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.
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To minimize the risk of patient re-identification, de-identified individual patient-level clinical data are available under restricted access. Upon a scientifically sound request, data access can be obtained via the NKI’s scientific repository at email@example.com, which will contact the corresponding author (C.U.B.). Data requests will be reviewed by the institutional review board of the Netherlands Cancer Institute (NKI) and will require the requesting researcher to sign a data access agreement with the NKI.
Dummer, R. et al. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Lancet Oncol. 21, 358–372 (2020).
Eggermont, A. M. et al. Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: new recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up. J. Clin. Oncol. 38, abstr. 10000 (2020).
Ascierto, P. A. et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 21, 465–1477 (2020).
Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016).
Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018).
Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018).
Menzies, A. M. et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Nat. Med. 27, 301–309 (2021).
Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019).
Rozeman, E. A. et al. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nat. Med. 27, 256–263 (2021).
Jansen, Y. J. L. et al. Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. Ann. Oncol. 30, 1154–1161 (2019).
Long, G. V. et al. 4-year survival and outcomes after cessation of pembrolizumab (pembro) after 2-years in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in KEYNOTE-006. J. Clin. Oncol. 35, abstr. 9503 (2017).
Robert, C. 5-Year characterization of complete responses in patients with advanced melanoma who received nivolumab plus ipilimumab or nivolumab alone. Ann. Oncol. 31, s734–s735 (2020).
van Akkooi, A. C. et al. Morbidity and prognosis after therapeutic lymph node dissections for malignant melanoma. Eur. J. Surg. Oncol. 33, 102–108 (2007).
de Vries, M., Vonkeman, W. G., van Ginkel, R. J. & Hoekstra, H. J. Morbidity after axillary sentinel lymph node biopsy in patients with cutaneous melanoma. Eur. J. Surg. Oncol. 31, 778–783 (2005).
de Vries, M., Vonkeman, W. G., van Ginkel, R. J. & Hoekstra, H. J. Morbidity after inguinal sentinel lymph node biopsy and completion lymph node dissection in patients with cutaneous melanoma. Eur. J. Surg. Oncol. 32, 785–789 (2006).
Kretschmer, L. et al. Postoperative morbidity of lymph node excision for cutaneous melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection. Melanoma Res. 18, 16–21 (2008).
de Vries, M., Hoekstra, H. J. & Hoekstra-Weebers, J. E. Quality of life after axillary or groin sentinel lymph node biopsy, with or without completion lymph node dissection, in patients with cutaneous melanoma. Ann. Surg. Oncol. 16, 2840–2847 (2009).
Gjorup, C. A. et al. Health-related quality of life in melanoma patients: impact of melanoma-related limb lymphoedema. Eur. J. Cancer 85, 122–132 (2017).
Schermers, B. et al. Surgical removal of the index node marked using magnetic seed localization to assess response to neoadjuvant immunotherapy in patients with stage III melanoma. Br. J. Surg. 106, 519–522 (2019).
Reijers, I. L. M. et al. Representativeness of the index lymph node for total nodal basin in pathologic response assessment after neoadjuvant checkpoint inhibitor therapy in patients with stage III melanoma. JAMA Surg 157, 335–342 (2022).
Rawson, R. V. et al. Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma. Ann. Oncol. 32, 766–777 (2021).
Giesinger, J. M. et al. Thresholds for clinical importance were established to improve interpretation of the EORTC QLQ-C30 in clinical practice and research. J. Clin. Epidemiol. 118, 1–8 (2020).
Ji, X. et al. Application of ultrasound-guided placement of markers for locating axillary lymph nodes of breast cancer. Gland Surg. 10, 3067–3074 (2021).
Smith, S., Taylor, C. R., Kanevsky, E., Povoski, S. P. & Hawley, J. R. Long-term safety and efficacy of breast biopsy markers in clinical practice. Expert Rev. Med. Devices 18, 121–128 (2021).
van Akkooi, A. C. J. et al. Neoadjuvant systemic therapy (NAST) in patients with melanoma: surgical considerations by the International Neoadjuvant Melanoma Consortium (INMC). Ann. Surg. Oncol. https://doi.org/10.1245/s10434-021-11236-y (2022).
Swenson, K. K. et al. Comparison of side effects between sentinel lymph node and axillary lymph node dissection for breast cancer. Ann. Surg. Oncol. 9, 745–753 (2002).
Wrightson, W. R. et al. Complications associated with sentinel lymph node biopsy for melanoma. Ann. Surg. Oncol. 10, 676–680 (2003).
