CoChat
Sign Up
Cited by 248Cancer Immunotherapy and BiomarkersCutaneous Melanoma Detection and ManagementMelanoma and MAPK Pathways

Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab

Open access
Weber, Jeffrey, Gibney, Geoffrey, Kudchadkar, Ragini, Yu, Bin, Cheng, Pingyan, Martinez, Alberto J., Kroeger, Jodie, Richards, Allison +6 more·2016·Cancer Immunology Research
DOI 10.1158/2326-6066.cir-15-0193PMC PMC4818672

Published version of a preprint

Open this paper in CoChat — free account

Abstract

The checkpoint inhibitor nivolumab is active in patients with metastatic melanoma who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab-refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3–4 drug-related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. The response rate for ipilimumab-refractory patients was 30% (95% CI, 21%–41%). The median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when patients were followed up for a median of 16 months. One- and 2-year survival rates were 68.4% and 31.2%, respectively. Ipilimumab-naïve and ipilimumab-refractory patients showed no significant difference in survival. The 21 patients with prior grade 3–4 toxicity to ipilimumab that was managed with steroids tolerated nivolumab well, with 62% (95% CI, 38%–82%) having complete or partial responses or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSC) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3–4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab. Cancer Immunol Res; 4(4); 345–53. ©2016 AACR.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/2326-6066.cir-15-0193

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Patients with cancer who have high levels of circulating MDSCs respond poorly to checkpoint blockade.

    “patients with cancer who have high levels of circulating MDSCs have been found to respond poorly to checkpoint blockade”

    From LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer (2018) · cites this paper as Weber et al., 2016

    The Results (Immune Biomarkers) associate fewer pretreatment circulating monocytic MDSCs with response or stable disease after nivolumab, and the Discussion links higher levels to poorer outcomes. The claim generalizes this finding from metastatic melanoma patients receiving nivolumab to cancer patients and checkpoint blockade broadly; the paper does not establish that broader scope. Page numbers are not available in the supplied passages. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 24

