PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction?

Research in cancer immunology is currently accelerating following a series of cancer immunotherapy breakthroughs during the last 5 years. Various monoclonal antibodies which block the interaction between checkpoint molecules PD-1 on immune cells and PD-L1 on cancer cells have been used to successfully treat non-small cell lung cancer (NSCLC), including some durable responses lasting years. Two drugs, nivolumab and pembrolizumab, are now FDA approved for use in certain patients who have failed or progressed on platinum-based or targeted therapies while agents targeting PD-L1, atezolizumab and durvalumab, are approaching the final stages of clinical testing. Despite impressive treatment outcomes in a subset of patients who receive these immune therapies, many patients with NSCLC fail to respond to anti-PD-1/PD-L1 and the identification of a biomarker to select these patients remains highly sought after. In this review, we discuss the recent clinical trial results of pembrolizumab, nivolumab, and atezolizumab for NSCLC, and the significance of companion diagnostic testing for tumor PD-L1 expression.

[1]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[2]  J. Cheville,et al.  Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. , 2006, Cancer research.

[3]  J. Crowley,et al.  The IASLC Lung Cancer Staging Project: Validation of the Proposals for Revision of the T, N, and M Descriptors and Consequent Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant Tumours , 2007, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[4]  Axel Hoos,et al.  Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria , 2009, Clinical Cancer Research.

[5]  S. Qiu,et al.  Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma , 2009, Clinical Cancer Research.

[6]  Israel Lowy,et al.  Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  C. Mu,et al.  High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation , 2011, Medical oncology.

[8]  C. Mu,et al.  Clinical Significance of Programmed Death-1 Ligand-1 Expression in Patients with Non-Small Cell Lung Cancer: A 5-year-follow-up Study , 2012, Tumori.

[9]  C. Mu,et al.  Clinical Significance of Programmed Death-1 Ligand-1 Expression in Patients with Non-Small Cell Lung Cancer: A 5-year-follow-up Study , 2012 .

[10]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[11]  D. Pardoll,et al.  Immune Checkpoint Inhibitors: Making Immunotherapy a Reality for the Treatment of Lung Cancer , 2013, Cancer Immunology Research.

[12]  J. Lunceford,et al.  Clinical efficacy and correlation with tumor PD-L1 expression in patients (pts) with melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475. , 2014 .

[13]  L. Bracci,et al.  Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer , 2013, Cell Death and Differentiation.

[14]  T. Illidge,et al.  Radiation Therapy Induces an Adaptive Upregulation of PD-L1 on Tumor Cells Which May Limit the Efficacy of the Anti-Tumor Immune Response But Can Be Circumvented by Anti-PD-L1 , 2014 .

[15]  R. Herbst,et al.  Programmed death ligand-1 expression in non-small cell lung cancer , 2014, Laboratory Investigation.

[16]  Yih-Leong Chang,et al.  Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes. , 2014, European journal of cancer.

[17]  H. Kohrt,et al.  Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients , 2014, Nature.

[18]  J. Taube,et al.  Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial. , 2014 .

[19]  Y. Nakanishi,et al.  Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  P. Hegde,et al.  MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer , 2014, Nature.

[21]  R. Weichselbaum,et al.  Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. , 2014, The Journal of clinical investigation.

[22]  J. Wolchok,et al.  Genetic basis for clinical response to CTLA-4 blockade in melanoma. , 2014, The New England journal of medicine.

[23]  S. Gettinger,et al.  Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: Interim phase I results. , 2014 .

[24]  J. Taube,et al.  Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy , 2014, Clinical Cancer Research.

[25]  J. Lunceford,et al.  Abstract CT105: MK-3475 (anti-PD-1 monoclonal antibody) for non-small cell lung cancer (NSCLC): Antitumor activity and association with tumor PD-L1 expression , 2014 .

[26]  S. Gettinger,et al.  Clinical activity and safety from a phase II study (FIR) of MPDL3280A (anti-PDL1) in PD-L1–selected patients with non-small cell lung cancer (NSCLC). , 2015 .

[27]  J. Yi,et al.  14LBA Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer: Primary analyses for efficacy, safety and predictive biomarkers from a randomized phase II study (POPLAR) , 2015 .

[28]  P. Jänne,et al.  16LBA Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC) , 2015 .

[29]  L. Crinò,et al.  Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[30]  R. Rosell,et al.  Assays for predicting and monitoring responses to lung cancer immunotherapy , 2015, Cancer biology & medicine.

[31]  P. Klenerman,et al.  POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer , 2015, Clinical Cancer Research.

