Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment1; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma (NCT02519322). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.

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Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information. Whole-exome sequencing, T cell receptor sequencing and Nanostring digital spatial profiling data are available from the European Genome-phenome Archive under accession number EGAS00001003178.

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

Change history

  • 25 October 2018

    In the version of this article originally published, there was an error in Fig. 1. In the neoadjuvant phase column, the n values for arms A and B were both reported to be 20. The n values for arms A and B were actually 12 and 11, respectively. Also, the URL underlying the accession code in the data availability section was incorrect. The URL was originally https://www.ebi.ac.uk/ega/studies/EGAS00001002698. It should have been https://www.ebi.ac.uk/ega/studies/EGAS00001003178. The errors have been corrected in the print, HTML and PDF versions of this article.

  • 25 October 2018

    In the version of this article originally published, there was an error in Fig. 2b. RECIST ORR and pCR were both listed as 25%. RECIST ORR was actually 73%, and pCR was 45%. Also, an author’s name was incorrect in the author list. Danny K. Wells should have been listed as Daniel K. Wells. The errors have been corrected in the print, HTML and PDF versions of this article.


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We thank the patients and their families for participating in this clinical trial. The clinical aspects of this study were funded by Bristol-Myers Squibb. The correlative research was supported by the philanthropic contributions to The University of Texas MD Anderson Cancer Center Melanoma Moon Shot Program, The Parker Institute for Cancer Immunotherapy and US Department of Defense Grant CA150619.

Author information

Author notes

  1. These authors contributed equally: Rodabe N. Amaria, Sangeetha M. Reddy.

  2. These authors jointly supervised this work: Michael T. Tetzlaff, Jennifer A. Wargo.


  1. Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA

    • Rodabe N. Amaria
    • , Hussein A. Tawbi
    • , Michael A. Davies
    • , Isabella C. Glitza
    • , Wen-Jen Hwu
    • , Adi Diab
    • , Michael K. Wong
    • , Scott Woodman
    • , Patrick Hwu
    • , Sapna P. Patel
    • , Lauren Simpson
    •  & Liberty Posada
  2. Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA

    • Sangeetha M. Reddy
  3. Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA

    • Merrick I. Ross
    • , Janice N. Cormier
    • , Richard Royal
    • , Richard Ehlers
    • , Anthony Lucci
    • , Jeffrey E. Lee
    • , Jeffrey Gershenwald
    • , Elizabeth M. Burton
    • , Lauren Haydu
    • , Vancheswaran Gopalakrishnan
    • , Alexandre Reuben
    • , Miles C. Andrews
    •  & Jennifer A. Wargo
  4. Department of Head and Neck Surgery, MD Anderson Cancer Center, Houston, TX, USA

    • Carol Lewis
    • , Ehab Hanna
    • , Neil Gross
    • , Randal Weber
    • , Stephen Y. Lai
    •  & Amy Hessel
  5. Department of Immunology, MD Anderson Cancer Center, Houston, TX, USA

    • Jorge Blando
    • , Padmanee Sharma
    •  & James Allison
  6. Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA

    • Denái R. Milton
  7. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA

    • Robin Kageyama
    •  & Daniel K. Wells
  8. Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA

    • Linghua Wang
    • , Shaojun Zhang
    • , Christine N. Spencer
    •  & Jennifer A. Wargo
  9. Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA

    • Alexander J. Lazar
    • , Courtney W. Hudgens
    • , Victor Prieto
    •  & Michael T. Tetzlaff
  10. Department of Genitourinary Cancers, MD Anderson Cancer Center, Houston, TX, USA

    • Padmanee Sharma
  11. Department of Translational and Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA

    • Michael T. Tetzlaff


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R.N.A. and J.A.W. designed the study. R.N.A., H.A.T., M.A.D., M.I.R., I.C.G., J.N.C., C.L., W.-J.H., E.H., A.D., M.K.W., R.R., N.G., R.W., S.Y.L., R.E., P.H., S.P.P., A.L., A.H., J.E.L., J.G., L.S. and J.A.W. recruited and/or treated patients. R.N.A., S.M.R., J.B., D.R.M., S.W., R.K., D.K.W., L.H., L.S., E.M.B., L.P., L.W., S.Z., A.J.L., C.W.H., V.G., A.R., M.C.A., C.N.S., V.P., P.S., J.A., M.T.T. and J.A.W. analyzed and interpreted data. D.R.M. developed the statistical analysis plan. All authors developed and approved the manuscript.

Competing Interests

R.N.A. received grants from Merck, Bristol-Myers Squibb and Array Biopharma, all outside the submitted work. S.M.R. received support from National Institutes of Health T32 Training Grant T32 CA 009666, outside the submitted work. H.A.T. received personal fees from Novartis, grants from Merck and Celgene, and grants and personal fees from BMS and Genentech, all outside of the submitted work. M.A.D. received personal fees from Novartis, BMS and Vaccinex, grants from AstraZeneca and Merck, and grants and personal fees from Roche/Genentech and Sanofi-Aventis, all outside the submitted work. W.-J.H. received research grants from Merck, Bristol-Myers Squibb, MedImmune, and GlaxoSmithKline and has served on an advisory board for Merck, all outside the submitted work. M.K.W. received personal fees from Merck and EMD Serono, outside the submitted work. J.G. has participated in the advisory board of Merck and Castle Biosciences. A.J.L. received personal fees from BMS, Novartis, Merck and Genentech/Roche, personal fees and nonfinancial support from ArcherDX and Beta-Cat, grants and nonfinancial support from Medimmune/AstraZeneca and Sanofi and grants, personal fees and nonfinancial support from Janssen, all outside the submitted work. V.G. reports a US patent (PCT/US17/53,717), consultant fees from Microbiome DX, and honoraria from CAP18, outside of the submitted work. A.R. reports a US patent (PCT/US17/53,717) and is supported by the Kimberley Clark Foundation Award for Scientific Achievement provided by MD Anderson’s Odyssey Fellowship Program. M.C.A. is supported by the National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (1148680), and reports advisory board participation, travel support and honoraria from Merck Sharpe and Dohme. C.N.S. reports a US patent (PCT/US17/53,717), outside of the submitted work. P.S. received consultant or advisor fees from Bristol-Myers Squibb, GlaxoSmithKline, AstraZeneca, Amgen, Jounce, Kite Pharma, Neon, Evelo, EMD Serono and Astellas, during the conduct of the study; has stocks from Jounce, Kite Pharma, Evelo, Constellation and Neon, outside the submitted work; and has a patent licensed to Jounce, outside the submitted work. M.T.T. reports personal fees from Myriad Genetics, Seattle Genetics and Novartis, all outside the submitted work. J.A.W. reports a US patent (PCT/US17/53,717), has received compensation for speaker’s bureau and honoraria from Dava Oncology, Bristol-Myers Squibb and Illumina and has served on advisory committees for GlaxoSmithKline, Roche/Genentech, Novartis and AstraZeneca. All other authors declare no competing interests.

Corresponding author

Correspondence to Jennifer A. Wargo.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–10, Supplementary Tables 1–11 and Supplementary Note

  2. Reporting Summary

  3. Supplementary Dataset

    Integrated correlative data

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