Long et al. performed a pooled analysis of long-term efficacy of neoadjuvant ICB and targeted therapies in stage IIIB-D melanoma. Pathological response was higher for ICB than for BRAF/MEKis, and higher for combination ICB than anti-PD-1 alone. Pathological response was associated with event-free, recurrence-free, and overall survival. Patients who had a pathological response to neoadjuvant ICB did not benefit from adjuvant ICB.
ABSTRACT: Neoadjuvant immune checkpoint inhibitors (ICIs) are standard of care for resectable stage IIIB-D melanoma, but knowledge gaps remain regarding optimal treatment type, long-term survival, postsurgical management and clinical, histopathological or molecular subgroups. We analyzed 1,038 patients treated with neoadjuvant ICIs (n = 735), BRAF and MEK inhibitors (BRAF/MEKis; n = 119) or ICI plus any targeted therapy (ICI + TT; n = 184) from 26 international sites in both trial (755, 72.7%) and nontrial (283, 27.3%) settings. ICI regimens included anti-programmed cell death protein 1 (PD-1) alone (PD-1 alone; n = 242) and anti-PD-1 plus other immuno-oncology agent(s) (PD-1 + IO; n = 489). Outcomes included major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). An MPR was achieved in 57.8% of patients with ICIs, 51.4% with BRAF/MEKis and 44.6% with ICI + TT. PD-1 + IO elicited higher MPR rates than PD-1 alone (61.4% versus 49.5%). The 5-year RFS rate was 61.0% with PD-1 alone, 73.9% with PD-1 + IO, 37.4% with BRAF/MEKis and 76.4% with ICI + TT; the 5-year OS rates were 83.3%, 87.5%, 69.8% and 83.9%, respectively. ICI-treated patients with MPR had 5-year OS rates of 98.8% with PD-1 alone and 97.9% with PD-1 + IO and gained no benefit from continuing ICIs into the adjuvant setting. Neoadjuvant ICIs were active in BRAF-mutant melanoma (MPR, 46.3%), acral melanoma (38.1%), in-transit metastases (66.7%) and oligometastases (41.2%), although subgroup sizes and relative effectiveness varied. Survival outcomes were excellent with neoadjuvant ICIs, particularly in patients achieving MPR, but poor with BRAF/MEKis and mixed with ICI + TT. Predictive biomarker-driven trials, effective adjuvant strategies and subgroup-specific research are needed for nonresponders.
Author Info: (1) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Faculty of Health and Medicine, The University of Sydne
Author Info: (1) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Faculty of Health and Medicine, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. (2) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. Champalimaud Foundation, Lisbon, Portugal. (3) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. (4) Tygat Institute for Intestinal and Liver Research, Amsterdam UMC, Amsterdam, The Netherlands. (5) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. (6) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Fiona Stanley Hospital, University of Western Australia, Perth, Western Australia, Australia. (7) Universit degli Studi di Napoli 'Federico II', Naples, Italy. Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale', Naples, Italy. (8) University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. (10) Gustave Roussy, Dpartement de Mdecine Oncologique, Universit Paris-Saclay, Villejuif, France. (11) LMU University Hospital, Munich, Germany. (12) Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. (13) Centro de Referncia em Tumores Cutneos, AC Camargo Cancer Center, So Paulo, Brazil. (14) Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (15) H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (16) FSBI 'N. N. Blokhin National Medical Research Center of Oncology' of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. (17) University of Tbingen, Tbingen, Germany. (18) Universit Paris Cite, AP-HP Dermato-oncology and CIC, Cancer Institute APHP.nord Paris cit, INSERM U1342-Equipe-CNRS EMR8000, Saint Louis Hospital, Paris, France. (19) Vanderbilt University Medical Center, Nashville, TN, USA. (20) Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. (21) Vall d'Hebrn Hospital and Vall d'Hebrn Institute of Oncology (VHIO), Barcelona, Spain. (22) The Angeles Clinic and Research Institute, Los Angeles, CA, USA. (23) Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale', Naples, Italy. (24) Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale', Naples, Italy. (25) Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. (26) Gustave Roussy, Dpartement de Mdecine Oncologique, Universit Paris-Saclay, Villejuif, France. (27) Gustave Roussy, Dpartement de Mdecine Oncologique, Universit Paris-Saclay, Villejuif, France. (28) LMU University Hospital, Munich, Germany. (29) Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. (30) H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (31) FSBI 'N. N. Blokhin National Medical Research Center of Oncology' of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. (32) University of Tbingen, Tbingen, Germany. (33) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia. (34) University Medical Center Groningen, Groningen, The Netherlands. (35) Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. (36) European Institute of Oncology, IRCCS Milan, Milan, Italy. (37) Leiden University Medical Center, Leiden, The Netherlands. (38) Erasmus Medical Center, Rotterdam, The Netherlands. (39) University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. (40) Universit Paris Cite, AP-HP Dermato-oncology and CIC, Cancer Institute APHP.nord Paris cit, INSERM U1342-Equipe-CNRS EMR8000, Saint Louis Hospital, Paris, France. (41) Vanderbilt University Medical Center, Nashville, TN, USA. (42) Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. (43) The Angeles Clinic and Research Institute, Los Angeles, CA, USA. (44) Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. (45) Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. (46) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. (47) University of Texas MD Anderson Cancer Center, Houston, TX, USA. (48) University of Texas MD Anderson Cancer Center, Houston, TX, USA. (49) University of California San Francisco, San Francisco, CA, USA. (50) Netherlands Cancer Institute, Amsterdam, The Netherlands. (51) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. NSW Health Pathology, Sydney, New South Wales, Australia. (52) Leiden University Medical Center, Leiden, The Netherlands. University Clinic Regensburg, Regensburg, Germany. European Institute of Oncology, Milan, Italy. (53) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia.
