Correlation of safety and efficacy of atezolizumab therapy across indications

Abstract

Background: The association between safety and efficacy of immune checkpoint inhibitors is known, but the correlation between severity and impact of specific organ involvement by immune-related adverse events (irAE) and cancer outcomes is poorly understood. Most irAEs are mild-to-moderate but severe irAEs may pose clinical management challenges and affect patient outcomes.

Methods: We assessed the association between irAE grade (G) and specific organ involvement with overall survival (OS) in 9,521 patients across 14 studies involving atezolizumab as mono (IO) or with chemo/targeted (C-IO) therapy as compared with chemo/targeted therapy (C) in advanced non-small cell lung, small-cell lung, renal cell, urothelial, and triple-negative breast cancers. We used a mixed-effect Cox proportional hazard model for time-varying covariates to address immortal-time bias; adjusted for baseline factors associated with irAEs and OS to control for confounding bias; and focused on five common irAEs (dermatologic, thyroid dysfunction, hepatitis, pneumonitis, and colitis) to avoid low statistical power for rare events.

Results: For patients treated with IO or C-IO, G1-2 irAEs were associated with improved OS (HR=0.65, p<0.01) and G3-4 irAEs showed a slight increased risk of death (HR=1.18, p=0.10) versus patients without irAEs. By specific irAE, G1-2 cutaneous irAEs, thyroid dysfunction, or pneumonitis were associated with improved OS (p<0.05), while G3-4 pneumonitis and colitis were associated with worse OS (p<0.01). There was no association between hepatitis and OS by any grade. Findings were consistent across indications.

Conclusions: This analysis demonstrates a correlation between irAEs and improved OS with atezolizumab by severity grade and the most common irAEs by organ involvement. Low-grade irAEs are significantly associated with improved OS, while specific high-grade irAEs are associated with poorer OS, underscoring the importance of early recognition and management of toxicity to optimize benefit/risk balance.

Keywords: Immune Checkpoint Inhibitor; Immune related adverse event - irAE; Survivorship.