigor210 and IMvigor211 studies.

“Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of urothelial carcinoma. However, the mechanism of response to this kind of treatment and how immune-related AEs may affect oncological outcomes remains poorly understood,” said Daniele Robesti from the Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Urological Research Institute, Milan, Italy, at EAU 2023.

Therefore, Robesti and colleagues investigated the link between immune-related AEs and oncological outcomes in advanced urothelial cancer patients receiving ICIs. The researchers used individual participant data from two prospective trials evaluating participants receiving atezolizumab treatment for urothelial cancer (n=896; median age 68 years, 58 percent female). Of these, 195 had experienced immune-related AEs while the rest did not. More than 90 percent of the overall cohort had transitional cell carcinoma. [EAU 2023, abstract A0535]

Of those who have had immune-related AEs, 40 percent had >2 prior lines of systemic therapy (57 percent on cisplatin only) and a third had T1 disease. More than two-thirds had visceral metastasis.

In the adjusted multivariable Cox regression analysis, immune-related AEs were found to be statistically significant predictors of improved overall survival (OS; hazard ratio [HR], 0.51, 95 percent confidence interval [CI], 0.41–0.64; p<0.001), progression-free survival (PFS; HR, 0.50, 95 percent CI, 0.40–0.61; p<0.001), and cancer-specific survival (CSS; HR, 0.55, 95 percent CI, 0.45–0.72; p<0.001) after accounting for well-known confounding factors.

Landmark analysis

“However, these results may have suffered from immortal time bias, which is a well-known statistical distortion,” noted Robesti. This is the period wherein participants have not experienced any event of interest; in this study, it is the period between the time from randomization and the development of immune-related AEs.

A sensitivity analysis was conducted using a landmark point of 48 days. “[This] is the median time to develop an immune-related AE. All events occurring before this landmark time were excluded from this analysis,” noted Robesti.

In the landmark analysis, immune-related AEs remained associated with improved OS (adjusted HR [aHR], 0.54, 95 percent CI, 0.43–0.72; p<0.001), PFS (aHR, 0.53, 95 percent CI, 0.41–0.67; p<0.001), and CSS (aHR, 0.53, 95 percent CI, 0.41–0.67; p<0.001).

The immune-related AE paradox

“In conclusion, [our study shows] the immune-related AE paradox in locally advanced or metastatic urothelial cancer patients receiving atezolizumab,” said Robesti.

“The development of immune-related AEs due to atezolizumab immunotherapy [in this patient setting] was associated with improved oncologic outcomes,” he continued.

The findings were verified after accounting for immortal time bias.