Pre-treatment soluble PD-L1 as a predictor of overall survival for immune checkpoint inhibitor therapy: a systematic review and meta-analysis

Our plain-English summary of Pre-treatment soluble PD-L1 as a predictor of overall survival for immune checkpoint inhibitor therapy: a systematic review and meta-analysis, by Á. Széles, T. Fazekas, S. Váncsa, et al (Cancer Immunology, Immunotherapy, 2023).

The study

• Authors: Á. Széles, T. Fazekas, S. Váncsa, M. Váradi, P.T. Kovács, U. Krafft, V. Grünwald, B. Hadaschik, A. Csizmarik, P. Hegyi, A. Váradi, P. Nyirády, T. Szarvas
• Journal: Cancer Immunology, Immunotherapy
• Published: 2023;72(5):1061-1073
• Type of article: Meta-analysis, Systematic review
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Immune checkpoint inhibitors (ICI) such as anti-PD-L1 and anti-PD-1 agents have been proven to be effective in various cancers. However, the rate of non-responders is still high in all cancer entities. Therefore, the identification of biomarkers that could help to optimize therapeutic decision-making is of great clinical importance. Soluble PD-L1 (sPD-L1) and PD-1 (sPD-1) are emerging blood-based biomarkers and were previously shown to be prognostic in various clinical studies.

Objective: We aimed to evaluate the prognostic relevance of sPD-L1 and sPD-1 in patients with different tumor entities who underwent ICI therapy.

Methods: We searched for articles in PubMed via Medline, Embase, Scopus, and Cochrane databases. The primary outcome was overall survival (OS) and progression-free survival (PFS); furthermore, we analyzed on-treatment serum level changes of sPD-L1 and sPD-1 during ICI therapy.

Results: We synthesized the data of 1,054 patients with different cancer types from 15 articles. Pooled univariate analysis showed that elevated levels of sPD-L1 were significantly associated with inferior OS (HR = 1.67; CI:1.26-2.23, I2 = 79%, p < 0.001). The strongest association was found in non-small cell lung cancer, whereas weaker or no association was observed in melanoma as well as in renal cell and esophageal cancers. Pooled multivariate analysis also showed that elevated levels of sPD-L1 correlated with worse OS (HR = 1.62; CI: 1.00-2.62, I2 = 84%, p = 0.05) and PFS (HR = 1.71; CI:1.00-2.94, I2 = 82%, p = 0.051). Furthermore, we observed that one or three months of anti-PD-L1 treatment caused a strong (27.67-fold) elevation of sPD-L1 levels in malignant mesothelioma and urothelial cancer.

Conclusions: We found significantly inferior OS in ICI-treated cancer patients with elevated pre-treatment sPD-L1 levels, but this association seems to be tumor type dependent. In addition, sPD-L1 increases during anti-PD-L1 therapy seems to be therapy specific.

© 2022. The Author(s).

In plain English

This systematic review and meta-analysis did not study asbestos exposure. The authors searched four databases for studies of cancer patients treated with immune checkpoint inhibitors. Studies had to compare survival between patients with high and low blood levels of soluble PD-L1 (sPD-L1) or soluble PD-1. They included 16 articles covering 1,054 patients. Cancer types were non-small cell lung cancer (NSCLC), renal cell carcinoma, melanoma, esophageal squamous cell cancer, urothelial cancer and mesothelioma. Pooled across 13 articles, high pre-treatment sPD-L1 was associated with worse overall survival (HR 1.67; CI 1.26 to 2.23). The association was strongest in NSCLC (HR 2.93; CI 2.52 to 3.40). For progression-free survival, the pooled estimate found no statistically significant association (HR 1.20; CI 0.85 to 1.70). sPD-L1 stayed unchanged under anti-PD-1 drugs. In the two anti-PD-L1 studies, in urothelial cancer and mesothelioma, levels rose a median 27.67-fold. In the mesothelioma study, median sPD-L1 rose from 70.0 pg/mL (29 patients) to 1960.0 pg/mL (14 patients) during treatment. The authors concluded that the survival association seems tumor type dependent. They named differences between the included studies as a limitation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: systematic review and meta-analysis of published studies, searching PubMed, Scopus, Embase and the Cochrane library
• Who was studied: 1,054 cancer patients treated with immune checkpoint inhibitors, drawn from 16 published articles (14 pooled statistically, 2 described only). Cancer types were NSCLC, renal cell carcinoma, melanoma, esophageal squamous cell cancer, urothelial cancer and mesothelioma. The mesothelioma study was a single Italian study of 40 patients treated with durvalumab and tremelimumab.
• Exposure: High versus low blood (serum or plasma) levels of soluble PD-L1 and/or soluble PD-1 before immune checkpoint inhibitor treatment. No asbestos exposure was studied.
• Main results:
  • All tumor types pooled (13 articles, univariate): high pre-treatment sPD-L1 was associated with worse overall survival, HR 1.67 (CI 1.26 to 2.23), p less than 0.001.
  • Four articles with multivariate analysis, pooled: high sPD-L1 was associated with shorter overall survival, HR 1.62 (CI 1.00 to 2.62), p = 0.05.
  • NSCLC subgroup (six studies): high sPD-L1 was associated with poor overall survival, HR 2.93 (CI 2.52 to 3.40).
  • Melanoma subgroup (three publications): overall survival was poorer with high sPD-L1, HR 1.73 (CI 1.01 to 2.97), p = 0.047.
  • Mixed tumor types subgroup: no statistically significant overall survival difference between high and low sPD-L1, HR 1.22 (CI 0.86 to 1.72), p = 0.263.
  • Progression-free survival, all tumor types pooled (11 articles, univariate): no statistically significant difference between high and low sPD-L1 groups, HR 1.20 (CI 0.85 to 1.70), p = 0.305.
  • Progression-free survival, NSCLC subgroup: high sPD-L1 was a risk factor, HR 2.08 (CI 1.81 to 2.38).
  • Levels during treatment: sPD-L1 remained unchanged under anti-PD-1 therapy. Under anti-PD-L1 therapy, levels rose a median 27.67-fold. This median comes from the only two anti-PD-L1 studies in Table 2, one in urothelial cancer (27.34-fold) and one in mesothelioma (28.00-fold).
  • Mesothelioma study (anti-PD-L1): median sPD-L1 was 70.0 pg/mL in 29 patients before treatment and 1960.0 pg/mL in 14 patients after 1 to 3 months of treatment, a 28.00-fold change.
• The authors' conclusion: The authors concluded that ICI-treated cancer patients with high baseline sPD-L1 had significantly worse overall survival, but that this association seems to depend on tumor type. They said the biological background and clinical significance of the sPD-L1 rise during anti-PD-L1 treatment need further study.
• Limitations the authors state:
  • The included studies differed in cohort size, tumor type, the immune checkpoint drugs used, and the cut-off values for high and low levels.
  • Radiographic response data were not available.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: PD-L1, Overall Survival, checkpoint inhibitors, Systematic Review, Meta-Analysis, Biomarker, Progression-Free Survival, Non-Small Cell Lung Cancer.

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