Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC)

• Published in: Nature medicine Vol. 27; no. 2; pp. 301 - 309
• Main Authors: Menzies, Alexander M., Amaria, Rodabe N., Rozeman, Elisa A., Huang, Alexander C., Tetzlaff, Michael T., van de Wiel, Bart A., Lo, Serigne, Tarhini, Ahmad A., Burton, Elizabeth M., Pennington, Thomas E., Saw, Robyn P. M., Xu, Xiaowei, Karakousis, Giorgos C., Ascierto, Paolo A., Spillane, Andrew J., van Akkooi, Alexander C. J., Davies, Michael A., Mitchell, Tara C., Tawbi, Hussein A., Scolyer, Richard A., Wargo, Jennifer A., Blank, Christian U., Long, Georgina V.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2021; Nature Publishing Group
• Subjects: 631/67/1813/1634; 692/308/53/2422; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biomedical and Life Sciences; Biomedicine; Cancer Research; Clinical trials; Consortia; Disease-Free Survival; Drug therapy; Female; Humans; Immunotherapy; Immunotherapy - adverse effects; Infectious Diseases; Ipilimumab - administration & dosage; Ipilimumab - adverse effects; Male; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - immunology; Melanoma - pathology; Metabolic Diseases; Middle Aged; Molecular Medicine; Molecular Targeted Therapy; Monoclonal antibodies; Neoadjuvant therapy; Neoadjuvant Therapy - adverse effects; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - pathology; Neurosciences; Nivolumab - administration & dosage; Nivolumab - adverse effects; Patient outcomes; Patients; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Proto-Oncogene Proteins B-raf - genetics; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Survival; Therapy; Toxicity; Young Adult; Australia
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-020-01188-3

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P  < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P  = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma. A pooled analysis of neoadjuvant immunotherapy trials in melanoma shows that the degree of pathological response associates with patient survival and might represent a surrogate marker for long-term outcomes.