Download PDF
Zentralbl Chir 2024; 149(S 01): S35-S44
DOI: 10.1055/a-2353-6336
Thoraxchirurgie
Übersicht

Perioperative Immuntherapie beim operablen Lungenkarzinom: aktuelle Studienlage und neue Therapiestandards

Perioperative Immunotherapy for Resectable Non-Small Cell Lung Cancer: Current Evidence and New Standard of Care
Uyen-Thao Le
1   Klinik für Thoraxchirurgie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Deutschland
,
Birte Ohm
1   Klinik für Thoraxchirurgie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Deutschland
,
Severin Schmid 
1   Klinik für Thoraxchirurgie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Deutschland
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Zusammenfassung

Die Einführung der Immuntherapie hat die Behandlung des Lungenkarzinoms drastisch verändert, wobei auch die perioperative Applikation bei lokal fortgeschrittenen nicht kleinzelligen Lungenkarzinomen ermutigende Ergebnisse gezeigt hat. Die neoadjuvanten und perioperativen Therapieregime der CheckMate-816- und KEYNOTE-671-Studie sowie die adjuvanten Therapien nach dem IMPower010- und dem PEARLS/KEYNOTE-091-Protokoll wurden bereits von der Europäischen Arzneimittel-Agentur (EMA) für die Behandlung ausgewählter Fälle zugelassen. Weitere Therapieregime und Kombinationstherapien mit unterschiedlichen Wirkstoffgruppen und Therapiemodalitäten werden derzeit auf ihre Wirksamkeit und Verträglichkeit überprüft. Aus der veränderten Therapielandschaft ergeben sich neue Möglichkeiten, aber auch Herausforderungen für die behandelnden Disziplinen. Die aktuelle Studienlage zur perioperativen Immuntherapie des resektablen Lungenkarzinoms und die sich daraus ergebenden Handlungsempfehlungen, insbesondere bez. der Patientenselektion sowohl für eine neoadjuvante als auch adjuvante Immuntherapie sowie die derzeitigen Forschungsbemühungen werden in diesem Artikel beleuchtet.

Abstract

Immunotherapy has drastically changed the treatment of lung cancer not only in systemic disease but also in the perioperative setting in locally advanced non-small cell lung cancer. In particular, the neoadjuvant and perioperative therapy regimes of the CheckMate 816 and KEYNOTE-671 studies as well as the adjuvant therapy according to the IMPower010 and the PEARLS/KEYNOTE-091 protocols have already been approved by the European Medicines Agency (EMA) for the treatment of selected cases. Other therapy protocols and combination therapies with varying drug classes and therapy modalities are currently being examined for their effectiveness and tolerance. The new treatment landscape creates new opportunities but also challenges for the treating disciplines. This article will focus on the current evidence for perioperative immunotherapy for resectable lung cancer and the resulting therapy standards, especially with regard to patient selection for both neoadjuvant and adjuvant immunotherapy, as well as current research efforts.

