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Soluble interleukin-2 receptor as a predictive biomarker for poor efficacy of combination treatment with anti-PD-1/PD-L1 antibodies and chemotherapy in non-small cell lung cancer patients

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Abstract

Soluble interleukin-2 receptor (sIL-2R) suppresses effector T-cells. Few studies have assessed serum sIL-2R in patients receiving immunotherapy. We evaluated the association between serum sIL-2R levels and the efficacy of anti-programmed cell death 1/ programmed death-ligand 1 (anti-PD-1/PD-L1) antibody combined with chemotherapy in non-small cell lung cancer (NSCLC) patients. We prospectively enrolled NSCLC patients who received anti-PD-1/PD-L1 antibody combined with platinum-based chemotherapy between 8/2019 and 8/2020 and measured their serum sIL-2R. The patients were divided into high and low sIL-2R groups based on the median of sIL-2R levels at pretreatment. Progression-free survival (PFS) and overall survival (OS) of patients in the high and low sIL-2R groups were compared. The Kaplan–Meier curves of PFS and OS were evaluated using the log-rank test. The multivariate analysis of PFS and OS was performed using the Cox proportional hazard models. Among 54 patients (median age 65, range 34–84), 39 were male and 43 had non-squamous cell carcinoma. The sIL-2R cut-off value was 533 U/mL. Median PFS was 5.1 months (95% CI, 1.8–7.5 months) and 10.1 months (95% CI, 8.3-not reached [NR] months) in the high and low sIL-2R groups (P = 0.007), respectively. Median OS was 10.3 months (95% CI, 4.0–NR months) and NR (95% CI, 10.3–NR months) in the high and low sIL-2R groups (P = 0.005), respectively. Multivariate Cox regression analysis showed that high sIL-2R was significantly associated with shorter PFS and OS. SIL-2R may be a biomarker for the poor efficacy of anti-PD-1/PD-L1 antibody combined with chemotherapy.

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Data Availability

The datasets in this study are available from the corresponding author on reasonable request.

Abbreviations

ALK:

anaplastic lymphoma kinase rearrangement

CI:

confidence intervals

EGFR:

Epidermal growth factor receptor

HR:

Hazard ratio

PD-L1:

programmed cell death-ligand 1

PS:

performance status

S-IL2R:

soluble interleukin 2 receptor

Sq:

squamous cell carcinoma

TPS:

tumor proportion score

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Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Funding

This research received no specific grant.

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Authors and Affiliations

  1. Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Takehiro Tozuka, Noriko Yanagitani, Hiroshi Yoshida, Ryo Manabe, Shinsuke Ogusu, Ryosuke Tsugitomi, Hiroaki Sakamoto, Yoshiaki Amino, Ryo Ariyasu, Ken Uchibori, Satoru Kitazono & Makoto Nishio

  2. Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan

    Takehiro Tozuka, Masahiro Seike & Akihiko Gemma

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  1. Takehiro Tozuka
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Contributions

Study concept and design: TT, SK, MN. Acquisition and analysis of data and statistical analysis: TT, NY, HY, RM, SO, RT, HS, YA, RA, KU, SK, MN. Interpretation of data and drafting of the manuscript: TT, NY, HY, RM, SO, RT, HS, YA, RA, KU, SK, MS, AG, MN. Critical revision of the manuscript for important intellectual content: TT, NY, MS, AG, MN. Study supervision: MN. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Makoto Nishio.

Ethics declarations

Ethics approval

This study was approved by the Ethics Committee of the Cancer Institute Hospital, Japanese Foundation for Cancer Research (approval number 2019 − 1043).

Consent to participate

Written informed consents were obtained from all the patients.

Competing interests

Makoto Nishio received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Boehringer-Ingelheim, MSD, Novartis; and received research funding from MSD, Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, Pfizer, Astellas; and had consulting/advisory roles for　Novartis, Daiichi Sankyo Healthcare, Taiho Pharmaceutical, Bristol Myers Squibb, Boehringer-ingelheim, Ono Pharmaceutical, Eli Lilly, Chugai Pharmaceutical, AstraZeneca, Merck Serono, MSD, Pfizer. Akihiko Gemma has received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo Healthcare, KYORIN Pharmaceutical, Accuray Japan, Boehringer-ingelheim, MSD, AstraZeneca, Kyowa Kirin, Otsuka Pharmaceutical, Eisai; and received research funding from Nippon Kayaku. Masahiro Seike has received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Boehringer-ingelheim, MSD; and received research funding from Taiho Pharmaceutical, Chugai Pharmaceutical, Boehringer-ingelheim. Noriko Yanagitani has received honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, MSD, Novartis, Bayer Yakuhin, and had consulting/advisory roles for Chugai Pharmaceutical. Ken Uchibori has received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Boehringer-ingelheim, and had consulting/advisory roles for　AstraZeneca, Chugai Pharmaceutical. Satoru Kitazono has received honoraria from Chugai Pharmaceutical Co., Ltd., MSD K.K., Bristol-Myers Squibb, ONO Pharmaceutical, AstraZeneca. All the other authors report no conflict of interest.

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Tozuka, T., Yanagitani, N., Yoshida, H. et al. Soluble interleukin-2 receptor as a predictive biomarker for poor efficacy of combination treatment with anti-PD-1/PD-L1 antibodies and chemotherapy in non-small cell lung cancer patients. Invest New Drugs 41, 411–420 (2023). https://doi.org/10.1007/s10637-023-01358-3

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