Abstract
Development of appropriate pharmacodynamic and safety markers early in drug development can result in a higher probability of success for new drug candidates. As the overarching goal of cancer therapy is to effectively eradicate cancer in a manner that is tolerable and safe for use in the intended patient population, application of biomarkers can facilitate effective patient selection with a positive impact on the final therapeutic outcome. Additionally, combination therapies for the treatment of cancer have emerged as an effective way to anticipate and overcome cancer heterogeneity and resistance. With the emergence of cancer immune oncology (IO), clinical trials for the combination of traditional oncology drugs and immune checkpoint blockade are ongoing. The discussions in this chapter are focused on the use of current and emergent biomarkers in the design and development of treatment combinations for cancer, with a special emphasis on emerging IO therapies.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Notes
- 1.
- 2.
- 3.
- 4.
Arthur Levinson: Presentation in October 2003.
- 5.
- 6.
- 7.
Abbreviations
- BIO:
-
Biotechnology innovation orgaization
- CAP:
-
College of American Pathologists
- CLIA:
-
Clinical Laboratory Improvement Amendments
- CO:
-
Companion diagnostics
- FDA:
-
Food and Drug Administration
- FFPE:
-
Formalin fixed paraformaldehyde embedded
- FIH:
-
First-in-human dose
- GEP:
-
Gene expression profile
- GLP:
-
Good laboratory practice
- H&E:
-
Hematoxylin and eosin
- HED:
-
Human equivalent dose
- HLA:
-
Human leukocyte antigen
- IHC:
-
Immunohistochemistry test
- IO:
-
Immuno-oncology
- irAEs:
-
Immune-related adverse events
- MABEL:
-
Minimally anticipated biological effect level
- MHC:
-
Major histocompatibility complex
- MMR:
-
DNA mismatch repair
- MoA:
-
Mechanism of action
- NHP:
-
Nonhuman primates
- NOAEL:
-
No observed adverse effect level
- NSCLC:
-
Non-small cell lung cancer
- PBMC:
-
Peripheral blood mononuclear cells
- PD:
-
Pharmacodynamic
- PFS:
-
Progression-free survival
- PoC:
-
Proof of concept
- PoM:
-
Proof of mechanism
- RO:
-
Receptor occupancy
- TCR:
-
T-cell receptor
- TPS:
-
Tumor proportion score
- TRAE:
-
Treatment-related adverse events
- VEGF:
-
Vascular endothelial growth factor
References
Agoram BM. Use of pharmacokinetic/ pharmacodynamic modelling for starting dose selection in first-in-human trials of high-risk biologics. Br J Clin Pharmacol. 2009;67(2):153ā60.
Angelo M, Bendall SC, Finck R, et al. Multiplexed ion beam imaging of human breast tumors. Nat Med. 2014;20(4):436ā42.
Ayers M, Lunceford J, Nebozhyn M, et al. IFN-Ī³-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930ā40.
Ballman KV. Biomarker: predictive or prognostic? J Clin Oncol. 2015;33(33):3968ā71.
Berman D, Parker SM, Siegel J, et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 2010;10:11.
Bosslet K, Straub R, Blumrich M, et al. Elucidation of the mechanism enabling tumor selective prodrug monotherapy. Cancer Res. 1998;58(6):1195ā201.
Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13(8):473ā86.
Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent antiāprogrammed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167ā75.
Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98ā106.
Cabel L, Riva F, Servois V, et al. Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study. Ann Oncol. 2017;28(8):1996ā2001.
Callahan MK, Wolchok JD. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J Leukoc Biol. 2013;94(1):41ā53.
Cha E, Klinger M, Hou Y, et al. Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients. Sci Transl Med. 2014;6(238):238ā70.
Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27(4):559ā74.
Chang S, Kohrt H, Maecker HT. Monitoring the immune competence of cancer patients to predict outcome. Cancer Immunol Immunother. 2014;63(7):713ā9.