Schlüsselwörter

Lungenkarzinom - Immuntherapie - neoadjuvante Therapie - adjuvante Therapie

Keywords

lung cancer - immunotherapy - neoadjuvant therapy - adjuvant therapy


Publication History

Received: 02 May 2024

Accepted after revision: 26 June 2024

Article published online:
13 August 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 Reck M, Rodríguez-Abreu D, Robinson AG. et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016; 375: 1823-1833
    CrossrefPubMedSearch in Google Scholar
  • 2 Antonia SJ, Villegas A, Daniel D. et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017; 377: 1919-1929
    CrossrefPubMedSearch in Google Scholar
  • 3 Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol 2005; 17: 133-144
    CrossrefPubMedSearch in Google Scholar
  • 4 Liu J, Blake SJ, Yong MCR. et al. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Cancer Discov 2016; 6: 1382-1399
    CrossrefPubMedSearch in Google Scholar
  • 5 Arriagada R, Auperin A, Burdett S. et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010; 375: 1267-1277
    CrossrefPubMedSearch in Google Scholar
  • 6 Xu Z, Zou Z, Hao X. et al. Adjuvant and neo-adjuvant immunotherapy in resectable non-small cell lung cancer (NSCLC): Current status and perspectives. Cancer Innov 2023; 2: 65-78
    CrossrefPubMedSearch in Google Scholar
  • 7 Felip E, Altorki N, Zhou C. et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol 2023; 34: 907-919
    CrossrefPubMedSearch in Google Scholar
  • 8 O’Brien M, Paz-Ares L, Marreaud S. et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 2022; 23: 1274-1286
    CrossrefPubMedSearch in Google Scholar
  • 9 Forde PM, Chaft JE, Smith KN. et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018; 378: 1976-1986
    CrossrefPubMedSearch in Google Scholar
  • 10 Rosner S, Reuss JE, Zahurak M. et al. Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer. Clinical Cancer Research 2023; 29: 705-710
    CrossrefPubMedSearch in Google Scholar
  • 11 Chaft JE, Oezkan F, Kris MG. et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial. Nat Med 2022; 28: 2155-2161
    CrossrefPubMedSearch in Google Scholar
  • 12 Zhang F, Guo W, Zhou B. et al. Three-Year Follow-Up of Neoadjuvant Programmed Cell Death Protein-1 Inhibitor (Sintilimab) in NSCLC. J Thorac Oncol 2022; 17: 909-920
    CrossrefPubMedSearch in Google Scholar
  • 13 Heinhuis KM, Ros W, Kok M. et al. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann Oncol 2019; 30: 219-235
    CrossrefPubMedSearch in Google Scholar
  • 14 Provencio M, Nadal E, Insa A. et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2020; 21: 1413-1422
    CrossrefPubMedSearch in Google Scholar
  • 15 Provencio M, Nadal E, González-Larriba JL. et al. Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2023; 389: 504-513
    CrossrefPubMedSearch in Google Scholar
  • 16 Rothschild SI, Zippelius A, Eboulet EI. et al. SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II Trial. J Clin Oncol 2021; 39: 2872-2880
    CrossrefPubMedSearch in Google Scholar
  • 17 Forde PM, Spicer J, Lu S. et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022; 386: 1973-1985
    CrossrefPubMedSearch in Google Scholar
  • 18 Forde PM, Spicer J, Girard N. et al. Neoadjuvant nivolumab (N) + platinum-doublet chemotherapy (C) for resectable NSCLC: 3-y update from CheckMate 816. J Thorac Oncol 2023; 18(4 Suppl): S89-S100
    CrossrefPubMedSearch in Google Scholar
  • 19 Wakelee H, Liberman M, Kato T. et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 2023; 389: 491-503
    CrossrefPubMedSearch in Google Scholar
  • 20 Heymach J V, Harpole D, Mitsudomi T. et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 2023; 389: 1672-1684
    CrossrefPubMedSearch in Google Scholar
  • 21 Zhao X, Su Y, You J. et al. Combining antiangiogenic therapy with neoadjuvant chemotherapy increases treatment efficacy in stage IIIA (N2) non-small cell lung cancer without increasing adverse effects. Oncotarget 2016; 7: 62619-62626
    CrossrefPubMedSearch in Google Scholar
  • 22 Aokage K, Shimada Y, Yoh K. et al. Pembrolizumab and ramucirumab neoadjuvant therapy for PD-L1-positive stage IB-IIIA lung cancer (EAST ENERGY). J Clin Oncol 2023; 41: 8509-8509
    CrossrefPubMedSearch in Google Scholar
  • 23 Cascone T, William WNJ, Weissferdt A. et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med 2021; 27: 504-514
    CrossrefPubMedSearch in Google Scholar
  • 24 Cascone T, Kar G, Spicer JD. et al. Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase II NeoCOAST Platform Trial. Cancer Discov 2023; 13: 2394-2411
    CrossrefPubMedSearch in Google Scholar
  • 25 Schuler M, Cuppens K, Plönes T. et al. Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial. Nat Med 2024; 30: 1602-1611
    CrossrefPubMedSearch in Google Scholar
