Immuntherapien beim fortgeschrittenen NSCLC

Martin Reck; Wolfgang Schütte; Nicolas J. Dickgreber; Niels Reinmuth; Thomas Wehler; Stefanie Morris; Achim Rittmeyer; Wilko Weichert

doi:10.1055/s-0043-122013

TumorDiagnostik & Therapie, Table of Contents

TumorDiagnostik & Therapie 2018; 39(06): 371-384
DOI: 10.1055/s-0043-122013

Thieme Onkologie aktuell

Immuntherapien beim fortgeschrittenen NSCLC

Neue Entwicklungen durch Immuntherapien mit Checkpoint-Inhibitoren und ihre Implikationen für die klinische PraxisImmunotherapies in advanced NSCLCNew developments by immunotherapies with checkpoint-inhibitors and their implications for clinical practice

Authors

Martin Reck

¹LungenClinic Grosshansdorf
Wolfgang Schütte

²Krankenhaus Martha-Maria Halle-Dölau
Nicolas J. Dickgreber

³Mathias-Spital Rheine
Niels Reinmuth

⁴Asklepios Fachkliniken München-Gauting
Thomas Wehler

⁵Universitätsklinikum des Saarlandes
Stefanie Morris

⁶Roche Pharma AG Grenzach-Wyhlen
Achim Rittmeyer

⁷Lungenfachklinik Immenhausen
Wilko Weichert

⁸Institut für Pathologie, Technische Universität München

Abstract

Zusammenfassung

Der Einzug von Immuntherapien mit Checkpoint-Inhibitoren in die Behandlung des fortgeschrittenen nicht kleinzelligen Lungenkarzinoms (NSCLC) hat die Erst- und Zweitlinientherapie revolutioniert. Nach langem therapeutischem Stillstand für die große Gruppe von Patienten ohne therapierbare Treibermutationen stehen nun erstmals neue Behandlungsoptionen zur Verfügung. Aktuell werden Kombinationstherapien geprüft, die das Potenzial der Immuntherapien noch besser ausschöpfen sollen. Für den Kliniker heißt das aber auch, dass die Therapieentscheidungen beim metastasierten NSCLC immer komplexer werden. Daher möchte die vorliegende Publikation vor allem folgende Fragen beantworten: Wie verändern die aktuell etablierten Immuntherapien unser Vorgehen in der klinischen Praxis? Welche Kriterien eignen sich zur Auswahl geeigneter Therapieschemata? Welche Herausforderungen müssen zukünftig noch gemeistert werden?

Abstract

The approval of immunotherapies has revolutionized the first and second line therapy of advanced non-small cell lung cancer (NSCLC). For a long time, no potent treatment was available for a large group of patients with NSCLC without treatable driver mutations. Now novel treatment options have become available for this group. Combination therapies aiming at further extending the potential of immunotherapies are currently under investigation. For clinicians, this also means that decision making in treating metastatic NSCLC is getting much more complex. Thus, the aim of the present publication primarily is to answer the following questions: How do immunotherapies change our procedures in clinical practice? Which criteria are appropriate for choosing the right treatment schedules? Which challenges have to be managed in the near future?

