Reijers et al. reported on the feasibility, safety, and efficacy of using the response to neoadjuvant ipilimumab plus nivolumab to direct further therapy in patients with stage III melanoma. In the PRADO trial, patients achieving major pathological response (MPR) in index lymph nodes (ILN) were omitted from therapeutic lymph node dissection (TLND), patients with pPR underwent TLND only, and patients with pNR underwent TLND and adjuvant therapy. The 24-month relapse-free survival and distant metastasis-free survival for each group and quality of life metrics supported elimination of TLND in MPR patients. Larger studies are needed to confirm the results in the other groups.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (2) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales
Author Info: (1) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (2) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia. Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. (3) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia. Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (4) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (5) Department of Psychosocial research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (6) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia. (7) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. (8) Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (9) Departments of Medical Oncology and Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. (10) Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. (11) Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. (12) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (13) Department of Head and Neck Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (14) Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (15) Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. (16) Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. (17) Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands. (18) Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands. (19) Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. (20) 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. (21) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (22) Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. (23) Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. (24) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. (25) Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany. (26) Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (27) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. (28) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia. (29) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. Faculty of Medicine and Health, 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. (30) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia. Department of Breast and Melanoma Surgery, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. (31) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (32) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. Faculty of Medicine and Health, 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. (33) Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (34) Department of Psychosocial research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. Department of Research and Development, Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands. Department of Medical and Clinical Psychology, Center of Research on Psychological and Somatic Disorders (CoRPS), Tilburg University, Tilburg, The Netherlands. (35) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. Faculty of Medicine and Health, 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. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. (36) Department of Psychosocial research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (37) Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia. Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. (38) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. c.blank@nki.nl. Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl.