  • 26 Peng Y, Li Z, Fu Y. et al. Progress and perspectives of perioperative immunotherapy in non-small cell lung cancer. Front Oncol 2023; 13: 1011810
    CrossrefPubMedSearch in Google Scholar
  • 27 Zhang Z, Liu X, Chen D. et al. Radiotherapy combined with immunotherapy: the dawn of cancer treatment. Signal Transduct Target Ther 2022; 7: 258
    CrossrefPubMedSearch in Google Scholar
  • 28 Lee J, Cho J, Lee C. et al. Phase Ib study of neoadjuvant concurrent chemoradiation plus durvalumab followed by surgery and adjuvant durvalumab for resectable stage III NSCLC. J Clin Oncol 2023; 41: 8556-8556
    CrossrefPubMedSearch in Google Scholar
  • 29 Schmid S, Minnella EM, Pilon Y. et al. Neoadjuvant Prehabilitation Therapy for Locally Advanced Non-Small-Cell Lung Cancer: Optimizing Outcomes Throughout the Trajectory of Care. Clin Lung Cancer 2022; 23: 593-599
    CrossrefPubMedSearch in Google Scholar
  • 30 Laza-Briviesca R, Cruz-Bermúdez A, Nadal E. et al. Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial. Clin Transl Med 2021; 11: e491
    CrossrefPubMedSearch in Google Scholar
  • 31 Provencio M, Serna-Blasco R, Nadal E. et al. Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial). J Clin Oncol 2022; 40: 2924-2933
    CrossrefPubMedSearch in Google Scholar
  • 32 Cascone T, Leung CH, Weissferdt A. et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial. Nat Med 2023; 29: 593-604
    CrossrefPubMedSearch in Google Scholar
  • 33 Gainor JF, Shaw AT, Sequist L V. et al. EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res 2016; 22: 4585-4593
    CrossrefPubMedSearch in Google Scholar
  • 34 Mazieres J, Drilon A, Lusque A. et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019; 30: 1321-1328
    CrossrefPubMedSearch in Google Scholar
  • 35 Chalmers AW, Patel S, Boucher K. et al. Phase I Trial of Targeted EGFR or ALK Therapy with Ipilimumab in Metastatic NSCLC with Long-Term Follow-Up. Target Oncol 2019; 14: 417-421
    CrossrefPubMedSearch in Google Scholar
  • 36 Vokes NI, Pan K, Le X. Efficacy of immunotherapy in oncogene-driven non-small-cell lung cancer. Ther Adv Med Oncol 2023; 15: 175883592311614
    CrossrefPubMedSearch in Google Scholar
  • 37 Su PL, Chen JY, Chu CY. et al. The impact of driver mutation on the treatment outcome of early-stage lung cancer patients receiving neoadjuvant immunotherapy and chemotherapy. Sci Rep 2022; 12: 3319
    CrossrefPubMedSearch in Google Scholar
  • 38 Tsuboi M, Weder W, Escriu C. et al. Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. Future Oncol 2021; 17: 4045-4055
    CrossrefPubMedSearch in Google Scholar
  • 39 Mo J, Hu X, Gu L. et al. Smokers or non-smokers: who benefits more from immune checkpoint inhibitors in treatment of malignancies? An up-to-date meta-analysis. World J Surg Oncol 2020; 18: 15
    CrossrefPubMedSearch in Google Scholar
  • 40 Meng G, Liu X, Ma T. et al. Predictive value of tumor mutational burden for immunotherapy in non-small cell lung cancer: A systematic review and meta-analysis. PLoS One 2022; 17: e0263629
    CrossrefPubMedSearch in Google Scholar
  • 41 Liu W, Zhang T, Zhang Q. et al. A systematic review and meta-analysis of neoadjuvant chemoimmunotherapy in stage III non-small cell lung cancer. BMC Pulm Med 2022; 22: 490
    CrossrefPubMedSearch in Google Scholar
  • 42 Shao M, Yao J, Wang Y. et al. Two vs three cycles of neoadjuvant sintilimab plus chemotherapy for resectable non-small-cell lung cancer: neoSCORE trial. Signal Transduct Target Ther 2023; 8: 146
    CrossrefPubMedSearch in Google Scholar
  • 43 Baxi S, Yang A, Gennarelli RL. et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ 2018; 360: k793
    CrossrefPubMedSearch in Google Scholar
  • 44 Sorin M, Prosty C, Ghaleb L. et al. Neoadjuvant Chemoimmunotherapy for NSCLC. JAMA Oncol 2024; 10: 621
    CrossrefPubMedSearch in Google Scholar
  • 45 Eisenhauer EA, Therasse P, Bogaerts J. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-247
    CrossrefPubMedSearch in Google Scholar
  • 46 Waxman ES, Lee Gerber D. Pseudoprogression and Immunotherapy Phenomena. J Adv Pract Oncol 2020; 11: 723-731
    CrossrefPubMedSearch in Google Scholar
  • 47 Seymour L, Bogaerts J, Perrone A. et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017; 18: e143-e152
    CrossrefPubMedSearch in Google Scholar
  • 48 Bott MJ, Yang SC, Park BJ. et al. Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer. J Thorac Cardiovasc Surg 2019; 158: 269-276
    CrossrefPubMedSearch in Google Scholar
  • 49 Sepesi B, Zhou N, William WNJ. et al. Surgical outcomes after neoadjuvant nivolumab or nivolumab with ipilimumab in patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 2022; 164: 1327-1337
    CrossrefPubMedSearch in Google Scholar
  • 50 Qiu B, Guo W, Zhang F. et al. Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC. Nat Commun 2021; 12: 6770
    CrossrefPubMedSearch in Google Scholar