Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment

K. Haratani, H. Hayashi, T. Tanaka, H. Kaneda, Y. Togashi, K. Sakai, K. Hayashi, Shuta Tomida, Y. Chiba, K. Yonesaka, Y. Nonagase, T. Takahama, J. Tanizaki, K. Tanaka, T. Yoshida, K. Tanimura, M. Takeda, H. Yoshioka, T. Ishida, T. MitsudomiK. Nishio, K. Nakagawa

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Background: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.

Patients and methods: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).

Results: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.

Conclusion: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

Original languageEnglish
Pages (from-to)1532-1539
Number of pages8
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Volume28
Issue number7
DOIs
Publication statusPublished - Jul 1 2017
Externally publishedYes

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erbB-1 Genes
Tumor Microenvironment
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Disease Progression
Mutation
Ligands
Tumor-Infiltrating Lymphocytes
Therapeutics
Disease-Free Survival
nivolumab
Confidence Intervals
Exome
Neoplasms
Immunologic Factors
DNA Sequence Analysis
Immunohistochemistry

Keywords

  • epidermal growth factor receptor
  • nivolumab
  • non-small-cell lung cancer
  • PD-L1
  • T790M
  • tumor-infiltrating lymphocyte

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment. / Haratani, K.; Hayashi, H.; Tanaka, T.; Kaneda, H.; Togashi, Y.; Sakai, K.; Hayashi, K.; Tomida, Shuta; Chiba, Y.; Yonesaka, K.; Nonagase, Y.; Takahama, T.; Tanizaki, J.; Tanaka, K.; Yoshida, T.; Tanimura, K.; Takeda, M.; Yoshioka, H.; Ishida, T.; Mitsudomi, T.; Nishio, K.; Nakagawa, K.

In: Annals of oncology : official journal of the European Society for Medical Oncology, Vol. 28, No. 7, 01.07.2017, p. 1532-1539.

Research output: Contribution to journalArticle

Haratani, K, Hayashi, H, Tanaka, T, Kaneda, H, Togashi, Y, Sakai, K, Hayashi, K, Tomida, S, Chiba, Y, Yonesaka, K, Nonagase, Y, Takahama, T, Tanizaki, J, Tanaka, K, Yoshida, T, Tanimura, K, Takeda, M, Yoshioka, H, Ishida, T, Mitsudomi, T, Nishio, K & Nakagawa, K 2017, 'Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment', Annals of oncology : official journal of the European Society for Medical Oncology, vol. 28, no. 7, pp. 1532-1539. https://doi.org/10.1093/annonc/mdx183
Haratani, K. ; Hayashi, H. ; Tanaka, T. ; Kaneda, H. ; Togashi, Y. ; Sakai, K. ; Hayashi, K. ; Tomida, Shuta ; Chiba, Y. ; Yonesaka, K. ; Nonagase, Y. ; Takahama, T. ; Tanizaki, J. ; Tanaka, K. ; Yoshida, T. ; Tanimura, K. ; Takeda, M. ; Yoshioka, H. ; Ishida, T. ; Mitsudomi, T. ; Nishio, K. ; Nakagawa, K. / Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment. In: Annals of oncology : official journal of the European Society for Medical Oncology. 2017 ; Vol. 28, No. 7. pp. 1532-1539.
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abstract = "Background: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.Patients and methods: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).Results: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95{\%} confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1{\%} or <1{\%}, respectively (P = 0.084; hazard ratio of 0.37, 95{\%} confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10{\%} and ≥50{\%}. The proportion of tumors with a PD-L1 level of ≥10{\%} or ≥50{\%} was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.Conclusion: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.",
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TY - JOUR

T1 - Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment

AU - Haratani, K.

AU - Hayashi, H.

AU - Tanaka, T.

AU - Kaneda, H.

AU - Togashi, Y.

AU - Sakai, K.

AU - Hayashi, K.

AU - Tomida, Shuta

AU - Chiba, Y.

AU - Yonesaka, K.

AU - Nonagase, Y.

AU - Takahama, T.

AU - Tanizaki, J.

AU - Tanaka, K.

AU - Yoshida, T.

AU - Tanimura, K.

AU - Takeda, M.

AU - Yoshioka, H.

AU - Ishida, T.

AU - Mitsudomi, T.

AU - Nishio, K.

AU - Nakagawa, K.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Background: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.Patients and methods: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).Results: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.Conclusion: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

AB - Background: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.Patients and methods: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).Results: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.Conclusion: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

KW - epidermal growth factor receptor

KW - nivolumab

KW - non-small-cell lung cancer

KW - PD-L1

KW - T790M

KW - tumor-infiltrating lymphocyte

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U2 - 10.1093/annonc/mdx183

DO - 10.1093/annonc/mdx183

M3 - Article

C2 - 28407039

AN - SCOPUS:85027586380

VL - 28

SP - 1532

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JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

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