Immune checkpoint inhibitors in non-small cell lung cancer (NSCLC): Approaches on special subgroups and unresolved burning questions

Our plain-English summary of Immune checkpoint inhibitors in non-small cell lung cancer (NSCLC): Approaches on special subgroups and unresolved burning questions, by J. Remon, N. Vilariño, N. Reguart (Cancer Treatment Reviews, 2018).

The study

• Authors: J. Remon, N. Vilariño, N. Reguart
• Journal: Cancer Treatment Reviews
• Published: 2018;64:21-29
• Type of article: Review
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Immune checkpoint inhibitors (ICIs) have been incorporated in the treatment strategy of advanced non-small cell lung cancer (NSCLC). Beyond the already approved indications in first- and second-line setting of advanced NSCLC, new data has recently emerged demonstrating its efficacy in locally advanced disease as maintenance after chemo-radiotherapy and currently several trials are also exploring its efficacy in earlier stages of the disease to evaluate whether these results could be extrapolated to the adjuvant setting. With the advent of all these new therapies, their potential in other thoracic malignancies such as mesothelioma and small-cell lung cancer are also being evaluated with encouraging preliminary data that endorses their short-term incorporation as new therapeutic options in these thoracic malignancies. However, despite all these new evidence, there are still several open questions that remain to be solved like the use of immune agents in special subpopulations such as elderly or fragile patients or the case of patients with brain metastases or autoimmune disorders. In addition some other open questions remain with regards ICIs activity in patients receiving corticosteroid or antibiotics, the potential use in oncogenic addicted tumours, as well as the safety of retreatment after the onset of immune-related adverse events (ir-AE) or the optimal dose schedule or time on treatment for ICIs administration. Herein, we propose to address all these questions, reviewing most recent evidence available in order to give readers some practical advises and guidance on how to deal with these challenges when treating NSCLC patients with immunotherapy.

Copyright © 2018 Elsevier Ltd. All rights reserved.

In plain English

This article is a review, not a new study. The authors summarized published trials and real-world cohorts on immune checkpoint inhibitors (such as nivolumab and pembrolizumab) in non-small cell lung cancer. It does not deal with asbestos. Mesothelioma is named in the abstract, but the main text gives no mesothelioma data. The review addressed brain metastases, poor performance status, autoimmune disease, steroid or antibiotic use, older age, and tumours driven by gene changes such as EGFR. It noted that most trials excluded people with autoimmune diseases, steroid use or brain metastases; older patients and those with poor performance status were under-represented. Among the studies it cited, one retrospective cohort of 74 patients linked antibiotic use within 6 weeks of starting anti-PD1 treatment with shorter progression-free and overall survival. The authors concluded that early evidence looked promising for older patients and for those with controlled autoimmune disorders or symptom-free brain metastases. They added that no data supported use in patients with poor performance status or gene-driven tumours, at least as first- or second-line treatment. They noted that much of the evidence came from small retrospective cohorts.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published trials and real-world cohorts; no new patients were studied
• Who was studied: No study population of its own. The review covered evidence on patients with non-small cell lung cancer (NSCLC). It looked at special subgroups and treatment circumstances: brain metastases, poor performance status (2 or higher), autoimmune disease, steroid or antibiotic use, elderly patients, and oncogene-driven tumours (EGFR, ALK, BRAF, MET). It stated that most trials excluded patients with autoimmune diseases, those receiving steroids, or those with brain metastases.
• Exposure: Treatment with immune checkpoint inhibitors. Anti-PD-1: nivolumab, pembrolizumab. Anti-PD-L1: atezolizumab, durvalumab, avelumab. Anti-CTLA-4: ipilimumab, tremelimumab. Some studies combined these with chemotherapy or tyrosine-kinase inhibitors. No asbestos exposure is discussed.
• Main results:
  • The review described patients with poor performance status as poorly represented in checkpoint inhibitor trials.
  • The review described elderly patients, especially those aged 75 or older, as usually under-represented in clinical trials.
  • Cited Italian expanded access program of nivolumab: in a cohort of 409 patients with asymptomatic and controlled brain metastases, overall response rate was 17% and disease control rate 40%. Median overall survival was 8.6 months in the brain metastasis group versus 11.3 months in the whole population.
  • Cited CheckMate 171 trial: in a cohort of patients with performance status 2 (N=98), median overall survival was 5.4 months. The authors judged that efficacy could not be endorsed in this group.
  • Cited retrospective cohort of 46 NSCLC patients with an autoimmune disease treated with nivolumab or pembrolizumab: the underlying autoimmune disease worsened in 17% of patients, and only 5% required systemic steroids.
  • Cited data on baseline steroids: daily prednisone above 20 mg was associated with worse outcome on checkpoint inhibitors. Median overall survival was 3 months versus 10 months for those taking less than 20 mg (p=0.005).
  • Cited retrospective cohort of 74 advanced NSCLC patients: those given antibiotics within 6 weeks of starting anti-PD1 treatment (N=18) had shorter progression-free survival (2.0 vs 3.8 months) and overall survival (4.0 vs 12.6 months) than patients who had not received antibiotics. Response rate was not affected.
  • Cited TATTON trial: osimertinib combined with durvalumab was stopped early because 38% of patients developed interstitial lung disease.
  • Cited series of 39 NSCLC patients re-treated after an immune-related adverse event: 24% developed the same toxicity and 26% a new toxicity, with 5% associated mortality.
• The authors' conclusion: The authors concluded that some preliminary lessons could be drawn. Efficacy looked promising in elderly patients and in those with controlled autoimmune disorders or asymptomatic brain metastases. No data currently supported use in patients with performance status 2 or higher, or with oncogene-driven tumours, at least as first- or second-line treatment. Treatment decisions in these groups must be individualized.
• Limitations the authors state:
  • The authors noted that evidence for these special subgroups comes mostly from small retrospective cohorts, because such patients are excluded from large registration trials.
  • The authors noted that the findings on steroids and antibiotics rest on retrospective cohorts and that further evidence is awaited.
  • The authors could not rule out that worse outcomes with higher-dose steroids reflect comorbidities or worse performance status rather than the steroid dose itself.
  • The authors stated that efficacy in patients aged 75 or older remains unclear because of small sample sizes.

Topics

Medical terms in this study, explained in our Lexicon: checkpoint inhibitors, Non-Small Cell Lung Cancer, Second-Line Therapy, Mesothelioma, Lung Cancer, Immune-Related Adverse Events, Immunotherapy.

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• A Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non-small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design — F. Passiglia, P. Bironzo, et al. (2021)
• PD-1/PD-L1 Checkpoint Inhibitor Immunotherapy for Malignant Pleural Mesothelioma: Case Series and Literature Review — M. Zhou, N. Joshi, et al. (2021)
• Immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab — J.S. Lin, D.Y. Wang, et al. (2020)
• Immune checkpoint inhibitors in malignant pleural mesothelioma: promises and challenges — G.L. Ceresoli, M. Bonomi, et al. (2016)

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