Figure 1. Radiographic and gross pathologic measurements of ‘tumor mass’ include areas of immune-mediated tumor ... Figure 1. Radiographic and gross pathologic.

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Figure 1. Radiographic and gross pathologic measurements of ‘tumor mass’ include areas of immune-mediated tumor ... Figure 1. Radiographic and gross pathologic measurements of ‘tumor mass’ include areas of immune-mediated tumor regression. (A) There is a significant correlation between the radiographic measurement of the post-treatment lung mass on CT scan and pathologic measurement of the mass in the resected lung specimen. The grossly measured mass includes the microscopically evident regression bed. (B) Representative example of post-neoadjuvant anti-PD-1 treatment lung mass measured on CT scan and the corresponding resected lung specimen. The mass measures ∼3.8 cm in greatest dimension by both modalities, though microscopic examination shows the mass is composed of only 50% RVT. (C) Microscopic examination reveals post-treatment lung masses are composed of varying proportions of fibroinflammatory regression stroma and RVT. Representative photomicrographs from a complete pathologic responder (top), partial pathologic responder (middle; residual tumor with black asterisk, regression bed with white asterisk), and tumors showing no treatment effect (bottom). Original magnification: ×400, all panels. Unless provided in the caption above, the following copyright applies to the content of this slide: © The Author(s) 2018. 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.This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) Ann Oncol, Volume 29, Issue 8, 06 June 2018, Pages 1853–1860, https://doi.org/10.1093/annonc/mdy218 The content of this slide may be subject to copyright: please see the slide notes for details.

Figure 2. Histologic features of pathologic response to neoadjuvant anti-PD-1 in NSCLC. (A) Post-treatment NSCLC ... Figure 2. Histologic features of pathologic response to neoadjuvant anti-PD-1 in NSCLC. (A) Post-treatment NSCLC specimens with MPR to therapy showed a distinct pattern of immune-mediated tumor regression, characterized by histologic features of immune activation, tumor cell death, and tissue repair. (B) Association of individual histologic features with MPR/complete pathologic response. Unless provided in the caption above, the following copyright applies to the content of this slide: © The Author(s) 2018. 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.This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) Ann Oncol, Volume 29, Issue 8, 06 June 2018, Pages 1853–1860, https://doi.org/10.1093/annonc/mdy218 The content of this slide may be subject to copyright: please see the slide notes for details.

Figure 3. Individual features of pathologic response co-localize in the regression bed surrounding residual tumor. (A) ... Figure 3. Individual features of pathologic response co-localize in the regression bed surrounding residual tumor. (A) Features of pathologic response identified in MPR specimens are also present in the regression bed of ‘partially responding tumors’. However, the tumors from patients 11, 14, and 16 (black box outlines on heat map) had minimal features suggestive of immune-mediated regression. These cases were notable for immune exclusion (patient 11, see Figure 5) and disease relapse (patients 14 and 16). (B) Photomicrograph of a partial responder with 30% cRVT (blue outline). The regression bed (green outline) typically surrounds the residual tumor foci, suggesting an ‘outside-in’ pattern of tumor regression. (C) A patient with a partially responding keratinizing, squamous cell NSCLC (bottom panel) had a regression bed containing residual keratin pearls (top panel, asterisk), further supporting the interpretation of this distinctive peritumoral region as ‘regression bed’. (D) Features of immune-mediated pathologic response may also be identified in lymph nodes, as shown here for patient 4. The double-headed arrow denotes the extent of the regression bed, which is positioned between normal lymph node tissue (asterisk) and RVT (black outline). These findings are notable, as they suggest that immune-mediated responses can be identified and potentially quantified using irPRC, even in tissues normally rich in immune cells. Additionally, the histologic features of regression bed are distinctive enough that responses in previously undiagnosed microscopic disease may also potentially be estimated. Original magnifications: (B) ×20, (C) ×400, (D) ×20 (top panel), and ×200 (bottom panels). Unless provided in the caption above, the following copyright applies to the content of this slide: © The Author(s) 2018. 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.This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) Ann Oncol, Volume 29, Issue 8, 06 June 2018, Pages 1853–1860, https://doi.org/10.1093/annonc/mdy218 The content of this slide may be subject to copyright: please see the slide notes for details.

Figure 4. Proposal for reproducible, quantitative irPRC Figure 4. Proposal for reproducible, quantitative irPRC. (A) %irRVT is assessed by dividing the total surface area of ... Figure 4. Proposal for reproducible, quantitative irPRC. (A) %irRVT is assessed by dividing the total surface area of RVT (circled in blue) by the total tumor bed area ×100. The total tumor bed area (circled in green) is composed of the regression bed area+RVT area+areas of necrosis (supplementary Table S1, available at Annals of Oncology online). The lymph node RVT (LN-irRVT) is calculated separately, but using the same approach, i.e. by measuring the cross-sectional area of RVT and dividing by total tumor bed area. If there are multiple lymph node foci, the areas of each component are summed together to give a %LN-irRVT that represents the total tumor burden in all the lymph nodes assessed. (B) irPRC improves interpathologist reproducibility for percent RVT (%irRVT). Four pathologists blinded to clinical outcome were trained on the tumor from patient 1, and then scored tumors from patients 2 to 20 by both irPRC and chemotherapy criteria. The mean±SD %irRVT and %cRVT scores for each case are shown in black and blue, respectively. Strong concordance was observed among pathologists for the specimens with very little residual tumor when using either the chemotherapy criteria or irPRC. In contrast, large discrepancies in scores for %cRVT were seen in specimens from partial responders. (C) The interpathologist variability in scoring of each case is presented as the range of %RVT scores from four pathologists using the chemotherapy (cRVT) and immune-related (irRVT) criteria (left), shown by blue and black lines, respectively. For each method, the median overall range is presented (right). The proposed immune-related response criteria significantly reduce interpathologist variability in scoring relative to the chemotherapy criteria in these post-immunotherapy specimens. Unless provided in the caption above, the following copyright applies to the content of this slide: © The Author(s) 2018. 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.This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) Ann Oncol, Volume 29, Issue 8, 06 June 2018, Pages 1853–1860, https://doi.org/10.1093/annonc/mdy218 The content of this slide may be subject to copyright: please see the slide notes for details.