Highly Variable Timing Renders Immunotherapy Efficacy and Toxicity Impractical Biomarkers of One Another in Clinical Practice

Authors

Mitchell S von Itzstein
Yuqiu Yang
Yiqing Wang
David Hsiehchen
Thomas Y Sheffield
Farjana Fattah
Vinita Popat
Murtaza Ahmed
Jade Homsi
Jonathan E Dowell
Sawsan Rashdan
Jay Lohrey
Hans J Hammers
Randall S Hughes
Tao Wang
Yang Xie
David E Gerber

Publication Date

1-1-2024

Journal

Frontiers in Immunology

DOI

10.3389/fimmu.2024.1351739

PMID

38690281

PMCID

PMC11058939

PubMedCentral® Posted Date

4-16-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Background: A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI.

Methods: Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women).

Results: Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE.

Conclusions: In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.

Keywords

Humans, Female, Male, Aged, Immune Checkpoint Inhibitors, Middle Aged, Neoplasms, Biomarkers, Immunotherapy, Treatment Outcome, Time Factors, efficacy, immune checkpoint inhibitor (ICI), immune-related adverse event (irAE), immunotherapy, monitoring, toxicity, biomarker

Published Open-Access

yes

Recommended Citation

von Itzstein, Mitchell S; Yang, Yuqiu; Wang, Yiqing; et al., "Highly Variable Timing Renders Immunotherapy Efficacy and Toxicity Impractical Biomarkers of One Another in Clinical Practice" (2024). Faculty, Staff and Student Publications. 6740.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6740