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Ann Oncol. 2019 Apr 1;30(4):589-596. doi: 10.1093/annonc/mdz019.

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.

Author information

1
Departments of Dermatology.
2
Biostatistics, Johns Hopkins University SOM, Baltimore.
3
The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins, Baltimore.
4
Department of Pathology, Johns Hopkins University SOM, Baltimore.
5
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston.
7
Fred Hutchinson Cancer Research Center, University of Washington, Seattle.
8
Earle A. Chiles Research Institute, Providence Cancer Center, Portland.
9
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University SOM, Baltimore.
10
Bristol-Myers Squibb, Princeton, USA.

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.

KEYWORDS:

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

PMID:
30689736
PMCID:
PMC6503625
DOI:
10.1093/annonc/mdz019

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