Chester C, Maecker HT. Algorithmic tools for mining high-dimensional cytometry data. J Immunol. 2015;195(3):773ā9.
Cooper ZA, Frederick DT, Juneja VR, et al. BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes. Oncoimmunology. 2013;2(10):e26615.
Dancey JE, Dobbin KK, Groshen S, et al. Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents. Clin Cancer Res. 2010;16(6):1745ā55.
Davis JC, Furstenthal L, Desai AA, et al. The microeconomics of personalized medicine: todayās challenge and tomorrowās promise. Nat Rev Drug Discov. 2009;8(4):279ā86.
Fong L, Kwek SS, OāBrien S, et al. Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res. 2009;69(2):609ā15.
Fong L, Oh DY, Cham J, et al. T cell repertoire diversification is associated with immune related toxicities following CTLA-4 blockade in cancer patients. Cancer Res. 2016;77(6), canres.2324.2016-1330.
Frederick DT, Piris A, Cogdill AP, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225ā31.
Frei E III, Freireich EJ. Progress and perspectives in the chemotherapy of acute leukemia. Adv Chemother. 1965;2:269ā98.
Funt S, Charen AS, Yusko E, et al. Correlation of peripheral and intratumoral T-cell receptor (TCR) clonality with clinical outcomes in patients with metastatic urothelial cancer (mUC) treated with atezolizumab. J Clin Oncol. 2017;34:3005.
Galon J. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960ā4.
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of nonāsmall-cell lung cancer. N Engl J Med. 2015;372(21):2018ā28.
Giesen C, Wang HA, Schapiro D, et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat Methods. 2014;11(4):417ā22.
Goldberg SB, Narayan A, Kole AJ, et al. Early assessment of lung cancer immunotherapy response via circulating tumor DNA. Clin Cancer Res. 2018;24(8):1872ā80. clincanres.1341.2017.
Granier C, De Guillebon E, Blanc C, et al. Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open. 2017;2(2):e000213.
Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515(7528):577ā81.
Guibert N, Mazieres J, Delaunay M, et al. Monitoring of KRAS-mutated ctDNA to discriminate pseudo-progression from true progression during anti-PD-1 treatment of lung adenocarcinoma. Oncotarget. 2017;8(23):38056ā60.
Hadrup SR, Bakker AH, Shu CJ, et al. Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers. Nat Methods. 2009;6(7):520ā6.
Hamid O, Schmidt H, Nissan A, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med. 2011;9(1):204.
Harrison RK. Phase II and phase III failures: 2013-2015. Nat Rev Drug Discov. 2016;15(12):817ā8.
Herbst RS, Soria J-C, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563ā7.
Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008;105(8):3005ā10.
Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013;31(Suppl 18):CRA9007.
Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014a;2(7):632ā42.
Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014b;312(17):1744ā53.
Huss DJ, Mehta DS, Sharma A, et al. In vivo maintenance of human regulatory T cells during CD25 blockade. J Immunol. 2015;194(1):84ā92.
Iijima Y, Hirotsu Y, Amemiya K, et al. Very early response of circulating tumour-derived DNA in plasma predicts efficacy of nivolumab treatment in patients with non-small cell lung cancer. Eur J Cancer. 2017;86:349ā57.
Ilie M, Hofman V, Dietel M, et al. Assessment of the PD-L1 status by immunohistochemistry: challenges and perspectives for therapeutic strategies in lung cancer patients. Virchows Arch. 2016;468(5):511ā25.
Kerr KM, Tsao M-S, Nicholson AG, et al. Programmed death-ligand 1 immunohistochemistry in lung cancer: in what state is this art? J Thorac Oncol. 2015;10(7):985ā9.
Khanna R, Guler I, Nerkar A. Fail often, fail big, and fail fast? Learning from small failures and R&D performance in the pharmaceutical industry. Acad Manag J. 2016;59(2):436ā59.
Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497ā508.
Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867ā76. https://doi.org/10.1056/NEJMoa1408868.
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23ā34.
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509ā20.
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409ā13.
Lee JW, Weiner RS, Sailstad JM, et al. Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development: a conference report. Pharm Res. 2005;22(4):499ā511.
Lee JW, Kelley M, King LE, et al. Bioanalytical approaches to quantify ?Total? And ?Free? Therapeutic antibodies and their targets: technical challenges and PK/PD applications over the course of drug development. AAPS J. 2011;13(1):99ā110.
Liang M, Schwickart M, Schneider AK, et al. Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development. Cytometry B Clin Cytom. 2016;90(2):117ā27.
Mandrekar SJ, Sargent DJ. Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. J Clin Oncol. 2009;27(24):4027ā34.
Manson G, Norwood J, Marabelle A, et al. Biomarkers associated with checkpoint inhibitors. Ann Oncol. 2016;27(7):1199ā206.
Marton MJ, Weiner R. Practical guidance for implementing predictive biomarkers into early phase clinical studies. Biomed Res Int. 2013;2013:891391ā9.
Masucci GV, Cesano A, Hawtin R, et al. Validation of biomarkers to predict response to immunotherapy in cancer: volume I ? Pre-analytical and analytical validation. J Immunother Cancer. 2016;4(1):1129.
McDermott JE, Wang J, Mitchell H, et al. Challenges in biomarker discovery: combining expert insights with statistical analysis of complex omics data. Expert Opin Med Diagn. 2013;7(1):37ā51.
McNeel DG. TCR diversityāa universal cancer immunotherapy biomarker? J Immunother Cancer. 2016;4(1):69.
Melero I, Berman DM, Aznar MA, et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8):457ā72.
Muller PY, Milton M, Lloyd P, et al. The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies. Curr Opin Biotechnol. 2009;20(6):722ā9.
Oh DY, Cham J, Zhang L, et al. Immune toxicities elicted by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire. Cancer Res. 2017;77(6):1322ā30.
Osada T, Chong G, Tansik R, et al. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol Immunother. 2008;57(8):1115ā24.
Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547(7662):217ā21.
Page DB, Yuan J, Redmond D, et al. Deep sequencing of T-cell receptor DNA as a biomarker of clonally expanded TILs in breast cancer after immunotherapy. Cancer Immunol Res. 2016;4(10):835ā44.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252ā64.
Patel SP, Kim DW, Bassett RL, et al. A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma. Cancer Immunol Immunother. 2017;33(17):1889ā8.
Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015a;372(21):2006ā17.
Postow MA, Manuel M, Wong P, et al. Peripheral T cell receptor diversity is associated with clinical outcomes following ipilimumab treatment in metastatic melanoma. J Immunother Cancer. 2015b;3(1):23.
Puzanov I. Combining targeted and immunotherapy: BRAF inhibitor dabrafenib (D) Ā± the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation-positive unresectable or metastatic melanoma (MM). J Transl Med. 2015;13(1):K8.
Rationalizing combination therapies. Nat Med. 2017;23(10):1113.
Ribas A, Tumeh PC. The future of cancer therapy: selecting patients likely to respond to PD1/L1 blockade. Clin Cancer Res. 2014;20(19):4982ā4.
Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365ā6.
Ribas A, Butler M, Lutzky J, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol. 2017a;33:3003.
Ribas A, Hodi FS, Lawrence D. KEYNOTE-022 update: phase 1 study of first-line pembrolizumab (pembro) plus dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma. Ann Oncol. 2017b;28(Suppl 5):v428ā48.
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124ā8.
Robbins PF, Lu Y-C, El-Gamil M, et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med. 2013;19(6):747ā52.
Robert L, Tsoi J, Wang X, et al. CTLA4 blockade broadens the peripheral T-cell receptor repertoire. Clin Cancer Res. 2014;20(9):2424ā32.
