The combination of soluble forms of PD-1 and PD-L1 as a predictive marker of PD-1 blockade in patients with advanced cancers: a multicenter retrospective study

Our plain-English summary of The combination of soluble forms of PD-1 and PD-L1 as a predictive marker of PD-1 blockade in patients with advanced cancers: a multicenter retrospective study, by T. Kurosaki, K. Chamoto, S. Suzuki, et al (Frontiers in Immunology, 2023).

The study

• Authors: T. Kurosaki, K. Chamoto, S. Suzuki, H. Kanemura, S. Mitani, K. Tanaka, H. Kawakami, Y. Kishimoto, Y. Haku, K. Ito, T. Sato, C. Suminaka, M. Yamaki, Y. Chiba, T. Yaguchi, K. Omori, T. Kobayashi, K. Nakagawa, T. Honjo, H. Hayashi
• Journal: Frontiers in Immunology
• Published: 2023;14:1325462
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: The clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) remains unclear. We here investigated the relation between the efficacy of PD-1 blockade and pretreatment plasma levels of sPD-1 and sPD-L1 across a broad range of cancer types.

Methods: We retrospectively analyzed clinical data from 171 patients with advanced solid tumors who received nivolumab or pembrolizumab monotherapy regardless of treatment line. The concentrations of sPD-1 and sPD-L1 were measured with a fully automated immunoassay (HISCL system).

Results: The study subjects comprised patients with head and neck cancer (n = 50), urothelial cancer (n = 42), renal cell cancer (n = 37), gastric cancer (n = 20), esophageal cancer (n = 10), malignant pleural mesothelioma (n = 6), or microsatellite instability-high tumors (n = 6). High or low levels of sPD-1 or sPD-L1 were not significantly associated with progression-free survival (PFS) or overall survival (OS) for PD-1 blockade in the entire study population. Comparison of treatment outcomes according to combinations of high or low sPD-1 and sPD-L1 levels, however, revealed that patients with low sPD-1 and high sPD-L1 concentrations had a significantly poorer PFS (HR of 1.79 [95% CI, 1.13-2.83], p = 0.01) and a tendency toward poorer OS (HR of 1.70 [95% CI, 0.99-2.91], p = 0.05) compared with all other patients.

Conclusion: Our findings suggest that the combination of low sPD-1 and high sPD-L1 levels is a potential negative biomarker for PD-1 blockade therapy.

Copyright © 2023 Kurosaki, Chamoto, Suzuki, Kanemura, Mitani, Tanaka, Kawakami, Kishimoto, Haku, Ito, Sato, Suminaka, Yamaki, Chiba, Yaguchi, Omori, Kobayashi, Nakagawa, Honjo and Hayashi.

In plain English

This retrospective study at two Japanese university hospitals looked at 171 patients with advanced solid cancers treated with nivolumab or pembrolizumab, drugs that block PD-1. Six of the patients had malignant pleural mesothelioma. The study did not look at asbestos exposure. Before treatment, the authors measured blood levels of soluble PD-1 and soluble PD-L1. Each marker was classed high or low at the median for each cancer type. Neither marker alone was significantly linked to progression-free survival (time until the cancer worsened or the patient died from any cause) or to overall survival. Patients with low soluble PD-1 and high soluble PD-L1 had shorter progression-free survival than all others (median 2.3 vs. 4.3 months; hazard ratio 1.79, 95% CI 1.13–2.83). They also tended toward shorter overall survival (median 6.3 vs. 16.9 months; hazard ratio 1.70, 95% CI 0.99–2.91, p = 0.05). After adjustment for other factors, both links were statistically significant. The authors concluded that this combination is a potential negative biomarker needing prospective confirmation. They noted there was no validation group and too few patients to study single cancer types in detail.