[32]  C. Rudin,et al.  Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[33]  David C. Smith,et al.  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. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  J. Lunceford,et al.  Pembrolizumab for the treatment of non-small-cell lung cancer. , 2015, The New England journal of medicine.

[35]  H. Burris,et al.  An ongoing phase IIIb/IV safety trial of nivolumab (NIVO) in patients (pts) with advanced or metastatic non-small-cell lung cancer (NSCLC) who progressed after receiving 1 or more prior systemic regimens. , 2015 .

[36]  B. Zhu,et al.  T-cell exhaustion in the tumor microenvironment , 2015, Cell Death and Disease.

[37]  H. Ishwaran,et al.  Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer , 2015, Nature.

[38]  G. Linette,et al.  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. , 2015, The Lancet. Oncology.

[39]  Keunchil Park,et al.  Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). , 2015 .

[40]  Bert Vogelstein,et al.  PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. , 2015, The New England journal of medicine.

[41]  D. Schadendorf,et al.  Nivolumab in previously untreated melanoma without BRAF mutation. , 2015, The New England journal of medicine.

[42]  M. Valsecchi.  Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. , 2015, The New England journal of medicine.

[43]  S. Ou,et al.  Safety and efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. , 2015 .

[44]  J. Larkin,et al.  Pembrolizumab versus Ipilimumab in Advanced Melanoma. , 2015, The New England journal of medicine.

[45]  K. Steele,et al.  Phase Ib study of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in patients (pts) with advanced NSCLC. , 2015 .

[46]  Y. Xing,et al.  Oncotargets and Therapy Dovepress Prognostic Value of Programmed Cell Death-ligand 1 Expression in Patients with Non-small-cell Lung Cancer: Evidence from an Updated Meta-analysis , 2022 .

[47]  Patrick Schöffski,et al.  Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). , 2015 .

[48]  J. Utikal,et al.  Efficacy based on tumor PD-L1 expression in KEYNOTE-002, a randomized comparison of pembrolizumab (pembro; MK-3475) versus chemotherapy in patients (pts) with ipilimumab-refractory (IPI-R) advanced melanoma (MEL). , 2015 .

[49]  T. Jiang,et al.  The impact of clinical characteristics on outcomes from maintenance therapy in non-small cell lung cancer: A systematic review with meta-analysis. , 2015, Lung cancer.

[50]  A. Chella,et al.  PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients , 2014, British Journal of Cancer.

[51]  B. Chan,et al.  Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. , 2015, Translational lung cancer research.

[52]  Yong Song,et al.  PD-L1 over-expression and survival in patients with non-small cell lung cancer: a meta-analysis. , 2015, Translational lung cancer research.

[53]  H. Zhang,et al.  The prognostic value of PD-L1 expression for non-small cell lung cancer patients: a meta-analysis. , 2015, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[54]  Martin L. Miller,et al.  Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer , 2015, Science.

[55]  K. Kelly,et al.  Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: A phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. , 2015 .

[56]  C. Mathers,et al.  Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 , 2015, International journal of cancer.

[57]  F. Cappuzzo,et al.  Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. , 2015, The Lancet. Oncology.

[58]  G. Coukos,et al.  Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[59]  H. An,et al.  Clinicopathological and prognostic significance of programmed cell death ligand1 (PD-L1) expression in patients with non-small cell lung cancer: a meta-analysis. , 2015, Journal of thoracic disease.

[60]  A. Jemal,et al.  Cancer statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[61]  Keunchil Park,et al.  Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial , 2016, The Lancet.

[62]  N. Chen,et al.  Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer , 2016, Scientific Reports.

[63]  R. Bourgon,et al.  Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial , 2016, The Lancet.

[64]  S. Gettinger,et al.  CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. , 2016 .

[65]  Marius Ilie,et al.  Assessment of the PD-L1 status by immunohistochemistry: challenges and perspectives for therapeutic strategies in lung cancer patients , 2016, Virchows Archiv.

[66]  Y. Shentu,et al.  Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial , 2016, The Lancet.

[67]  K. Steele,et al.  Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. , 2016, The Lancet. Oncology.

[68]  Manish R. Patel,et al.  Safety, clinical activity, and PD-L1 expression of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with metastatic urothelial carcinoma from the JAVELIN Solid Tumor phase Ib trial. , 2016 .

[69]  P. Baas,et al.  Pembrolizumab for the treatment of non-small cell lung cancer , 2017, Expert review of anticancer therapy.

[70]  F. Hirsch,et al.  PD‐L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD‐L1 IHC Assay Comparison Project , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[71]  R. Herbst,et al.  Immunotherapy in Lung Cancer. , 2017, Hematology/oncology clinics of North America.