Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC)
T R Cottrell, E D Thompson, P M Forde, J E Stein, A S Duffield, V Anagnostou, N Rekhtman, R A Anders, J D Cuda, P B Illei, E Gabrielson, F B Askin, N Niknafs, K N Smith, M J Velez, J L Sauter, J M Isbell, D R Jones, R J Battafarano, S C Yang, L Danilova, J D Wolchok, S L Topalian, V E Velculescu, D M Pardoll, J R Brahmer, M D Hellmann, J E Chaft, A Cimino-Mathews, J M Taube, T R Cottrell, E D Thompson, P M Forde, J E Stein, A S Duffield, V Anagnostou, N Rekhtman, R A Anders, J D Cuda, P B Illei, E Gabrielson, F B Askin, N Niknafs, K N Smith, M J Velez, J L Sauter, J M Isbell, D R Jones, R J Battafarano, S C Yang, L Danilova, J D Wolchok, S L Topalian, V E Velculescu, D M Pardoll, J R Brahmer, M D Hellmann, J E Chaft, A Cimino-Mathews, J M Taube
Abstract
Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed.
Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed.
Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002).
Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
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Source: PubMed