Schlüsselwörter

NSCLC - Immuntherapie - Checkpoint-Inhibitoren

Key words

non-small cell lung cancer - immunotherapy - immune checkpoint inhibitor

Full Text

References

Literatur
1 Griesinger F. et al. DGHO-Leitlinie nicht-kleinzelliges Lungenkarzinom. Stand: April 2017 https://www.onkopedia.com/de/onkopedia/guidelines/lungenkarzinom-nicht-kleinzellig-nsclc/@@view/html/index.html (Abruf am 19.4.2017)
2 Tsao AS. et al. Scientific Advances in Lung Cancer 2015. J Thorac Oncol 2016; 11 (05) 613-638
3 Pardoll DM. et al. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252-264
4 Igney FH. et al. Immune escape of tumors: apoptosis resistance and tumor counterattack. J Leukoc Biol 2002; 71 (06) 907-920
5 Goubran HA. et al. Regulation of tumor growth and metastasis: the role of tumor microenvironment. Cancer Growth Metastasis 2014; 7: 9-18
6 Paterson AM. et al. The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J Immunol 2011; 187: 1097-1105
7 Schmid P. et al. Association of PD-L2 expression in human tumors with atezolizumab activity. J Clin Oncol 2016 34. (suppl; abstr 11506)
8 Fehrenbacher L. 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. Lancet 2016; 387: 1837-1846
9 Chen DS. et al. Molecular Pathways: Next-Generation Immunotherapy – Inhibiting Programmed Death-Ligand 1 and Programmed Death-1. Clin Cancer Res 2012; 18 (24) 6580-6587
10 Herbst RS. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515: 563-567
11 Yang J. et al. The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 2011; 187 (03) 1113-1119
12 Brown JA. et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 2003; 170 (03) 1257-1266
13 Akbari O. et al. PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunol 2010; 3 (01) 81-91
14 Butte MJ. et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27 (01) 111-122
15 Butte Mj. et al. Interaction of human PD-L1 and B7-1. Mol Immunol 2008; 45 (13) 3567-3572
16 Park JJ. et al. B7-H1 / CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 2010; 116 (08) 1291-1298
17 Fachinformation Keytruda^®, 25 mg, 25 mg/ml. Stand: März 2017
18 Reck M. et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016; 375 (19) 1823-1833
19 Reck M. et al. ESMO 2016, Presidential Symposium 2, abstr. LBA8_PR
20 Brahmer JR. et al. Progression after the next line of therapy (PFS2) and updated OS among patients with advanced NSCLC and PD-L1 TPS ≥50% enrolled in KEYNOTE-024. J Clin Oncol; 2017 35. (suppl; abstr 9000)
21 Brahmer J. et al. Health-related Quality of Life for Pembrolizumab vs. Chemotherapy in advanced NSCLC with PD-L1 TPS ≥50%; Data from KEYNOTE-024. abstr. PL04a.01
22 Carbone DP. et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med 2017; 376 (25) 2415-2426
23 Fachinformation Opdivo^® . Stand: Juni 2017
24 Fachinformation Tecentriq^® . Stand: September 2017
25 Borghaei H. et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373: 1627-1639
26 Brahmer J. et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373: 123-135
27 Herbst RS. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387: 1540-1550
28 Rittmeyer A. et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. The Lancet 2017; 389: 255-265
29 Felip Font E. et al. Three-year follow-up from CheckMate 017/057: Nivolumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC). Ann Onc 2017; 28 (Suppl. 05) v460-v496
30 Peters S. et al. Analysis of Early Survival in Patients With Advanced Non-squamous NSCLC Treated With Nivolumab vs Docetaxel in CheckMate-057. Presented at: IASLC 17th World Conference on Lung Cancer; Vienna, Austria: December 4–7, 2016. Abstract OA03.05
31 Reck M. et al. Overall health status (HS) in patients (pts) with advanced (adv) non-squamous (NSQ) NSCLC treated with nivolumab (nivo) or docetaxel (doc) in CheckMate 057. ESMO; 2016 abstr. 1217PD
32 Gralla R. et al. Lung Cancer Symptom Scale (LCSS) as a marker of treatment (tx) benefit with nivolumab (nivo) vs docetaxel (doc) in patients (pts) with advanced (adv) non-squamous (NSQ) NSCLC from CheckMate 057. J Clin Oncol; 2016 34. (suppl; abstr 9031)
33 Reck M. et al. Evaluation of overall health status in patients with advanced squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 017. Paper presented at: European Cancer Congress; September 25–29, 2015; Vienna
34 Herbst RS. et al. Factors associated with better overall survival (OS) in patients with previously treated, PD-L1–expressing, advanced NSCLC: Multivariate analysis of KEYNOTE-010. J Clin Oncol 2017 35. no. 15_suppl: 9090-909035
35 Barlesi F. et al. Assessment of health-related quality of life (HRQoL) in KEYNOTE-010: A phase 2/3 study of pembrolizumab vs docetaxel in patients with previously treated advanced NSCLC. Annals of Oncology 2016; 27 (Suppl. 06) vi416-vi454, 1219P
