Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma


Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients1,2. In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy3. Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy4. To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg−1 and nivolumab 1 mg kg−1, as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm). Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6 months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Waterfall plot, RFS, and overall survival.
Fig. 2: TCR sequencing, DSP, and RNA sequencing.

Similar content being viewed by others

Data availability

The RNA and DNA sequencing datasets generated during the current study have been deposited into the European Genome-phenome Archive under accession number EGAS00001003099 and are available on request. Every request will be reviewed by the institutional review board of the NKI; the researcher will need to sign a data access agreement with the NKI after approval. The TCR sequencing data that support the findings of this study are available from Adaptive Biotechnologies; however, restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. However, data are available from the authors on reasonable request and with the permission of Adaptive Biotechnologies. The DSP data that support the findings of this study are available from NanoString; however, restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. However, data are available from the authors on reasonable request and with permission from NanoString.


  1. Eggermont, A. M. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375, 1845–1185 (2016).

    Article  CAS  Google Scholar 

  2. Weber, J. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377, 1824–1835 (2017).

    Article  CAS  Google Scholar 

  3. Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).

    Article  CAS  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  Google Scholar 

  5. Balch, C. M. et al. Final version of 2009 AJCC melanoma staging and classification. J. Clin. Oncol. 27, 6199–6206 (2009).

    Article  Google Scholar 

  6. Balch, C. M. et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J. Clin. Oncol. 19, 3622–3634 (2001).

    Article  CAS  Google Scholar 

  7. Burmeister, B. H. et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 13, 589–597 (2012).

    Article  Google Scholar 

  8. Eggermont, A. M. et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3trial. Lancet Oncol. 16, 522–530 (2015).

    Article  CAS  Google Scholar 

  9. Long, G. V. et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N. Engl. J. Med. 377, 1813–1823 (2017).

    Article  CAS  Google Scholar 

  10. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 1270–1271 (2015).

    Article  Google Scholar 

  11. Long, G. V. et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol. 18, 1202–1210 (2017).

    Article  CAS  Google Scholar 

  12. Steenbruggen, T. G. et al. Neoadjuvant therapy for breast cancer: established concepts and emerging strategies. Drugs 77, 1313–1336 (2017).

    Article  CAS  Google Scholar 

  13. Blank, C. U., Haanen, J. B., Ribas, A. & Schumacher, T. N. CANCER IMMUNOLOGY. The “cancer immunogram”. Science 352, 658–660 (2016).

    Article  CAS  Google Scholar 

  14. Larkin, J. et al. Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis. Oncologist 22, 709–718 (2017).

    Article  CAS  Google Scholar 

  15. Forde, P. M. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 378, 1976–1986 (2018).

    Article  CAS  Google Scholar 

  16. van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, e439–442 (2013).

    Article  Google Scholar 

  17. Blank, C. et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 64, 1140–1145 (2004).

    Article  CAS  Google Scholar 

  18. Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).

    Article  Google Scholar 

  19. Reddy, S. M. et al. Neoadjuvant nivolumab versus combination ipilimumab and nivolumab followed by adjuvant nivolumab in patients with resectable stage III and oligometastatic stage IV melanoma: preliminary findings. In 32nd SITC Annual Meeting abstr. O15.(National Harbor, MD, USA, 2017).

  20. Eroglu, Z. et al. Mature results of combination nivolumab plus ipilimumab as adjuvant therapy in stage IIIC/IV melanoma. Annual Meeting Society of Melanoma Research (SMR) (Brisbane, Queensland, Australia, 2017).

  21. Straver, M. E., Loo, C. E., Alderliesten, T., Rutgers, E. J. & Vrancken Peeters, M. T. Marking the axilla with radioactive iodine seeds (MARI procedure) may reduce the need for axillary dissection after neoadjuvant chemotherapy for breast cancer. Br. J. Surg. 97, 1226–1231 (2010).

    Article  CAS  Google Scholar 

  22. Lui, V. K., Karpuchas, J., Dent, P. B., McCulloch, P. B. & Blajchman, M. A. Cellular immunocompetence in melanoma: effect of extent of disease and immunotherapy. Br. J. Cancer 32, 323–330 (1975).

    Article  CAS  Google Scholar 

  23. Meerveld-Eggink, A. et al. Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience. Ann. Oncol. 28, 862–867 (2017).

    Article  CAS  Google Scholar 

  24. Eggermont, A. M. et al. Ipilimumab versus placebo after complete resection of stage III melanoma: initial efficacy and safety results from the EORTC 18071 phase III trial. J. Clin. Oncol. 32, LBA9008–LBA9008 (2014).

    Article  Google Scholar 

  25. Memarnejadian, A. et al. PD-1 blockade promotes epitope spreading in anticancer CD8+ T cell responses by preventing fratricidal death of subdominant clones to relieve immunodomination. J. Immunol. 199, 3348–3359 (2017).

