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)

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 (MPR) 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. Pre-treatment tumor biopsies and pre-resection 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 (1) immune activation—dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (2) massive tumor cell death—cholesterol clefts; and (3) tissue repair—neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders vs. non-responders, p < 0.05). This distinct constellation of histologic findings was not identified in any pre-treatment 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 inter-observer consistency compared to %cRVT [median per-case %RVT variability 5% (0-29%) vs. 10% (0-58%), p = 0.007] and a two-fold decrease in median standard deviation across pathologists within a sample (4.6 vs. 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.