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Serum immune modulators associated with immune-related toxicities and efficacy of atezolizumab in patients with non-small cell lung cancer

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Abstract

Purpose

Identifying patients at high risk of immune-related adverse events (irAEs) that impede the achievement of durable efficacy of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy is important in improving their management. Identification of a novel predictive factor of therapeutic benefit is also important in improving patient selection for treatment with PD-1/PD-L1 inhibitors. Further determinants driving response and linking with irAEs are urgently required.

Methods

To address these unmet needs in the field, we explored whether 27 soluble checkpoint proteins and immunomodulatory proteins in serum at the therapy baseline and after week 3 were associated with irAE onset and therapeutic efficacy using MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel assays in a prospective, multicenter cohort of 81 patients with non-small cell lung cancer (NSCLC) receiving atezolizumab monotherapy.

Results

By competing-risks regression analysis, we identified that high levels of B cell-activating factor (BAFF) at baseline were a significant and strong risk factor of irAEs (hazard ratio, 5.61; 95% confidence interval, 2.43–12.96; P < 0.0001). We also identified that increased inducible T cell co-stimulator (ICOS) during the first therapeutic cycle was an independent factor associated with prolonged progression-free survival and overall survival.

Conclusion

These findings are in keeping with the reported mechanistic basis of these molecules and may provide potential guidance for clinical decision-making to improve patient care. Further validation studies are warranted.

Trial registration UMIN000035616 (January 28, 2019)

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BAFF:

B cell-activating factor

BTLA:

B and T lymphocyte attenuator

CD40L:

CD40 ligand

CI:

Confidence interval

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

DNAM-1:

DNAX accessory molecule 1

FGL1:

Fibrinogen-like protein 1

GITR:

Glucocorticoid-induced TNFR-related protein

GITRL:

GITR ligand

HR:

Hazard ratio

HVEM:

Herpesvirus entry mediator

ICI:

Immune-checkpoint inhibitor

ICOS:

Inducible T cell co-stimulator

ICOSL:

ICOS ligand

irAE:

Immune-related adverse event

LAG-3:

Lymphocyte-activation gene 3

LIPI:

Lung immune prognostic index

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PD-1:

Programmed cell death 1

PD-L1:

Programmed death ligand 1

PD-L2:

Programmed death ligand 2

PFS:

Progression-free survival

PVR:

Poliovirus receptor cell adhesion molecule

TIM-3:

T cell immunoglobulin and mucin-domain containing-3

TLR-2:

Toll-like receptor 2

4-1BBL:

4-1BB ligand

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Acknowledgements

The authors would like to thank the patients, their families, and all the investigators who participated in this study. We also thank H. Nikki March, Ph.D., from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported by Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan

    Yusuke Inoue, Naoki Inui, Masato Karayama, Hideki Yasui, Hironao Hozumi, Yuzo Suzuki, Kazuki Furuhashi, Noriyuki Enomoto, Tomoyuki Fujisawa & Takafumi Suda