    Article  CAS  Google Scholar 

  26. Kvistborg, P. et al. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci. Transl. Med. 6, 254ra128 (2014).

    Article  Google Scholar 

  27. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article  CAS  Google Scholar 

  28. Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

    Article  CAS  Google Scholar 

  29. Robins, H. S. et al. Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. Blood 114, 4099–4107 (2009).

    Article  CAS  Google Scholar 

  30. Carlson, C. S. et al. Using synthetic templates to design an unbiased multiplex PCR assay. Nat. Commun. 4, 2680 (2013).

    Article  Google Scholar 

  31. Robins, H. et al. Ultra-sensitive detection of rare T cell clones. J. Immunol. Methods 375, 14–19 (2012).

    Article  CAS  Google Scholar 

  32. Toebes, M. et al. Design and use of conditional MHC class I ligands. Nat. Med. 12, 246–251 (2006).

    Article  CAS  Google Scholar 

Download references


We thank the patients and their families for participating in the study. We thank A. Gangaev for performing the experiments involving MHC tetramer staining; M. Valenti, T. Kuilman, and other members from the Blank, Peeper, and Schumacher laboratory for valuable discussions; W. Uyterlinde, A. Koenen, M. Wouters, and J. vd Hage for the clinical care of the patients included in the trial; C. Bierman for assisting with the pathological revisions of tumor samples; the NKI-AVL flow facility and the NKI-AVL Core Facility Molecular Pathology & Biobanking for supplying the NKI-AVL biobank material and/or laboratory support; E. Hooijberg for supervising the immunohistochemistry analysis; S. Vanhoutfin for financial management; A. Cesano for scientific input on the NanoString analyses; and D. Walker, C. Pfeiffer, B. Lamon, B. Stegenga, and V. Goodman from Bristol-Myers Squibb for scientific input and support.

Author information

Authors and Affiliations



C.U.B. and T.N.S. designed the study and wrote the manuscript. E.A.R. analyzed and interpreted the clinical and translational data. L.F.F. performed the bioinformatics analyses. K.S. performed the statistical analysis on the clinical data. B.vd.W. assessed the pathological response of neoadjuvant-treated patients. M.vd.B. and D.P. performed the experiments for the MHC tetramer analysis. P.K. supervised the MHC tetramer analysis. C.U.B., J.V.v.T, J.B.A.G.H., H.A.M., S.A., and S.t.M., were responsible for the clinical care of the patients. L.G.G.-O. was responsible for data management. L.M.P. is the clinical project manager for this study. A. Broeks was responsible for storing and processing the tumor samples. A. Bruining performed the radiological evaluations. S.W. was responsible for the DSP analysis. R.M.G. was responsible for TCR sequencing. H.v.T. created the statistical design. A.C.J.v.A. performed the surgeries. A.C.J.v.A., D.S.P., O.K., and J.B.A.G.H. gave critical input. All authors critically revised the manuscript.

Corresponding authors

Correspondence to Christian U. Blank or Ton N. Schumacher.

Ethics declarations

Competing interests

C.U.B. reports personal fees for advisory roles for MSD, BMS, Roche, GSK, Novartis, Pfizer, GenMab, and Lilly, and grants from BMS, NanoString, and Novartis,outside the submitted work. E.A.R. reports travel support from NanoString Technologies and MSD, outside the submitted work. L.F.F., K.S., B.vd.W., P.K., O.K., M.vd.B., D.P., A. Broeks., H.A.M., S.A., S.t.M., L.M.P., L.G.G.-O., A. Bruining, and H.v.T. have nothing to disclose. J.V.v.T reports travel support from Roche, outside the submitted work. R.M.G. has a financial interest in Adaptive Biotechnologies. S.W. is an employee of and is a stockholder in NanoString Technologies, has an advisory role with Roche, and is a former employee of the Oncofactor Corporation, outside the submitted work. D.S.P. reports research support from BMS. J.B.A.G.H. reports that NKI received fees for his advisory roles from BMS, MSD, Roche, Neon Therapeutics, Immunocore, Novartis, AstraZeneca/MedImmune, Pfizer, and Ipsen; NKI received grants from BMS, Merck, Novartis, and Neon Therapeutics, outside the submitted work. A.C.J.v.A. reports personal fees for an advisory role with Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, and Merck-Pfizer, and grants from Amgen and Novartis, all outside the submitted work. T.N.S. is consultant for Adaptive Biotechnologies, AIMM Therapeutics, Amgen, Neon Therapeutics, Scenic Biotech, and reports grant/research support from Merck, Bristol-Myers Squibb, and Merck KGaA; he is a stockholder in AIMM Therapeutics and Neon Therapeutics.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Tables 1 and 2, and Supplementary Protocol

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blank, C.U., Rozeman, E.A., Fanchi, L.F. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 24, 1655–1661 (2018).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing