Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial
Reijers, Irene L M; Menzies, Alexander M; van Akkooi, Alexander C J; Versluis, Judith M; van den Heuvel, Noëlle M J; Saw, Robyn P M; Pennington, Thomas E; Kapiteijn, Ellen; van der Veldt, Astrid A M; Suijkerbuijk, Karijn P M; Hospers, Geke A P; Rozeman, Elisa A; Klop, Willem M C; van Houdt, Winan J; Sikorska, Karolina; van der Hage, Jos A; Grünhagen, Dirk J; Wouters, Michel W; Witkamp, Arjen J; Zuur, Charlotte L; Lijnsvelt, Judith M; Torres Acosta, Alejandro; Grijpink-Ongering, Lindsay G; Gonzalez, Maria; Jóźwiak, Katarzyna; Bierman, Carolien; Shannon, Kerwin F; Ch'ng, Sydney; Colebatch, Andrew J; Spillane, Andrew J; Haanen, John B A G; Rawson, Robert V; van de Wiel, Bart A; van de Poll-Franse, Lonneke V; Scolyer, Richard A; Boekhout, Annelies H; Long, Georgina V; Blank, Christian U
(2022) Nature Medicine, volume 28, issue 6, pp. 1178 - 1188
(Article)
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
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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.
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Keywords: General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 1078-8956
Publisher: Nature Publishing Group
Note: Funding Information: We thank all patients and their families for participation in the trial and the participating study teams. We gratefully acknowledge the support of all colleagues from Melanoma Institute Australia, Royal Prince Alfred Hospital, Royal North Shore and Mater Hospital, University Medical Center Utrecht, Erasmus Medical Center, Leiden University Medical Center, University Medical Center Groningen and the Netherlands Cancer Institute; B. Schermers from Sirius Medical for providing magnetic seeds and a magnetic seed detector; S. Vanhoutvin for financial management; R. Zucker, M. J. Gregorio, K. de Joode, A. M. van Eggermond, E. H. J. Tonk and J. Kingma-Veenstra for administrative support and data management; and A. Evans and B. Stegenga from Bristol Myers Squibb for scientific input and long-term support of our neoadjuvant immunotherapy efforts. A.M.M. is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant, Melanoma Institute Australia and Nicholas and Helen Moore. R.P.M.S. is supported by Melanoma Institute Australia. R.V.R. is supported by a Clinical Research Scholarship from Sydney Research. R.A.S. is supported by an NHMRC Program Grant and Practitioner Fellowship. G.V.L. is supported by an NHMRC Investigator Grant and the University of Sydney Medical Foundation. Financial support for the trial was provided by Bristol Myers Squibb. Funding Information: No author has received financial support for the work on this manuscript, and no medical writer was involved at any stage of the preparation of this manuscript. A.M.M. has served on advisory boards for Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Roche, Pierre Fabre and QBiotics. R.P.M.S. has received honoraria for advisory board participation from MSD, Novartis and Qbiotics and speaking honoraria from BMS and Novartis. E.K. received honoraria for consultancy/advisory relationships (all paid to the institute) from BMS, Novartis, Merck and Pierre Fabre and received research grants not related to this paper from BMS. A.A.M.v.d.V. received compensation for advisory roles and honoraria (all paid to the institute) from BMS, MSD, Merck, Roche, Eisai, Pfizer, Sanofi, Novartis, Pierre Fabre and Ipsen. K.P.M.S. received compensation for advisory roles and honoraria (all paid to the institute) from BMS, MSD, Roche, Novartis, Pierre Fabre and Abbvie and received research funding from Novartis, TigaTx and BMS. G.A.P.H. received compensation for consulting and advisory roles (all paid to the institute) from Amgen, Roche, MSD, BMS, Pfizer, Novartis and Pierre Fabre and received research grants (paid to the institute) from BMS and Seerave. W.J.v.H. received compensation for advisory roles (all paid to the institute) from BMS, Amgen and Sanofi. D.J.G. received compensation for advisory roles (all paid to the institute) from Amgen and Novartis. M.W.W. received compensation for advisory roles (all paid to the institute) from Novartis. A.J.S. has served on an advisory board for QBiotics and received fees for professional services from Eli Lily Australia. J.B.A.G.H. received compensation (all paid to the institute) for advisory roles from AIMM, Amgen, BioNTech, BMS, GlaxoSmithKline, Ipsen, MSD, Merck Serono, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures and Vaximm; stock option ownership of Neogene Therapeutics; and institutional research funding from Amgen, BioNTech, BMS, MSD and Novartis. B.A.v.d.W. has served on the advisory board for BMS. A.v.A. had served on advisory boards and received consultancy honoraria (all paid to the institute) for Amgen, BMS, Novartis, MSD, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical and 4SC and received research grants (all paid to the institute) from Amgen and Merck-Pfizer. R.A.S. has received fees for professional services from F. Hoffmann-La Roche, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, MSD, NeraCare, Amgen, BMS, Myriad Genetics and GlaxoSmithKline. A.H.B. has received a research grant from BMS. G.V.L. is consultant advisor for Aduro, Amgen, Array Biopharma, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics, MSD, Novartis, Oncosec, Pierre Fabre, Provectus, QBiotics and Regeneron Pharmaceuticals. C.U.B. reports receiving compensation for advisory roles from BMS, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Eli Lilly, GenMab, Pierre Fabre and Third Rock Ventures and receiving research funding from BMS, MSD, Novartis, 4SC and NanoString. Furthermore, C.U.B. reports to be co-founder of Immagene BV. All compensations and funding for C.U.B. were paid to the institute, except for Third Rock Ventures and Immagene. The other authors declare no conflicts of interest. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
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