  2. Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan

    Yusuke Inoue & Naoki Inui

  3. Department of Clinical Oncology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan

    Masato Karayama

  4. Department of Respiratory Medicine, Shizuoka General Hospital, 4-27-1 Kita-ando, Shizuoka, 420-8527, Japan

    Kazuhiro Asada

  5. Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda, 426-8677, Japan

    Shun Matsuura

  6. Department of Respiratory Medicine, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Shizuoka, 422-8527, Japan

    Masaki Ikeda

  7. Department of Respiratory Medicine, Iwata City Hospital, 512-3 Ohkubo, Iwata, 438-8550, Japan

    Tomohiro Uto

  8. Department of Respiratory Medicine, Shizuoka City Shizuoka Hospital, 10-93 Otemachi, Shizuoka, 420-8630, Japan

    Masato Fujii

  9. Department of Pulmonary Medicine, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, 430-8558, Japan

    Dai Hashimoto

  10. Department of Respiratory Medicine, Seirei Mikatahara General Hospital, 3453 Mikatahara, Hamamatsu, 433-8558, Japan

    Takashi Matsui

  11. Department of Respiratory Medicine, Japanese Red Cross Shizuoka Hospital, 8-2 Otemachi, Shizuoka, 420-0853, Japan

    Hiroyuki Matsuda

  12. Department of Respiratory Medicine, Shizuoka City Shimizu Hospital, 1231 Miyakami, Shizuoka, 424-8636, Japan

    Nao Inami

  13. Department of Respiratory Medicine, Hamamatsu Rosai Hospital, 25 Shougen-cho, Hamamatsu, 430-8525, Japan

    Mikio Toyoshima

  14. Department of Respiratory Medicine, Ensyu Hospital, 1-1-1 Chuou, Hamamatsu, 430-0929, Japan

    Yusuke Kaida

Authors
  1. Yusuke Inoue
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  2. Naoki Inui
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Contributions

Y.I.: Conceptualization, acquisition of data, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, validation, visualization, writing—original draft, writing—review and editing. N.I.: Conceptualization, acquisition of data, data curation, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, visualization, writing—original draft, writing—review and editing. M.K, K.A., S.M., M.I., T.U., M.F., D.H., T.M., H.M., N.I., M.T., Y.K., H.Y., H.H., Y.S., K.F., N.E., T.F., T.S: Acquisition of data, data curation, supervision, validation, writing—review and editing.

Corresponding author

Correspondence to Yusuke Inoue.

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Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Consent to participate

All patients provided written informed consent to participate in the study.

Ethics approval

This study was approved by the institutional review board at each site (Hamamatsu University School of Medicine, #18-164) and was conducted in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. This study was registered at the UMIN Clinical Trials Registry as UMIN000035616.

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432_2022_4193_MOESM1_ESM.tif

Supplementary file1 (TIF 961 KB) Supplementary Fig. S1. Subset analyses of BAFF according to EGFR genotype and prior treatment with immune checkpoint inhibitors (ICIs). a Serum BAFF values at therapeutic baseline in patients with EGFR wild-type (WT) tumors without prior ICI treatment (EGFR-WT, N = 56), EGFR-WT tumors with prior ICI treatment (ICI-rechallenged; N = 10), and EGFR-mutant tumors (N = 15). The Kruskal–Wallis test followed by adjustment using the method of Holm was applied. b Cumulative incidence curves for the onset of any-grade immune-related adverse events (irAEs) according to EGFR mutation status and history of prior ICI treatment. c and d Cumulative incidence curves for the onset of (c) any-grade irAEs and (d) pneumonitis according to serum BAFF levels in patients with EGFR-WT tumors without prior ICI treatment. e and f Cumulative incidence curves for the onset of (e) any-grade irAEs and (f) pneumonitis according to serum BAFF levels in patients with EGFR-mutant tumors.

432_2022_4193_MOESM2_ESM.tif

Supplementary file2 (TIF 937 KB) Supplementary Fig. S2. Prognostic impact of serum ICOS variation 3 weeks after atezolizumab initiation on progression-free survival (PFS) and overall survival (OS) in adenocarcinoma patients according to EGFR genotype. a. Kaplan–Meier curves of PFS according to serum ICOS variation in patients with EGFR-WT adenocarcinoma. b Kaplan–Meier curves of OS according to serum ICOS variation in patients with EGFR-WT adenocarcinoma. c Kaplan–Meier curves of PFS according to serum ICOS variation in patients with EGFR-mutant adenocarcinoma. d Kaplan–Meier curves of OS according to serum ICOS variation in patients with EGFR-mutant adenocarcinoma.

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Inoue, Y., Inui, N., Karayama, M. et al. Serum immune modulators associated with immune-related toxicities and efficacy of atezolizumab in patients with non-small cell lung cancer. J Cancer Res Clin Oncol 149, 2963–2974 (2023). https://doi.org/10.1007/s00432-022-04193-w

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