Saber H, Gudi R, Manning M, et al. An FDA oncology analysis of immune activating products and first-in-human dose selection. Regul Toxicol Pharmacol. 2016;81:448ā56.
Saeys Y, Van Gassen S, Lambrecht BN. Computational flow cytometry: helping to make sense of high-dimensional immunology data. Nat Rev Immunol. 2016;16(7):449ā62.
Sahin U, Derhovanessian E, Miller M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017;547(7662):222ā6.
Schindler K, Harmankaya K, Kuk D, et al. Correlation of absolute and relative eosinophil counts with immune-related adverse events in melanoma patients treated with ipilimumab. J Clin Oncol. 2017;32:9096.
Shahabi V, Berman D, Chasalow SD, et al. Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events. J Transl Med. 2013;11(1):75.
Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205ā14.
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189ā99.
Snyder A, Wolchok JD, Chan TA. Genetic basis for clinical response to CTLA-4 blockade. N Engl J Med. 2015;372(8):783.
Stewart JJ, Green CL, Jones N, et al. Role of receptor occupancy assays by flow cytometry in drug development. Cytometry B Clin Cytom. 2016;90(2):110ā6.
Subudhi SK, Aparicio A, Gao J, et al. Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc Natl Acad Sci U S A. 2016;113(42):11919ā24.
Suh HY, Peck CC, Yu K-S, Lee H. Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013. Drug Des Devel Ther. 2016;10:4005ā16.
Sullivan RJ, Gonzalez R, Lewis KD, et al. Atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in BRAFV600-mutant metastatic melanoma (mel): updated safety and clinical activity. J Clin Oncol. 2017;35:3057.
Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018ā28.
Tarhini AA, Zahoor H, Lin Y, et al. Baseline circulating IL-17 predicts toxicity while TGF-Ī²1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J Immunother Cancer. 2015;3(1):39.
Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4(127):127ā37.
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24(2):207ā12.
Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16(5):275ā87.
Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344(6184):641ā5.
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568ā71.
Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350(6257):207ā11.
van der Veldt AAM, Hendrikse NH, Smit EF, et al. Biodistribution and radiation dosimetry of 11C-labelled docetaxel in cancer patients. Eur J Nucl Med Mol Imaging. 2010;37(10):1950ā8.
van Rooij N, van Buuren MM, Philips D, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013;31(32):e439ā42.
Waitz R, Solomon SB, Petre EN, et al. Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy. Cancer Res. 2012;72(2):430ā9.
Williams GW. The other side of clinical trial monitoring; assuring data quality and procedural adherence. Clin Trials. 2006;3(6):530ā7.
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013a;369(2):122ā33.
Wolchok JD, Hodi FS, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013b;1291(1):1ā13.
Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345ā56.
Woodcock J, Griffin JP, Behrman RE. Development of novel combination therapies. N Engl J Med. 2011;364(11):985ā7.
Xi L, Pham TH-T, Payabyab EC, et al. Circulating tumor DNA as an early indicator of response to T-cell transfer immunotherapy in metastatic melanoma. Clin Cancer Res. 2016;22(22):5480ā6.
Yadav M, Jhunjhunwala S, Phung QT, et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature. 2014;515(7528):572ā6.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
Ā© 2018 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Sukumar, S., Caculitan, N.G. (2018). Translational Biomarkers: Application in the Clinical Development of Combination Therapies. In: Tabrizi, M., Bornstein, G., Klakamp, S. (eds) Development of Antibody-Based Therapeutics. Adis, Singapore. https://doi.org/10.1007/978-981-13-0496-5_12
Download citation
DOI: https://doi.org/10.1007/978-981-13-0496-5_12
Published:
Publisher Name: Adis, Singapore
Print ISBN: 978-981-13-0495-8
Online ISBN: 978-981-13-0496-5
eBook Packages: MedicineMedicine (R0)