Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response

J. E. Stein, A. Soni, Liudmila V Danilova, T. R. Cottrell, T. F. Gajewski, F. S. Hodi, S. Bhatia, W. J. Urba, William Sharfman, M. Wind-Rotolo, R. Edwards, Evan Lipson, Janis M Taube

Research output: Contribution to journalArticle

Abstract

BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.

Original languageEnglish (US)
Pages (from-to)589-596
Number of pages8
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Volume30
Issue number4
DOIs
StatePublished - Apr 1 2019

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Secondary Prevention
Melanoma
Biomarkers
Biopsy
Therapeutics
Survival
Neoplasms
Immune System Diseases
Residual Neoplasm
Hematoxylin
Eosine Yellowish-(YS)
Plasma Cells
Wound Healing
Fibrosis
Necrosis

Keywords

  • melanoma
  • MPR
  • MPRbx
  • pathologic response
  • pathology
  • PD-1

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1 : evidence for an early, on-therapy biomarker of response. / Stein, J. E.; Soni, A.; Danilova, Liudmila V; Cottrell, T. R.; Gajewski, T. F.; Hodi, F. S.; Bhatia, S.; Urba, W. J.; Sharfman, William; Wind-Rotolo, M.; Edwards, R.; Lipson, Evan; Taube, Janis M.

In: Annals of oncology : official journal of the European Society for Medical Oncology, Vol. 30, No. 4, 01.04.2019, p. 589-596.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10{\%} residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95{\%}CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50{\%}) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.",
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author = "Stein, {J. E.} and A. Soni and Danilova, {Liudmila V} and Cottrell, {T. R.} and Gajewski, {T. F.} and Hodi, {F. S.} and S. Bhatia and Urba, {W. J.} and William Sharfman and M. Wind-Rotolo and R. Edwards and Evan Lipson and Taube, {Janis M}",
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T1 - Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1

T2 - evidence for an early, on-therapy biomarker of response

AU - Stein, J. E.

AU - Soni, A.

AU - Danilova, Liudmila V

AU - Cottrell, T. R.

AU - Gajewski, T. F.

AU - Hodi, F. S.

AU - Bhatia, S.

AU - Urba, W. J.

AU - Sharfman, William

AU - Wind-Rotolo, M.

AU - Edwards, R.

AU - Lipson, Evan

AU - Taube, Janis M

PY - 2019/4/1

Y1 - 2019/4/1

N2 - BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.

AB - BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.

KW - melanoma

KW - MPR

KW - MPRbx

KW - pathologic response

KW - pathology

KW - PD-1

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DO - 10.1093/annonc/mdz019

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JO - Annals of Oncology

JF - Annals of Oncology

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