@article{840d22c3da264104923246a3947e0fb5,
title = "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",
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",
author = "Stein, {J. E.} and A. Soni and L. Danilova and Cottrell, {T. R.} and Gajewski, {T. F.} and Hodi, {F. S.} and S. Bhatia and Urba, {W. J.} and Sharfman, {W. H.} and M. Wind-Rotolo and R. Edwards and Lipson, {E. J.} and Taube, {J. M.}",
note = "Funding Information: In addition, FSH has a patent {\textquoteleft}Methods for Treating MICA-Related Disorders{\textquoteright} (#20100111973) with royalties paid, a patent {\textquoteleft}Tumor antigens and uses thereof{\textquoteright} (#7250291) issued, a patent {\textquoteleft}Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response{\textquoteright} (#20170248603) pending, a patent {\textquoteleft}Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms{\textquoteright} (#20160340407) pending, a patent {\textquoteleft}Therapeutic peptides{\textquoteright} (#20160046716) pending, a patent {\textquoteleft}Therapeutic Peptides{\textquoteright} (#20140004112) pending, a patent {\textquoteleft}Therapeutic Peptides{\textquoteright} (#20170022275) pending, a patent {\textquoteleft}Therapeutic Peptides{\textquoteright} (#20170008962) pending, a patent {\textquoteleft}Therapeutic Peptides{\textquoteright} (#9402905) issued, and a patent {\textquoteleft}Methods Of Using Pembrolizumab and Trebananib{\textquoteright} pending. SB reports advisory board participation (with honorarium) from Genentech, EMD-Serono and Bristol-Myers-Squibb (BMS) and research funding to his institution (University of Washington) from Oncosec Medical Inc., EMD-Serono, Merck, BMS, NantKwest and Immune Design. WJU receives institutional research support from Bristol-Myers Squibb, Merck, and MedImmune, serves on a Data and Safety Monitoring Board and is a consultant for AstraZeneca, Celldex, and New Link Genetics. JMT receives institutional research funding from Bristol-Myers Squibb and serves as a consultant to Bristol-Myers Squibb, Amgen, Merck, and AstraZeneca. Funding Information: JES, AS, LD, and TRC have no relevant financial interests to report. WHS receives institutional research funding from and is a consultant for Bristol-Myers Squibb, Novartis, and Merck. RD and MW-R are employed at Bristol-Myers Squibb. EJL is a consultant for Array BioPharma, Bristol-Myers Squibb, EMD Serono, Macrogenics, Merck, Millennium, Novartis, Regeneron, Sanofi Genzyme, and receives institutional research funding from Bristol-Myers Squibb and Merck. TFG is a consultant for Merck, Bayer, Aduro, Jounce, FogPharma, Adaptimmune, and FivePrime; receives research support from Bristol-Myers Squibb, Merck, Genentech, Seattle Genetics, Incyte, Bayer, Ono, Aduro, and Evelo; has stock ownership in Jounce; and intellectual property licensing to Aduro and Evelo. FSH receives institutional research funding from Bristol-Myers Squibb and he receives personal fees for consultancy/advisory capacities from Bristol-Myers Squibb, Merck, EMD Serono, Novartis, Celldex, Amgen, Genentech/Roche, Incyte, Apricity, Bayer, Aduro, Partners Therapeutics, Sanofi, Pfizer, 7 Hills Pharma, Verastem. Funding Information: This work was supported by the Melanoma Research Alliance (JMT); Harry J. Lloyd Trust (JMT); the Emerson Collective (JMT); Moving for Melanoma of Delaware (EJL); the Barney Family Foundation (EJL); The Laverna Hahn Charitable Trust (EJL); The Roland Park Country School (EJL); Bristol-Myers Squibb (JMT, JES); Sidney Kimmel Cancer Center Core Grant P30 CA006973 (JMT, EJL, LD); National Cancer Institute R01 CA142779 (JMT); NIH T32 CA193145 (JES, AS, TRC); and The Bloomberg-Kimmel Institute for Cancer Immunotherapy. No funding organization or sponsor had a role in the design and conduct of the study, collection, management, analysis, and interpretation of the data. Bristol-Myers Squibb reviewed and approved the manuscript. Publisher Copyright: {\textcopyright} 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
year = "2019",
month = apr,
doi = "10.1093/annonc/mdz019",
language = "English (US)",
volume = "30",
pages = "589--596",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "4",
}