Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial
Nature Medicine, vol. 28, pp. 1178–1188
Abstract
Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free survival (RFS). The PRADO extension cohort of the OpACIN-neo trial ( NCT02977052 ) addressed the feasibility and effect on clinical outcome of using pathologic response after neoadjuvant ipilimumab and nivolumab as a criterion for further treatment personalization. In total, 99 patients with clinical stage IIIb–d nodal melanoma were included and treated with 6 weeks of neoadjuvant ipilimumab 1 mg kg−1 and nivolumab 3 mg kg−1. In patients achieving major pathologic response (MPR, ≤10% viable tumor) in their index lymph node (ILN, the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with pathologic partial response (pPR; >10 to ≤50% viable tumor) underwent TLND only, whereas patients with pathologic non-response (pNR; >50% viable tumor) underwent TLND and adjuvant systemic therapy ± synchronous radiotherapy. Primary objectives were confirmation of pRR (ILN, at week 6) of the winner neoadjuvant combination scheme identified in OpACIN-neo; to investigate whether TLND can be safely omitted in patients achieving MPR; and to investigate whether RFS at 24 months can be improved for patients achieving pNR. ILN resection and ILN-response-tailored treatment were feasible. The pRR was 72%, including 61% MPR. Grade 3–4 toxicity within the first 12 weeks was observed in 22 (22%) patients. TLND was omitted in 59 of 60 patients with MPR, resulting in significantly lower surgical morbidity and better quality of life. The 24-month relapse-free survival and distant metastasis-free survival rates were 93% and 98% in patients with MPR, 64% and 64% in patients with pPR, and 71% and 76% in patients with pNR, respectively. These findings provide a strong rationale for randomized clinical trials testing response-directed treatment personalization after neoadjuvant ipilimumab and nivolumab. Results from the PRADO extension cohort of the OpACIN-neo trial show that pathologic response rate to neoadjuvant ipilimumab and nivolumab can be used as a criterion for personalization of further treatment in stage III nodal melanoma, with the potential to reduce treatment morbidity and increase patient quality of life.
Authors 37
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The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The University of Sydney · Royal North Shore Hospital · Melanoma Institute Australia
Affiliation as printed
Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
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The University of Sydney · The Netherlands Cancer Institute · Melanoma Institute Australia
Affiliation as printed
Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
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The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Psychosocial research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The University of Sydney · Melanoma Institute Australia
Affiliation as printed
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
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The University of Sydney · Melanoma Institute Australia
Affiliation as printed
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
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Leiden University Medical Center
Affiliation as printed
Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Departments of Medical Oncology and Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Head and Neck Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands
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Leiden University Medical Center · The Netherlands Cancer Institute
Affiliation as printed
Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
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Leiden University Medical Center · The Netherlands Cancer Institute
Affiliation as printed
Department of Head and Neck Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Department of Otorhinolaryngology Head Neck Surgery, Leiden University Medical Center, Leiden, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The University of Sydney · Melanoma Institute Australia
Affiliation as printed
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
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Medizinische Hochschule Brandenburg Theodor Fontane
Affiliation as printed
Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany
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The Netherlands Cancer Institute
Affiliation as printed
Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The University of Sydney · Melanoma Institute Australia
Affiliation as printed
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
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The University of Sydney · Melanoma Institute Australia
Affiliation as printed
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
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The University of Sydney · Royal Prince Alfred Hospital · Melanoma Institute Australia · NSW Health Pathology
Affiliation as printed
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia
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Leiden University Medical Center · The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The University of Sydney · Royal Prince Alfred Hospital · Melanoma Institute Australia · NSW Health Pathology
Affiliation as printed
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia
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The Netherlands Cancer Institute
Affiliation as printed
Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Tilburg University · The Netherlands Cancer Institute · Netherlands Comprehensive Cancer Organisation
Affiliation as printed
Department of Medical and Clinical Psychology, Center of Research on Psychological and Somatic Disorders (CoRPS), Tilburg University, Tilburg, The Netherlands
Department of Psychosocial research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Department of Research and Development, Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands
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The University of Sydney · Royal Prince Alfred Hospital · Melanoma Institute Australia · NSW Health Pathology
Affiliation as printed
Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia
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The Netherlands Cancer Institute
Affiliation as printed
Department of Psychosocial research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The University of Sydney · Royal North Shore Hospital · Melanoma Institute Australia
Affiliation as printed
Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
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Leiden University Medical Center · The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. c.blank@nki.nl
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl
Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl
Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
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