Skip to main content

Advertisement

Springer Nature Link
Log in

Discontinuation of immune checkpoint inhibitor (ICI) above 18 months of treatment in real-life patients with advanced non-small cell lung cancer (NSCLC): INTEPI, a multicentric retrospective study

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

The optimal treatment duration of ICIs for patients with advanced NSCLC remains uncertain. In phase 3 clinical trials, treatment continued for 2 years or until disease progression with similar long-term survival rates. Real-life data are missing.

Patients and methods

This academic multicentric retrospective study aims at analyzing the characteristics of patients who discontinued treatment after at least 18 months of ICI monotherapy, in the setting of controlled disease.

Results

Of the 1127 patients treated with immunotherapy in the given period in six centers, 107 patients had their tumor controlled after at least 18 months of treatment and 54 (50%) of them had discontinued ICI. The median duration of treatment was 26 months. Treatment was stopped due to prescriber choice or toxicity in 46% and 22% of cases, respectively. After a median follow-up of 21 months from ICI discontinuation (95% CI 15.0–26.1 months), 18 (33%) patients experienced tumor progression after a median time of 10.0 months (range 2–33). From discontinuation, 12-month overall survival (OS) and progression-free survival (PFS) were 90% (95% CI 77.7–95.7) and 71% (95% CI 56.8–81.5), respectively; 24-month OS and PFS were 84% (95% CI 68.7–92.2) and 63% (95% CI 46.1–76.2), respectively. Duration of disease control after ICI discontinuation was correlated with tumor response at treatment discontinuation: PFS rate at 12 months was 76% after complete response (CR n = 11) or partial response (PR n = 37) and 22% after only stable disease (SD n = 6) as best response, p-value = 0.0002. PFS rate at 12 months was 80% for CR and/or complete metabolic response with 18F-FDG PET/CT (CMR) and 65% for others. Fourteen patients out of the 18 relapse patients received a subsequent treatment: seven with ICI rechallenge (best response 14% PR and 86% SD) and five with localized therapy with 60% CR.

Conclusions

This real-life study provides new insight into long-term outcomes of patients with advanced NSCLC treated with ICI for at least 18 months before treatment discontinuation in the absence of PD. Tumor response and CMR with FDG PET just before therapy discontinuation may be a predictive factor of prolonged disease control upon discontinuation. These results call for caution in discontinuing treatment in patients with stable disease as the best response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

All data and materials reported can be requested at the corresponding author.

Abbreviations

CMR:

Complete metabolic response

CR:

Complete response

ICI:

Immune checkpoint inhibitor(s)

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PFS:

Progression-free survival

PMR:

Partial metabolic response

PR:

Partial response

SD:

Stable disease

SMD:

Stable metabolic disease

References

  1. Groot PM, de Wu CC, Carter BW et al (2018) The epidemiology of lung cancer. Transl Lung Cancer Res 7(3):220–233

    Article  Google Scholar 

  2. Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics. CA Cancer J Clin 71(1):7–33

    Article  Google Scholar 

  3. Borghaei H, Paz-Ares L, Horn L et al (2015) Nivolumab versus docetaxel in advanced non-squamous non-small cell lung cancer. N Engl J Med 373(17):1627–1639

    Article  CAS  Google Scholar 

  4. Brahmer J, Reckamp KL, Baas P et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135

    Article  CAS  Google Scholar 

  5. Herbst RS, Baas P, Kim DW et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550

    Article  CAS  Google Scholar 

  6. Rittmeyer A, Barlesi F, Waterkamp D et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066):255–265

    Article  Google Scholar 

  7. Reck M, Rodríguez-Abreu D, Robinson AG et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833

    Article  CAS  Google Scholar 

  8. Mok TSK, Wu YL, Kudaba I et al (2019) Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. The Lancet 393(10183):1819–1830

    Article  CAS  Google Scholar 

  9. Gandhi L, Rodríguez-Abreu D, Gadgeel S et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092

    Article  CAS  Google Scholar 

  10. Paz-Ares L, Luft A, Vicente D et al (2018) Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379(21):2040–2051

    Article  CAS  Google Scholar 

  11. Socinski MA, Jotte RM, Cappuzzo F et al (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288–2301

    Article  CAS  Google Scholar 

  12. Gettinger S, Horn L, Jackman D et al (2018) Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study. J Clin Oncol 36(17):1675–1684

    Article  CAS  Google Scholar 

  13. Garon EB, Hellmann MD, Rizvi NA et al (2019) Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol 37(28):2518–2527

    Article  CAS  Google Scholar 

  14. Leighl NB, Hellmann MD, Hui R et al (2019) Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study. Lancet Respir Med 4:347–357

    Article  Google Scholar 

  15. Brahmer JR, Rodriguez-Abreu D, Robinson AG et al (2020) KEYNOTE-024 5-year OS update: first-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥ 50%. Annals of Oncol 31(Suppl_4):S1142–S1215

    Google Scholar 

  16. Herbst RS, Garon EB, Kim D-W et al (2020) Long-term outcomes and retreatment among patients with previously treated, programmed death-ligand 1-positive, advanced non-small-cell lung cancer in the Keynote-010 study. J Clin Oncol 38(14):1580–1590

    Article  CAS  Google Scholar 

  17. Waterhouse DM, Garon EB, Chandler J et al (2020) Continuous versus 1-year fixed-duration nivolumab in previously treated advanced non-small-cell lung cancer: checkmate 153. J Clin Oncol 38(33):3863–3873

    Article  CAS  Google Scholar 

  18. Nadal E, Massuti B, Dómine M et al (2019) Immunotherapy with checkpoint inhibitors in non-small cell lung cancer: insights from long-term survivors. Cancer Immunol Immunother 68(3):341–352

