Prolonged Response to Anti–PD-1 Antibody Therapy in Chemotherapy-Refractory Cholangiocarcinoma With High Tumor Mutational Burden

Authors: Olumide Gbolahan MBBS a , Neda Hashemi-Sadraei MBBS b and Bert O’Neil MD c
View More View Less
  • a University of Alabama at Birmingham School of Medicine, Birmingham, Alabama;
  • b University of New Mexico School of Medicine, Albuquerque, New Mexico; and
  • c Indiana University School of Medicine, Indianapolis, Indiana.
Volume/Issue:
Volume 17: Issue 6
Online Publication Date:
Jun 2019
DOI:
https://doi.org/10.6004/jnccn.2019.7304
Restricted access

All currencies in US Dollar

PayPal Logo

Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.

Submitted August 9, 2018; accepted for publication March 29, 2019.

Disclosures: The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.

Correspondence: Olumide Gbolahan, MBBS, University of Alabama at Birmingham School of Medicine, NP2540J, 1802 Sixth Avenue South, Birmingham, AL 35233. Email: ogbolahan@uabmc.edu
  • 1.

    Endo I, Gonen M, Yopp AC, . Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 2008;248:84–96.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    de Jong MC, Nathan H, Sotiropoulos GC, . Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 2011;29:3140–3145.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Valle J, Wasan H, Palmer DH, .. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273–1281.
  • 4.

    Saha SK, Zhu AX, Fuchs CS, . Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist 2016;21:594–599.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Bang YJ, Doi T, De Braud F, . Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: interim results of KEYNOTE-028 [abstract]. Eur J Cancer 2015;51(Suppl 3):Abstract 525.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Frampton GM, Fichtenholtz A, Otto GA, . Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013;31:1023–1031.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Schadendorf D, Hodi FS, Robert C, . Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015;33:1889–1894.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Reck M, Rodríguez-Abreu D, Robinson AG, .. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–1833.
  • 9.

    Grigg C, Rizvi NA. PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction? J Immunother Cancer 2016;4:48.
  • 10.

    McLaughlin J, Han G, Schalper KA, . Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol 2016;2:46–54.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Le DT, Uram JN, Wang H, . PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–2520.
  • 12.

    Liontos M, Anastasiou I, Bamias A, . DNA damage, tumor mutational load and their impact on immune responses against cancer. Ann Transl Med 2016;4:264.
  • 13.

    Goodman AM, Kato S, Bazhenova L, . Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 2017;16:2598–2608.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Snyder A, Makarov V, Merghoub T, . Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189–2199.
  • 15.

    Rizvi H, Sanchez-Vega F, La K, . Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 2018;36:633–641.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Salem ME, Xiu J, Weinberg BA, . Characterization of tumor mutation burden (TMB) in gastrointestinal (GI) cancers [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 530.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Jain A, Shroff RT, Zuo M, . Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC) [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 4086.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Chalmers ZR, Connelly CF, Fabrizio D, . Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017;9:34.
  • 19.

    Hellmann MD, Ciuleanu TE, Pluzanski A, . Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018;378:2093–2104.
  • 20.

    Bartley AN, Luthra R, Saraiya DS, . Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing. Cancer Prev Res (Phila) 2012;5:320–327.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Cicek MS, Lindor NM, Gallinger S, . Quality assessment and correlation of microsatellite instability and immunohistochemical markers among population- and clinic-based colorectal tumors results from the Colon Cancer Family Registry. J Mol Diagn 2011;13:271–281.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Lee JH, Cragun D, Thompson Z, . Association between IHC and MSI testing to identify mismatch repair-deficient patients with ovarian cancer. Genet Test Mol Biomarkers 2014;18:229–235.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Vilkin A, Niv Y, Nagasaka T, . Microsatellite instability, MLH1 promoter methylation, and BRAF mutation analysis in sporadic colorectal cancers of different ethnic groups in Israel. Cancer 2009;115:760–769.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Gras E, Catasus L, Argüelles R, . Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors. Cancer 2001;92:2829–2836.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Golan T, Raitses-Gurevich M, Kelley RK, . Overall survival and clinical characteristics of BRCA-associated cholangiocarcinoma: a multicenter retrospective study. Oncologist 2017;22:804–810.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Zou S, Li J, Zhou H, . Mutational landscape of intrahepatic cholangiocarcinoma. Nat Commun 2014;5:5696.
  • 27.

    Birkbak NJ, Kochupurakkal B, Izarzugaza JM, . Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations. PLoS One 2013;8:e80023.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Strickland KC, Howitt BE, Shukla SA, . Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget 2016;7:13587–13598.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
Copyright:
Copyright © 2019 by the National Comprehensive Cancer Network 2019
Page Numbers:
644–648
Article Category:
Other
Received:
09 Aug 2018
Accepted:
29 Mar 2019
Print Publication Date:
01 Jun 2019
Online Publication Date:
Jun 2019
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 2224 626 48
PDF Downloads 809 395 72
EPUB Downloads 0 0 0