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.

• Authors: J E Stein, A Soni, L Danilova, T R Cottrell, T F Gajewski, F S Hodi, S Bhatia, W J Urba, W H Sharfman, M Wind-Rotolo, R Edwards, E J Lipson, J M Taube
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 30 Issue 4 Pg. 589-596 (04 01 2019) ISSN: 1569-8041 [Electronic] England
• PMID: 30689736 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)
• Copyright: © 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: [email protected].

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• Biomarkers, Tumor
• Ipilimumab
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Nivolumab
• pembrolizumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Antineoplastic Agents, Immunological (pharmacology, therapeutic use)
• Biomarkers, Tumor (analysis)
• Biopsy
• Female
• Humans
• Ipilimumab (pharmacology, therapeutic use)
• Kaplan-Meier Estimate
• Male
• Melanoma (drug therapy, immunology, mortality, pathology)
• Middle Aged
• Neoplasm, Residual
• Nivolumab (pharmacology, therapeutic use)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology)
• Prospective Studies
• Response Evaluation Criteria in Solid Tumors
• Skin (drug effects, pathology)
• Skin Neoplasms (drug therapy, immunology, mortality, pathology)