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Predictive value of serum VEGF levels for elderly patients or for patients with poor performance status receiving anti-PD-1 antibody therapy for advanced non-small-cell lung cancer

Cancer Immunology, Immunotherapy volume 69, pages 1229–1236 (2020)Cite this article

Abstract

The efficacy of immune checkpoint inhibitors (ICIs) in elderly and poor performance status (PS) patients is controversial, because clinical evidence is limited. This study aimed to find a predictive biomarker for the efficacy of anti-programmed cell death 1 (PD-1) antibodies in these patient populations. We retrospectively reviewed medical records of advanced non-small-cell lung cancer (NSCLC) patients who were ≥ 75 years of age or classified as PS 2 and received anti-PD-1 antibody treatment between December 2015 and May 2018. We evaluated the association between the efficacy of the anti-PD-1 antibody in these patients and the clinical variables thought to affect ICI efficacy. A total of 235 patients with advanced NSCLC were treated with anti-PD-1 antibodies, among whom 31 patients were ≥ 75 years of age and 22 were PS 2. A Cox proportional hazard model showed that only high levels of serum vascular endothelial growth factor (VEGF) were significantly associated with a shorter progression-free survival in patients aged ≥ 75 years and those with PS 2. Among these cohorts, the overall response rate to anti-PD-1 treatment tended to be lower when serum VEGF was high compared to patients with low serum VEGF. Our results demonstrate that serum VEGF concentration may be a negative predictive biomarker in elderly and poor PS advanced NSCLC patients receiving anti-PD-1 antibody treatment. This finding may help identify patients who will not benefit from anti-PD-1 antibody therapy.

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Abbreviations

CI:

Confidence interval

DCR:

Disease control rate

ECOG:

Eastern Cooperative Oncology Group

HR:

Hazard ratio

ICI:

Immune checkpoint inhibitor

NR:

Not reached

NSCLC:

Non-small-cell lung cancer

ORR:

Overall response rate

OS:

Overall survival

PD-1:

Programmed cell death 1

PD-L1:

Programmed death-ligand 1

PFS:

Progression-free survival

PS:

Performance status

VEGF:

Vascular endothelial growth factor

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Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

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Affiliations

  1. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan

    Ryota Shibaki, Shuji Murakami, Yuki Shinno, Yuji Matsumoto, Tatsuya Yoshida, Yasushi Goto, Shintaro Kanda, Hidehito Horinouchi, Yutaka Fujiwara, Noboru Yamamoto & Yuichiro Ohe

  2. Department of Pulmonary Medicine and Oncology, Wakayama Medical University, Wakayama, Japan

    Ryota Shibaki & Nobuyuki Yamamoto

Authors
  1. Ryota Shibaki
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  2. Shuji Murakami
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Contributions

RS contributed to the collection of clinical data, data quality control, statistical data analysis, interpretation of results, and writing of the manuscript. SM interpreted the results and participated in writing the manuscript. YS, YM, TY, YG, SK, HH, YF, Nobuyuki Y, Noboru Y, and YO contributed to manuscript writing and editing. All authors have approved the manuscript’s final version.

Corresponding author

Correspondence to Shuji Murakami.

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Conflict of interest

Shuji Murakami has served on speakers’ bureaus for Taiho Pharmaceutical and Ono Pharmaceutical. Yasushi Goto has held consulting/advisory roles for Taiho Pharmaceutical; served on speakers’ bureaus for Taiho Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, and Merck Sharp and Dohme (MSD); and received research funding from Taiho Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. Shintaro Kanda has received research funding from Ono Pharmaceutical and honoraria from Ono Pharmaceutical and Bristol-Myers Squibb. Hidehito Horinouchi has received research funding from MSD, Bristol-Myers Squibb, Ono Pharmaceutical, and Taiho Pharmaceutical. Yutaka Fujiwara has received research funding from MSD and served on speakers’ bureaus for MSD, Taiho Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. Nobuyuki Yamamoto has held consulting/advisory roles for Taiho Pharmaceutical; served on speakers’ bureaus for Ono Pharmaceutical, Bristol-Myers Squibb, and MSD; and received honoraria from Ono Pharmaceutical and MSD. Noboru Yamamoto has received research funding from Taiho Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical; and served on speakers’ bureaus for Bristol-Myers Squibb and Ono Pharmaceutical. Yuichiro Ohe has received research funding from Taiho Pharmaceutical and MSD and honoraria from Taiho Pharmaceutical and MSD. All remaining authors declare no conflicts of interest.

Ethical approval

This study was approved by the Institutional Review Board of the National Cancer Center Hospital, Tokyo, Japan, and has been performed in accordance with the ethical standards described in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards (No. 2018–268).

Informed consent

Informed consent was not obtained from each patient, because this retrospective analysis of existing data did not require any interaction with patients and did not intervene in their treatment.

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262_2020_2539_MOESM1_ESM.tif

Supplementary Fig. 1 Patient selection for (a) elderly and (b) ECOG PS 2 cohorts. ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non-small cell lung cancer; PD-1, programmed cell death 1 (TIFF 996 kb)

262_2020_2539_MOESM2_ESM.tif

Supplementary Fig. 2 Receiver operating characteristic curves for serum VEGF based on progression for three months. VEGF, vascular endothelial growth factor; ECOG PS, Eastern Cooperative Oncology Group performance status (TIFF 1794 kb)

262_2020_2539_MOESM3_ESM.tif

Supplementary Fig. 3 Kaplan–Meier curves of TTF for (a) elderly and (b) ECOG PS 2 patients. TTF, time to treatment failure; ECOG PS, Eastern Cooperative Oncology Group performance status; VEGF, vascular endothelial growth factor (TIFF 1794 kb)

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Shibaki, R., Murakami, S., Shinno, Y. et al. Predictive value of serum VEGF levels for elderly patients or for patients with poor performance status receiving anti-PD-1 antibody therapy for advanced non-small-cell lung cancer. Cancer Immunol Immunother 69, 1229–1236 (2020). https://doi.org/10.1007/s00262-020-02539-2

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  • DOI: https://doi.org/10.1007/s00262-020-02539-2

Keywords

  • Anti-PD-1 antibody
  • Elderly
  • Non-small-cell lung cancer
  • Performance status
  • Vascular endothelial growth factor