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Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial

Nature Medicine volume 28, pages 1178–1188 (2022)Cite this article

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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.

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Fig. 1: Study scheme and flowchart of PRADO.
Fig. 2: Radiologic and pathologic response.
Fig. 3: Effect of ILN procedure on surgical morbidity and HRQoL.
Fig. 4: Survival outcomes.

Data availability

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 repository@nki.nl, 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.

References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. 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).

    Article  Google Scholar 

  3. 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).

    Article  Google Scholar 

  4. Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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).

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. 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).

    Google Scholar 

  12. 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).

    Article  Google Scholar 

  13. 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).

    Article  PubMed  Google Scholar 

  14. 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).

    Article  PubMed  Google Scholar 

  15. 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).

    Article  PubMed  Google Scholar 

  16. 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).

    Article  PubMed  Google Scholar 

  17. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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).

  22. 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).

    Article  PubMed  Google Scholar 

  23. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  24. 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).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

  26. 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).

    Article  PubMed  Google Scholar 

  27. Wrightson, W. R. et al. Complications associated with sentinel lymph node biopsy for melanoma. Ann. Surg. Oncol. 10, 676–680 (2003).

    Article  PubMed  Google Scholar 

  28. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Christensen, T. & Kehlet, H. Postoperative fatigue. World J. Surg. 17, 220–225 (1993).

    Article  CAS  PubMed  Google Scholar 

  30. Versluis, J. M. et al. Neoadjuvant ipilimumab plus nivolumab in synchronous clinical stage III melanoma. Eur. J. Cancer 148, 51–57 (2021).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    Article  PubMed  Google Scholar 

  33. Tetzlaff, M. T. et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann. Oncol. 29, 1861–1868 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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.

Author information

Author notes

  1. These authors contributed equally: Alexander M. Menzies, Alexander C. J. van Akkooi, Judith M. Versluis, Noëlle M. J. van den Heuvel.

  2. These authors jointly supervised this work: Annelies H. Boekhout, Georgina V. Long, Christian U. Blank.

Authors and Affiliations

  1. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Irene L. M. Reijers, Judith M. Versluis, Elisa A. Rozeman, Judith M. Lijnsvelt, John B. A. G. Haanen & Christian U. Blank

  2. Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia

    Alexander M. Menzies, Alexander C. J. van Akkooi, Robyn P. M. Saw, Thomas E. Pennington, Maria Gonzalez, Kerwin F. Shannon, Sydney Ch’ng, Andrew J. Colebatch, Andrew J. Spillane, Robert V. Rawson, Richard A. Scolyer & Georgina V. Long

  3. Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

    Alexander M. Menzies, Alexander C. J. van Akkooi, Robyn P. M. Saw, Sydney Ch’ng, Andrew J. Colebatch, Andrew J. Spillane, Robert V. Rawson, Richard A. Scolyer & Georgina V. Long

  4. Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia

    Alexander M. Menzies & Georgina V. Long

  5. Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Alexander C. J. van Akkooi, Winan J. van Houdt & Michel W. Wouters

  6. Department of Psychosocial research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Noëlle M. J. van den Heuvel, Lonneke V. van de Poll-Franse & Annelies H. Boekhout

  7. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands

    Ellen Kapiteijn, John B. A. G. Haanen & Christian U. Blank

  8. Departments of Medical Oncology and Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

    Astrid A. M. van der Veldt

  9. Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands

    Karijn P. M. Suijkerbuijk

  10. Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Geke A. P. Hospers

  11. Department of Head and Neck Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Willem M. C. Klop & Charlotte L. Zuur

  12. Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Karolina Sikorska, Alejandro Torres Acosta & Lindsay G. Grijpink-Ongering

  13. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

    Jos A. van der Hage

  14. Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands

    Dirk J. Grünhagen

  15. Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

    Michel W. Wouters

  16. Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands

    Arjen J. Witkamp

  17. Department of Otorhinolaryngology Head Neck Surgery, Leiden University Medical Center, Leiden, The Netherlands

    Charlotte L. Zuur

  18. Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany

    Katarzyna Jóźwiak

  19. Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Carolien Bierman & Bart A. van de Wiel

  20. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia

    Andrew J. Colebatch, Robert V. Rawson & Richard A. Scolyer

  21. Department of Breast and Melanoma Surgery, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia

    Andrew J. Spillane

  22. Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    John B. A. G. Haanen & Christian U. Blank

  23. Department of Research and Development, Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands

    Lonneke V. van de Poll-Franse

  24. Department of Medical and Clinical Psychology, Center of Research on Psychological and Somatic Disorders (CoRPS), Tilburg University, Tilburg, The Netherlands

    Lonneke V. van de Poll-Franse

  25. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia

    Richard A. Scolyer & Georgina V. Long

Authors
  1. Irene L. M. Reijers
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  2. Alexander M. Menzies
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  31. John B. A. G. Haanen
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  33. Bart A. van de Wiel
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  34. Lonneke V. van de Poll-Franse
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  36. Annelies H. Boekhout
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  37. Georgina V. Long
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  38. Christian U. Blank
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Contributions

C.U.B. designed the trial and wrote the trial protocol. E.A.R. provided additional input and wrote the amendment for the PRADO extension cohort during the 20th Workshop on ‘Methods in Clinical Cancer Research’ (Zeist, Netherlands). G.V.L. and A.v.A. reviewed the protocol. A.H.B. wrote the HRQoL part of the protocol. I.L.M.R., A.M.M., J.M.V., R.P.M.S., T.P., E.A.R., E.K., A.A.M.v.d.V., K.P.M.S., G.A.P.H., W.M.C.K., W.J.v.H., J.A.v.d.H., D.J.G., M.W.W., A.J.W., C.L.Z., J.M.L., K.F.S., S.C., J.S., A.S., A.v.A., G.V.L. and C.U.B. recruited and treated patients and collected data. A.J.C., R.V.R., R.A.S. and B.A.v.d.W. reviewed and scored the pathology of all cases. N.M.J.v.d.H., I.L.M.R., M.G., L.V.v.d.P.-F., A.H.B. and C.U.B. collected and interpreted data on HRQoL. K. Sikorska and I.L.M.R. performed statistical analysis of the clinical data. A.H.B. and K.J. performed the HRQoL statistical analyses. A.T.A. and L.G.G.-O. contributed to central and local data management. R.Z. and M.G. were clinical project managers of the trial. I.L.M.R., A.H.B. and C.U.B. wrote the first draft of the manuscript. All authors interpreted the data, reviewed the manuscript and approved the final version.

Corresponding author

Correspondence to Christian U. Blank.

Ethics declarations

Competing interests

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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Nature Medicine thanks Sin-Ho Jung, Douglas Johnson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Javier Carmona and Joao Monteiro, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Marker placement in the ILN.

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.

Extended Data Fig. 2 Objective radiologic response underestimates pathologic response.

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.

Extended Data Fig. 3 Flowchart for patient inclusion for surgical morbidity and HRQoL analyses.

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.

Extended Data Fig. 4 Effect of pathological response and treatment on HRQoL outcomes.

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).

Extended Data Fig. 5 HRQoL comparison between patients with MPR, pPR and pNR.

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’.

Extended Data Fig. 6 RFS by adjuvant treatment.

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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Supplementary Information

Supplementary Tables 1–11, references HRQoL questionnaire information and study protocol.

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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

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