Morton, D. L. et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann. Surg. 242, 302–311, discussion 311–303 (2005).
Christensen, T. & Kehlet, H. Postoperative fatigue. World J. Surg. 17, 220–225 (1993).
Versluis, J. M. et al. Neoadjuvant ipilimumab plus nivolumab in synchronous clinical stage III melanoma. Eur. J. Cancer 148, 51–57 (2021).
Weber, J. et al. Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease. Br. J. Dermatol 183, 559–563 (2020).
Cocks, K. et al. Evidence-based guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. J. Clin. Oncol. 29, 89–96 (2011).
Tetzlaff, M. T. et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann. Oncol. 29, 1861–1868 (2018).
Fay, M. P., Brittain, E. H. & Proschan, M. A. Pointwise confidence intervals for a survival distribution with small samples or heavy censoring. Biostatistics 14, 723–736 (2013).
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.
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.
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Schematic overview of magnetic seed placement in the ILN and retrieval of the ILN during the ILN procedure. (1) Magnetic seed, (2) Ultrasound image of positioning of the needle tip (red arrow) in the ILN (green arrow) before implantation of the magnetic seed, (3) Two cycles of ipilimumab plus nivolumab are given after the magnetic seed is implanted, (4) Magnetic detector (Endomag Sentimag®) used during surgery for seed detection, (5) Postoperative specimen X‐ray with magnetic seed (red arrow) in situ. This image has been adapted from Schermers B, Br J Surg, 201919.
Waterfall plot of the radiologic change in target lesions (in %) between baseline and week 6 of all PRADO patients with evaluable CT-scan (n = 96). Colours indicate the responses as pCR (dark green), near-pCR (light green), pPR (yellow), pNR (red) and distant metastases (grey). The dotted line indicates the cutoff for RECIST version 1.1 radiologic response.
a, Flow chart of patient inclusion for surgical morbidity analyses. For information regarding the execution of the ILN resection and TLND, see also Supplementary Table 2. b, HRQoL analyses of the PRADO trial.
Curves showing the unadjusted mean HRQoL scores of patients with MPR (n = 60, green line) versus patients without MPR (n = 31, orange line). Error bars indicate the 95% CI. The differences in mean HRQoL scores between patients with MPR and non-MPR (see also Supplementary Table 5) were adjusted for age, gender, adjuvant treatment and relapse status (no/yes). The adjusted score differences were interpreted in terms of statistical significance using a linear mixed effect model with a two tailed P value (P < 0.05), and by clinical relevance according to the guideline of Cocks et al32. Statistically significant adjusted differences were marked with * and clinically relevant differences were marked with # (Supplementary Table 5). Results were considered clinically relevant if the adjusted difference in mean scores between the two groups was at least ‘medium’ and clinically irrelevant if differences in mean scores were ‘trivial or small’. Questionnaire compliance rates in the MPR and non-MPR group were 87% vs 97% at baseline, 98% vs 94% at week 6, 90% vs 81% at week 12, 88% vs 81% at week 24, 92% vs 84% at week 36, 85% vs 68% at week 48, 80% vs 77% at week 60 and 87% vs 61% at week 104 (year 2).
Curves showing the unadjusted HRQoL scores between patients with MPR (n = 60, green line), pPR (n = 11, yellow line) and pNR (n = 20, red line). Error bars indicate the 95% CI. The differences in mean HRQoL scores between patients with MPR versus pPR and MPR versus pNR were adjusted for age, gender, adjuvant treatment and relapse status (no/yes). The adjusted score differences were interpreted in terms of statistical significance using a linear mixed effect model with a two tailed P value (P < 0.05), and by clinical relevance according to the guideline of Cocks et al32. Statistically significant adjusted differences were marked with * and clinically relevant differences were marked with #. Results were considered clinically relevant if the adjusted difference in mean scores between the two groups was at least ‘medium’ and clinically irrelevant if differences in mean scores were ‘trivial or small’.
RFS of patients with pNR from the PRADO trial by adjuvant therapy. Patients were treated with adjuvant nivolumab (n = 7, light blue line), adjuvant BRAF/MEK inhibition (n = 10, orange line) or no adjuvant therapy (n = 3, dark blue line). The patient who was lost to follow-up was excluded.
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Reijers, I.L.M., Menzies, A.M., van Akkooi, A.C.J. et al. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial. Nat Med 28, 1178–1188 (2022). https://doi.org/10.1038/s41591-022-01851-x