Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.

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Guidelines for pathologic evaluation of neoadjuvant specimens and pathologic response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the OpACIN-neo clinical trial of neoadjuvant combination anti-PD1/anti-CTLA4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS), and evaluate proposed INMC pathologic response categories for predicting recurrence and RFS.Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapy response score (ITRS). For a subset of cases (n=29), cellular composition of the tumour bed was analysed by flow cytometry.There was strong interobserver reproducibility in assessment of pathological response (ϰ=0.879) and percentage residual viable melanoma (ICC=0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P=0.008) and prolonged RFS (P=0.019). Amongst patients with criteria for pathologic non-response (pNR, >50% viable tumour), all who recurred had >70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P=0.002 and P=<0.0001). The number of B-lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P=0.046).There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of >70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.

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Authors: R V Rawson, C Adhikari, C Bierman, S Lo, E Shklovskaya, E A Rozeman, A M Menzies, A C J van Akkooi, K F Shannon, M Gonzalez M, A D Guminski, M T Tetzlaff, J R Stretch, H Eriksson, J V van Thienen, M W Wouters, J B A G Haanen, W M C Klop, C L Zuur, W J van Houdt, O E Nieweg, S Ch’ng, H Rizos, R P M Saw, A J Spillane, J S Wilmott, C U Blank, G V Long, B A van de Wiel, R A Scolyer