    Article  CAS  Google Scholar 

  19. Yilmaz M, Guven MS (2020) Durable response after discontinuation of nivolumab therapy in the absence of disease progression or toxicity with two advanced NSCLC patients. J Oncol Pharm Pract 26(3):761–767

    Article  Google Scholar 

  20. Kimura H, Araya T, Yoneda T et al (2019) Long-lasting responses after discontinuation of nivolumab treatment for reasons other than tumor progression in patients with previously treated, advanced non-small cell lung cancer. Cancer Commun (Lond) 39(1):1–5

    Article  Google Scholar 

  21. Haratani K, Hayashi H, Chiba Y et al (2018) Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol 4:374–378

    Article  Google Scholar 

  22. Ricciuti B, Genova C, De Giglio A et al (2019) Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis. J Cancer Res Clin Oncol 145(2):479–485

    Article  CAS  Google Scholar 

  23. McCoach CE, Blumenthal GM, Zhang L et al (2017) Exploratory analysis of the association of depth of response and survival in patients with metastatic non-small-cell lung cancer treated with a targeted therapy or immunotherapy. Ann Oncol 28:2707–2714

    Article  CAS  Google Scholar 

  24. Tan AC, Emmett L, Lo S et al (2018) FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma. Ann Oncol 29(10):2115–2120

    Article  CAS  Google Scholar 

  25. Kong BY, Menzies AM, Saunders CA et al (2016) Residual FDG-PET metabolic activity in metastatic melanoma patients with prolonged response to anti-PD-1 therapy. Pigment Cell Melanoma Res 29:572–577

    Article  CAS  Google Scholar 

  26. Brahmer JR, Drake CG, Wollner I et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28(19):3167–3175

    Article  CAS  Google Scholar 

  27. Centanni M, Moes DJAR, Trocóniz IF et al (2019) Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet 58(7):835–857

    Article  Google Scholar 

  28. Martins F, Sofiya L, Sykiotis GP et al (2019) Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 16(9):563–580

    Article  CAS  Google Scholar 

  29. Bantia S, Choradia N (2018) Treatment duration with immune-based therapies in Cancer: an enigma. J Immunother Cancer 6(1):143

    Article  Google Scholar 

  30. Simonaggio A, Michot JM, Voisin AL et al (2019) Evaluation of readministration of immune checkpoint inhibitors after immune-related adverse events in patients with cancer. JAMA Oncol 5:1310–1317

    Article  Google Scholar 

  31. Niki M, Nakaya A, Kurata T et al (2018) Immune checkpoint inhibitor re-challenge in patients with advanced non-small cell lung cancer. Oncotarget 9(64):32298–32304

    Article  Google Scholar 

  32. Giaj Levra M, Cotté FE, Corre R et al (2020) Immunotherapy rechallenge after nivolumab treatment in advanced non-small cell lung cancer in the real-world setting: A national data base analysis. Lung Cancer 140:99–106

    Article  Google Scholar 

  33. Gobbini E, Toffart AT, Pérol M et al (2020) Immune checkpoint inhibitors rechallenge efficacy in non–small-cell lung cancer patients. Clin Lung Cancer 21(5):e497–e510

    Article  CAS  Google Scholar 

Download references

Funding

This academic study did not receive any financial support.

Author information

Authors and Affiliations

  1. Medical Oncology, Institut Curie, Saint Cloud, France

    Geoffroy Bilger & Marie Ange Massiani

  2. Institut du Thorax Curie-Montsouris, Institut Curie, Paris, France

    Nicolas Girard

  3. Thoracic Oncology, Hopital Foch, Suresnes, France

    Hélène Doubre

  4. Thoracic Oncology Unit, CHU Grenobles Alpes, La Tronche, France

    Matteo Giaj Levra

  5. Respiratory Diseases and Thoracic Oncology, Hopital Ambroise Pare, Boulogne Billancourt, France

    Etienne Giroux-Leprieur

  6. Pneumo-Oncology, Hôpital Cochin, Paris, France

    Frederique Giraud

  7. Respiratory Diseases and Thoracic Oncology, Le Centre Hospitalier Annecy Genevois, Metz-Tessy, France

    Chantal Decroisette

  8. Unit of Biometry, Institut Curie, DRCI, PSL Research University, Paris, France

    Matthieu Carton

Authors
  1. Geoffroy Bilger
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Nicolas Girard
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Hélène Doubre
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Matteo Giaj Levra
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Etienne Giroux-Leprieur
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Frederique Giraud
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Chantal Decroisette
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Matthieu Carton
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Marie Ange Massiani
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

GB and MAM initiated the study concept, coordinated the entire study, and wrote the manuscript. GB, MAM, NG, HD, MGL, EGL, FG, MC, and CD collected and helped interpret clinical data. All authors approved the final version of the article, including the authorship list.

Corresponding author

Correspondence to Geoffroy Bilger.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

This study was performed in accordance with the ethical standards of the institutional research committee and the latest Declaration of Helsinki. Study ethics approval was obtained on December 9, 2019 (Observational Research Protocol Review Committee), of the Institut Curie, IRB 2215984.

Consent to participate

An information letter was given to each living patient providing him the opportunity to refuse study participation. All individuals agreed to the use of the obtained data for relevant publications.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bilger, G., Girard, N., Doubre, H. et al. Discontinuation of immune checkpoint inhibitor (ICI) above 18 months of treatment in real-life patients with advanced non-small cell lung cancer (NSCLC): INTEPI, a multicentric retrospective study. Cancer Immunol Immunother 71, 1719–1731 (2022). https://doi.org/10.1007/s00262-021-03114-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-021-03114-z

Keywords

Profiles

  1. Geoffroy Bilger View author profile