36 Scheel AH. et al. Predictive PD-L1 immunohistochemistry for non-small cell lung cancer: Current state of the art and experiences of the first German harmonization study. Pathologe 2016; 37 (06) 557-567
37 Scheel AH. et al. Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas. Mod Pathol 2016; 29 (10) 1165-1172
38 Hirsch FR. et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol 2017; 12 (02) 208-222
39 Rimm DL. et al. A Prospective, Multi-institutional, Pathologist-Based Assessment of 4 Immunohistochemistry Assays for PD-L1 Expression in Non-Small Cell Lung Cancer. JAMA Oncol 2017; [Epub ahead of print]
40 Gadgeel S. et al. Clinical efficacy of atezolizumab (Atezo) in PD-L1 subgroups defined by SP142 and 22C3 IHC assays in 2L+ NSCLC: Results from the randomized OAK study. ESMO; 2017 abstr. 1296O
41 Des Guetz G. et al. Anti PD-1 (nivolumab, pembrolizumab) or anti PD-L1 (atezolizumab) versus docetaxel for previously treated patients with advanced NSCLC: A meta-analysis. J Clin Oncol; 2016 34. (suppl; abstr e20555)
42 Rizvi NA. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348: 124-128
43 Lukas R. et al. P2.03b-014 Atezolizumab in Advanced NSCLC Patients with Baseline Brain Metastases: A Pooled Cohort Safety Analysis. Journal of Thoracic Oncology 2017; 12 (01) S941-S942
44 Goldberg SB. et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 2016; 17 (07) 976-983
45 Goldmann JW. et al. Nivolumab (nivo) in patients (pts) with advanced (adv) NSCLC and central nervous system (CNS) metastases (mets). J Clin Oncol; 2016 34. (suppl; abstr 9038)
46 Foller S. et al. Adverse events of immune checkpoint inhibitors. Urologe A 2017; 56 (04) 486-491
47 Pillai RN. et al. Evaluation of Toxicity Profile of PD-1 versus PD-L1 Inhibitors in Non-Small Cell Lung Cancer. Presented at the International Association for the study of Lung Cancer 17th World Conference on Lung Cancer; December 4–7, 2016 Vienna, Austria: abstr. 0A03.06
48 Khunger M. et al. Incidence of pneumonitis with use of PD-1 and PD-L1 inhibitors in non-small cell lung cancer: A Systematic Review and Meta-analysis of trials. Chest 2017;
49 Schvartsman G. et al. Response to single-agent (SA) chemotherapy (CTx) after immunotherapy exposure in nonsmall cell lung cancer (NSCLC). J Clin Oncol; 2017 35. (suppl; abstr 9083)
50 Leger PD. et al. Response to salvage chemotherapy following exposure to immune checkpoint inhibitors in patients with non-small cell lung cancer. J Clin Oncol; 2017 35. (suppl; abstr 9084)
51 Gandara DR. et al. Impact of atezolizumab (atezo) treatment beyond disease progression (TBP) in advanced NSCLC: Results from the randomized phase III OAK study. J Clin Oncol; 2017 35. (suppl; abstr 9001)
52 Kumar V. et al. Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. Front Pharmacol 2017; 8: 49
53 Oppel-Heuchel H. et al. Therapy monitoring and management of adverse events in PD-1/PD-L1 immune checkpoint inhibition. Urologe A 2016; 55 (05) 677-690
54 Gadgeeel SM. et al. OAK, a randomized Ph III study of atezolizumab vs docetaxel in patients with advanced NSCLC: results from subgroup analyses. WCLC; 2016 abstr. PL04a.02
55 Seng-Ryong W. et al. The STING pathway and the T cell-inflamed tumor microenvironment. Trends Immunol 2015; 36 (04) 250-256
56 Williams JA. et al. The SP142 PD-L1 IHC Assay for Atezolizumab Reflects Pre-Existing Immune Status in NSCLC and Correlates With PD-L1 mRNA. ESMO; 2016 abstr. 1171P
57 Fehrenbacher L. 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. Lancet 2016; 387: 1837-1846
58 Kowanetz M. et al. Tumor mutation burden (TMB) is associated with improved efficacy of atezolizumab in 1L and 2L+ NSCLC patients. WCLC; 2016 abstr. OA20.01
59 Peters S. et al. Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1–5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017; 77 (Suppl. 13) Abstract nr CT082
60 Danilova L. et al. Association of PD-1/PD-L axis expression with cytolytic activ- ity, mutational load, and prognosis in melanoma and other solid tumors. Proc Natl Acad Sci USA 2016; 113 (48) E7769-E7777
61 Weijie MA. et al. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. Journal of Hematology & Oncology 2016; 9: 47
62 Brahmer J. et al. Five-year follow-up from the CA209-003 study of Nivolumab in previously treated advanced non-small cell lung cancer: clinical characteristics of long-term survivors. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; Wahshington, DC: Abstract CT077
63 Anagnostou V. et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov 2016;
64 Medler RT. et al. Immune Response to Cancer Therapy: Mounting an Effective Antitumor Response and Mechanisms of Resistance. Trends Cancer 2015; 1 (01) 66-75
65 Twyman-Saint Victor C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520: 373-377