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: multicenter retrospective study of patient records and stored pretreatment blood samples
• Who was studied: 171 patients with advanced solid tumors other than non-small cell lung cancer or melanoma, from Kindai University Hospital and Kyoto University Hospital, Japan: head and neck cancer 50, urothelial cancer 42, renal cell cancer 37, gastric cancer 20, esophageal cancer 10, malignant pleural mesothelioma 6, microsatellite instability-high tumors 6. Study dates are not given.
• Exposure: PD-1 antibody monotherapy (nivolumab in 121 patients, pembrolizumab in 50). Pretreatment plasma (or serum) levels of soluble PD-1 and soluble PD-L1 were measured with the HISCL automated immunoassay. High and low levels were split at the median for each cancer type. No asbestos exposure was studied.
• Main results:
  • All patients, high vs. low soluble PD-1: progression-free survival was numerically longer in the high group (median 4.5 vs. 3.0 months, HR 0.76, 95% CI 0.54–1.07, p = 0.11), but the difference was not statistically significant.
  • All patients, high vs. low soluble PD-L1: overall survival tended to be shorter in the high group (median 12.7 vs. 16.4 months, HR 1.32, 95% CI 0.88–1.97, p = 0.18); the association was not significant.
  • Low soluble PD-1 with high soluble PD-L1 vs. all other patients: significantly shorter progression-free survival (median 2.3 vs. 4.3 months, HR 1.79, 95% CI 1.13–2.83, p = 0.01).
  • Same comparison: numerically shorter overall survival (median 6.3 vs. 16.9 months, HR 1.70, 95% CI 0.99–2.91, p = 0.05).
  • In multivariable analysis, the low soluble PD-1 with high soluble PD-L1 combination was significantly associated with progression-free survival (HR 1.62, 95% CI 1.03–2.58, p = 0.04) and overall survival (HR 1.86, 95% CI 1.06–3.26, p = 0.03).
  • Overall response rate was numerically lower in the low soluble PD-1 with high soluble PD-L1 group than in other patients (16.7% vs. 34.7%, p = 0.08).
  • By cancer type, the combination was significantly associated with shorter progression-free and overall survival in urothelial cancer, but not in head and neck cancer or renal cell cancer.
  • In the 6 patients with malignant pleural mesothelioma, median soluble PD-1 was 148 pg/ml (IQR 112–171) and median soluble PD-L1 was 247 pg/ml (IQR 246–273).
• The authors' conclusion: The authors concluded that low soluble PD-1 combined with high soluble PD-L1 before treatment is a potential negative biomarker of progression-free and overall survival for PD-1 antibody monotherapy across cancer types. They said prospective evaluation is needed to confirm this.
• Limitations the authors state:
  • There was no validation cohort to confirm the chosen cutoff values.
  • There was no control group treated with chemotherapy or targeted drugs, so it is unclear whether the findings are specific to PD-1 antibodies.
  • Only PD-1 antibody monotherapy was studied, not combination treatments.
  • The sample size was too small for detailed analysis of specific cancer types.

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Nivolumab (Opdivo), Pembrolizumab (Keytruda), Stomach Cancer, Esophageal Cancer, Pleural Mesothelioma, Microsatellite Instability (MSI-H), Progression-Free Survival.

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• Combination of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of cancer - a brief update — J. Park, B.S. Skålhegg (2025)
• Safety and efficacy of PD-1/PD-L1 immune checkpoint inhibitors in patients with pre-treated advanced stage malignant mesothelioma: a systematic review and meta-analysis — A. Zafar, A.A. Rashid, et al. (2024)
• CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study — R.E. Sanborn, O. Hamid, et al. (2021)
• Trametinib plus 4-Methylumbelliferone Exhibits Antitumor Effects by ERK Blockade and CD44 Downregulation and Affects PD-1 and PD-L1 in Malignant Pleural Mesothelioma — H. Cho, S. Matsumoto, et al. (2017)
• A phase 2, multicenter, open-label study of anti-LAG-3 ieramilimab in combination with anti-PD-1 spartalizumab in patients with advanced solid malignancies — C.C. Lin, E. Garralda, et al. (2024)

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