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

R V Rawson; C Adhikari; C Bierman; S N Lo; E Shklovskaya; E A Rozeman; A M Menzies; A C J van Akkooi; K F Shannon; M Gonzalez; 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

doi:10.1016/j.annonc.2021.03.006

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

Ann Oncol. 2021 Jun;32(6):766-777. doi: 10.1016/j.annonc.2021.03.006. Epub 2021 Mar 17.

Authors

R V Rawson¹, C Adhikari¹, C Bierman², S N Lo³, E Shklovskaya⁴, E A Rozeman², A M Menzies⁵, A C J van Akkooi², K F Shannon⁶, M Gonzalez³, A D Guminski⁷, M T Tetzlaff⁸, J R Stretch⁹, H Eriksson¹⁰, J V van Thienen², M W Wouters¹¹, J B A G Haanen², W M C Klop², C L Zuur², W J van Houdt², O E Nieweg⁹, S Ch'ng⁹, H Rizos⁴, R P M Saw⁹, A J Spillane⁵, J S Wilmott¹², C U Blank², G V Long⁵, B A van de Wiel², R A Scolyer¹³

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Departments of Tissue Pathology and Diagnostic Oncology, Sydney, Australia; Department of Melanoma Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia; NSW Health Pathology, Sydney, Australia.
² The Netherlands Cancer Institute, Amsterdam, The Netherlands.
³ Melanoma Institute Australia, The University of Sydney, Sydney, Australia.
⁴ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia.
⁵ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Royal North Shore Hospital, Sydney, Australia; Mater Hospital, Sydney, Australia.
⁶ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Departments of Tissue Pathology and Diagnostic Oncology, Sydney, Australia; Department of Melanoma Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia.
⁷ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Royal North Shore Hospital, Sydney, Australia; Mater Hospital, Sydney, Australia.
⁸ Department of Pathology, Dermatopathology and Oral Pathology Unit, The University of California, San Francisco, San Francisco, USA; Department of Dermatology, Dermatopathology and Oral Pathology Unit, The University of California, San Francisco, San Francisco, USA.
⁹ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Departments of Tissue Pathology and Diagnostic Oncology, Sydney, Australia; Department of Melanoma Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia; Mater Hospital, Sydney, Australia.
¹⁰ Theme Cancer, Skin Cancer Center/Department of Oncology, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
¹¹ The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
¹² Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
¹³ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Departments of Tissue Pathology and Diagnostic Oncology, Sydney, Australia; Department of Melanoma Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia; NSW Health Pathology, Sydney, Australia. Electronic address: Richard.Scolyer@health.nsw.gov.au.

PMID: 33744385
DOI: 10.1016/j.annonc.2021.03.006

Abstract

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.

Keywords: immunotherapy; metastatic melanoma; neoadjuvant; pathological response.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Humans
Immunotherapy
Ipilimumab
Melanoma* / drug therapy
Neoadjuvant Therapy
Reproducibility of Results
Skin Neoplasms* / drug therapy

Substances

Ipilimumab