Impact of steroid-sparing immunosuppressive agents on tumor outcome in the context of cancer immunotherapy with highlight on melanoma: a systematic literature review and meta-analysis

Front Immunol. 2024 Dec 16:15:1499478. doi: 10.3389/fimmu.2024.1499478. eCollection 2024.

Abstract

Background: The impact of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on tumor outcome is not well-known. This systematic review evaluates tumor outcomes for corticosteroid (CS) monotherapy versus CS with SSIA (CS-SSIA) for irAE treatment with a focus on melanoma.

Methods: Search was conducted through 1/5/23 using PubMed, Embase, Cochrane CENTRAL, and Web of Science. We included case series, retrospective/prospective observational studies and interventional clinical trials. Individual-level data was analyzed using KM curves and Cox regression for overall survival (OS) and progression free survival (PFS). Time to SSIA was treated as a time-varying exposure using landmark analysis (landmark timepoint=3 months after irAE) to account for immortal time bias. For group-level data, meta-analysis compared the use of SSIA to No SSIA for irAEs.

Results: Of twenty-two publications with individual-level data, 147 patients with any cancer (57 CS, 90 CS-SSIA) and 65 with melanoma (18 CS, 47 CS-SSIA) underwent landmark analysis. Twenty-two publications underwent group-level evaluation and four were included in the meta-analysis. CS-SSIA versus CS showed higher risk of all-cause mortality and progression (HR 2.75, 95%CI: 1.44-5.27, p<0.01 and HR 1.75, 95%CI: 1.07-2.85, p=0.03, respectively). Melanoma showed worse OS and PFS for CS-SSIA versus CS (HR 5.68, 95%CI: 1.31-24.67, p=0.02 and HR 2.68, 95%CI: 1.12-6.40, p=0.03, respectively). In the meta-analysis of group-level data (n=2558), we found worse OS and PFS for CS-SSIA versus No SSIA (HR 1.58, 95%CI: 1.25; 2.01, p<0.01 and 1.70, 95%CI: 1.25-2.33, p<0.01). Tumor necrosis factor-alpha inhibitors (TNFi) were the most common SSIA. In the melanoma cohort, TNFi had worse OS and PFS versus CS (HR 6.46, 95%CI: 1.43-29.19, p = 0.02 and HR 7.49, 95%CI: 2.29-24.48, p<0.01, respectively). TNFi versus Other SSIAs showed a trend toward worse OS and worse PFS (HR 6.96, 95%CI: 0.90-53.65, p=0.06 and HR 21.5, 95%CI: 2.63-175.8, p<0.01, respectively). Meta-analysis showed a concern for TNFi compared to Other SSIA (HR 1.56, 95%CI: 1.17-2.09, p<0.01 respectively).

Conclusions: While our results raise concern about the effects of CS-SSIA and TNFi for irAE therapy on tumor outcomes, prospective randomized controlled trials are needed to definitively assess the effect of SSIAs on tumor outcomes.

Keywords: ICI toxicity; TNF inhibitors (TNFi); biologics; cancer immunotherapy; disease-modifying antirheumatic drugs (DMARDs); immune related adverse events (irAEs); steroid-sparing agents; tumor outcome.

Publication types

  • Systematic Review
  • Meta-Analysis

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use
  • Humans
  • Immunosuppressive Agents* / therapeutic use
  • Immunotherapy* / adverse effects
  • Immunotherapy* / methods
  • Melanoma* / drug therapy
  • Melanoma* / immunology
  • Melanoma* / mortality
  • Melanoma* / therapy
  • Progression-Free Survival
  • Treatment Outcome

Substances

  • Immunosuppressive Agents
  • Adrenal Cortex Hormones

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. NS is supported by the National Institute of Arthritis And Musculoskeletal And Skin Diseases of the National Institutes of Health under Award Number K23AR079588. NA-W is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number K01AI163412 and received the University of Texas MD Anderson Cancer Center DoIM Development & Translational Science award, Bridge Funding award, Cancer Survivorship Seed Money Grant, Institutional Research Grant, Prioritizing Research Innovation and Mentoring Excellence (PRIME) award, Melanoma SPORE Career Enhancement Program (CEP) award, and the Cyrus Scholar Award for Outstanding Clinical Research. PR has received funding form COVID-19 Funds to Retain Clinical Scientists by the SECURED (Supporting Early Career University Researchers to Excel through Disruptions) Steering Committee as well as the University of Chicago Institute of Translational Medicine Clinical and Translational Science Award K12/KL2 Grant 5KL2TR002387-05.