  1. [1]Brahmer JR Drake CG Wollner I Powderly J Picus J Sharfman WH Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010 28 3167 3175 20516446 PMC4834717
  2. [2]Topalian SL Hodi FS Brahmer JR Gettinger SN Smith DC McDermott DF Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012 366 2443 2453 22658127 PMC3544539
  3. [3]Weber JS D'Angelo SP Minor D Hodi FS Gutzmer R Neyns B Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The Lancet Oncol 2015 16 4 375 84 25795410
  4. [6]Topalian SL Sznol M McDermott DF Kluger HM Carvajal RD Sharfman WH Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014 32 10 1020 30 24590637 PMC4811023
  5. [7]Hamid O Robert C Daud A Hodi FS Hwu WJ Kefford R Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013 369 134 144 23724846 PMC4126516
  6. [8]Patnaik A Kang SP Rasco D Papadopoulos KP Elassaiss-Schaap J Beeram M Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients With Advanced Solid Tumors. Clin Cancer Res 2015 pii: clincanres.2607.2014. [Epub ahead of print] 25977344
  7. [9]Taube JM Anders RA Young GD Xu H Sharma R McMiller TL Co-localization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 2012 4 127ra37 PMC3568523 22461641
  8. [10]Taube JM Klein A Brahmer JR Xu H Pan X Kim JH Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res Oct 1 2014 20 19 5064 74 24714771 PMC4185001
  9. [12]Taube JM Young GD McMiller TL Chen S Salas JT Pritchard TS Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade. Clin Cancer Res 2015 pii: clincanres.0244.2015. [Epub ahead of print PMC4558237 25944800
  10. [14]Wolchok JD Hoos A O'Day S Weber JS Hamid O Lebbé C Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009 15 23 7412 20 19934295
  11. [15]Gabrilovich DI Ostrand-Rosenberg S Bronte V Coordinated Regulation of Myeloid cells by Tumours Nat Reviews Immunology 2012 12 4 253 258 PMC3587148 22437938
  12. [17]Ansell SM Lesokhin AM Borrello I Halwani A Scott EC Gutierrez M PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015 372 4 311 9 25482239 PMC4348009
  13. [18]Gettinger SN Horn L Gandhi L Spigel DR Antonia SJ Rizvi NA Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small- Cell Lung Cancer. J Clin Oncol 2015 pii: JCO.2014.58.3708 PMC4672027 25897158
  14. [19]McDermott DF Drake CG Sznol M Choueiri TK Powderly JD Smith DC Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J Clin Oncol 2015 pii: JCO.2014.58.1041 Epub ahead of print PMC4517051 25800770
  15. [20]Garon EB Rizvi NA Hui R Leighl N Balmanoukian AS Eder JP KEYNOTE-001 Investigators. Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. N Engl J Med 19 4 2015 Epub ahead of print 25891174
  16. [22]Poschke I Mougiakakos D Hansson J Masucci GV Kiessling R Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res 2010 70 11 4335 4520 20484028
  17. [23]Gros A Turcotte S Wunderlich JR Ahmadzadeh M Dudley ME Rosenberg SA Myeloid cells obtained from the blood but not from the tumor can suppress T-cell proliferation in patients with melanoma. Clin Cancer Res 2012 18 19 5212 23 22837179 PMC6374773
  18. [24]Kitano S Postow MA Ziegler CG Kuk D Panageas KS Cortez C Computational algorithm-driven evaluation of monocytic myeloid-derived suppressor cell frequency for prediction of clinical outcomes. Cancer Immunol Res 2014 2 8 812 21 24844912 PMC4125466
  19. [25]Pico de Coaña Y Poschke I Gentilcore G Mao Y Nyström M Hansson J Ipilimumab treatment results in an early decrease in the frequency of circulating granulocytic myeloid-derived suppressor cells as well as their Arginase1 production. Cancer Immunol Res 2013 1 3 158 62 24777678
  20. [26]Tarhini AA Edington H Butterfield LH Lin Y Shuai Y Tawbi H Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One 2014 9 2 e87705 24498358 PMC3912016
  21. [27]Meyer C Cagnon L Costa-Nunes CM Baumgaertner P Montandon N Leyvraz L Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother 2014 63 3 247 57 24357148 PMC11029062
  22. [28]Weide B Martens A Zelba H Stutz C Derhovanessian E Di Giacomo AM Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A-specific T cells. Clin Cancer Res 2014 20 6 1601 9 24323899
  23. [29]Zhao F Hoechst B Dufy A Gamrekelashvili J Fioravanti S Manns MP S100A9: a new marker for monocytic human myeloid derived suppressor cells Immunology 2012 136 2 176 183 22304731 PMC3403264
  24. [33]Lipson EJ Sharfman WH Drake CG Wollner I Taube JM Anders RA Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 2013 19 2 462 8 23169436 PMC3548952

Cited by

Sorted by citations

Authors
Weber, J., Gibney, G., Kudchadkar, R., Yu, B., Cheng, P., Martinez, A. J., Kroeger, J., Richards, A., McCormick, L., Moberg, V., Cronin, H., Zhao, X., Schell, M., & Chen, Y. A.
Affiliations
Moffitt Cancer Center (US)
Corresponding author
Weber, Jeffrey
ORCID
Venue
Cancer Immunology Research
Publisher
American Association for Cancer Research (AACR)
Published
2016-03-31
Volume
4
Issue
4
Pages
345-353
ISSN
  • 2326-6066 (ISSN-L)
  • 2326-6074
DOI
10.1158/2326-6066.cir-15-0193
PMC
PMC4818672
OpenAlex
W2267367070
Cited by
248
References
8
Citations by year
2026: 6 · 2025: 11 · 2024: 14 · 2023: 18 · 2022: 21 · 2021: 35 · 2020: 42 · 2019: 26 · 2018: 31 · 2017: 34 · 2016: 10
FWCI
18.16
Type
journal article
Language
en
Open access
Locations
  • Cancer Immunology Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (RO1 CA 129594-01A2)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
nivolumab, metastatic melanoma, immune checkpoint inhibitors, myeloid-derived suppressor cells, immune-related adverse events, multipeptide vaccine, long-term survival, biomarkers, treatment safety
MeSH terms
Ipilimumab, Nivolumab, Adult, Aged, Antibodies, Monoclonal, Antineoplastic Agents, Combined Modality Therapy, Female, Humans, Male, Melanoma, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Cohort Studies, Biomarkers, Immunophenotyping, Treatment Outcome, Disease Progression, Drug Resistance, Neoplasm, Retreatment, Myeloid Cells, Kaplan-Meier Estimate

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review