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

Background: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 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 pathological response categories for predicting recurrence and RFS.
Patients and Methods: 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 immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry.
Results: There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 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 pathological 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).
Conclusions: 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.
Competing Interests: Disclosure EAR received travel support from Merck Sharpe & Dohme (MSD) and NanoString. AMM reports personal fees as a consultant advisor for Bristol Myers Squibb (BMS), MSD, Novartis, Roche, Pierre Fabre and QBiotics. ACJvA reports personal fees as a consultant advisor for Amgen, BMS, Novartis, MSD Merck, Merck–Pfizer, Sanofi and 4SC, and received grant support from Amgen, BMS and Novartis all paid to the institution (The Netherlands Cancer Institute). ADG received travel support from Merck KgA and Sun Pharma and has served as a consultant advisor for BMS, Pfizer, Merck KgA, Regeneron and Sun Pharma. MTT reports Advisory Board with Merck, Myriad Genetics, Novartis, Seattle Genetics and NanoString. RPMS has received honoraria for advisory board participation from MSD, Novartis and QBiotics and speaking honoraria from BMS. AJS has received honoraria for advisory board participation from QBiotics and Stryker. CUB reports personal fees as a consultant advisor for BMS, MSD, Roche, Novartis, Lilly, Pfizer, GSK, GenMab and Pierre Fabre for which the institution (The Netherlands Cancer Institute) received funding, has received research grants from BMS, Novartis and NanoString all paid to the institution (The Netherlands Cancer Institute), is shareholder of Unity Cars and co-founder of Immagene BV and received personal compensation as consultant advisor from Third Rock Ventures. GVL reports personal fees as a consultant advisor to Aduro Biotech Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, BMS, Highlight Therapeutics S.L., MSD, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, and SkylineDx B.V. (all not related to this work). BAvdW reports advisory role for BMS. RAS has received professional services fees from QBiotics, Merck Sharp Dohme, BMS, Novartis, GlaxoSmithKline, Myriad and NeraCare (not related to this work). WJvH reports personal fees as a consultant advisor for Amgen and Sanofi. JH received (institutional fees for advisory roles in Achilles Tx, BioNTech, BMS, Ipsen, Immunocore, MSD, Merck Serono, Molecular Partners, PokeAcel, Pfizer, Roche, Sanofi, T-knife, Third Rock Ventures. JH received personal fees for advisory role in Neogene Tx. JH received institutional grant support from Amgen, BioNTech US, BMS, MSD, Neogene Therapeutics, Novartis. All other authors have declared no conflicts of interest.
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