Elsevier

Lung Cancer

Volume 88, Issue 2, May 2015, Pages 117-123
Lung Cancer

Review
Optimal management of immune-related toxicities associated with checkpoint inhibitors in lung cancer

https://doi.org/10.1016/j.lungcan.2015.02.007Get rights and content

Highlights

  • •

    Most immune related toxicities are low grade and easily manageable with treatment protocols.

  • •

    It is important to recognise and manage side effects promptly to improve safe delivery of immunotherapy.

  • •

    Frequent immune related adverse events and their management are discussed.

Abstract

Antibodies against immune checkpoints including CTLA-4, PD-1 and PD-L1 are increasingly being used in lung cancer. They are associated with novel, immune related toxicities not previously encountered with established treatments for lung cancer including colitis, hepatitis, rashes, neuropathies and other rarer immune mediated toxicities. Although generally these are low grade, there is a potential to be life threatening if not managed promptly. Early recognition of toxicity and institution of management algorithms are key to ensuring patient safety. We review the common toxicities and provide recommendations on their management.

Section snippets

Background

Cytotoxic chemotherapy and targeted therapies have improved outcomes for lung cancer patients. Survival in early stage non-small cell lung cancer (NSCLC) is improved with adjuvant chemotherapy and, when combined with radiotherapy, improves survival in stage III inoperable NSCLC and small cell lung cancer (SCLC) [1], [2]. In the palliative setting chemotherapy can provide symptom relief and survival benefit [1], [3]. Targeted therapies against the epidermal growth factor receptor (EGFR) have

Immune related toxicity

The spectrum and mechanism of toxicity related to immune checkpoint inhibition is autoimmune in nature and distinct to that of other cancer therapies [14]. The incidence of ipilimumab and PD-1 inhibitor toxicity by organ system are outlined in Table 1 [7], [15].

A pooled analysis of ipilimumab studies demonstrated that approximately two-thirds of patients experienced an immune related adverse event (irAE) with the majority being grade 1 and 2 [16]. Most commonly reported irAEs were

Managing immune related adverse events

A critical first step in managing irAEs is awareness of this class of toxic effect and requires education of the multi-disciplinary team. Patient education about potential side effects and appropriate steps to take is also critically important to ensure early recognition and treatment of irAEs. There is evidence that early intervention reduces both the maximum severity and duration of irAEs [23].

The severity of toxicity should be graded using the Common Terminology Criteria for Adverse Events

Colitis

The impact on the gastrointestinal system reported with the use of immunotherapy has been associated with death due to bowel perforation. In phase 3 studies of ipilimumab in metastatic melanoma, total rates of diarrhoea were 27.5% (3 mg/kg) and 32.8% (10 mg/kg) and rates of colitis 7.6% and 4.5% respectively [17], [18]. Typically diarrhoea tends to commence around 6–7 weeks following commencement of treatment [19]. Bloody diarrhoea may be an indication of more severe colitis but is uncommon.

At

Discussion

Although the spectrum of irAEs varies between agents, experience so far suggests a class effect of these drugs that can be managed in the main with a common approach. For lower grades of toxicity, management involves increased monitoring and supportive treatment; immunotherapy does not usually have to be interrupted. For higher grade toxicity, treatment should be interrupted and high dose corticosteroids commenced. If admitted under the care of a non-oncology team, the opinion of the treating

Conflict of interest statement

Howell, Lee and Fusi declared no conflicts of interest. Bowyer declared honorarium from GaxoSmithKline. Lorigan declared personal fees from Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (Merck), Glaxo Smith Kline (GSK), Roche, Novartis, Amgen, Celgene outside the submitted work.

References (50)

  • A. Ribas et al.

    Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL)

    (2014)
  • J.S. Weber et al.

    LBA3_PR – a phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator's choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy

  • C. Robert et al.

    Nivolumab in previously untreated melanoma without BRAF mutation

    N Engl J Med

    (2014)
  • S.L. Topalian et al.

    Safety, activity, and immune correlates of anti-PD-1 antibody in cancer

    N Engl J Med

    (2012)
  • J. Brahmer et al.

    Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): survival and clinical activity by subgroup analysis

    (2014)
  • N. Rizvi et al.

    Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC)

    (2014)
  • J.D. Wolchok et al.

    The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation

    Oncologist

    (2008)
  • P.A. Ascierto et al.

    Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort

    J Transl Med

    (2014)
  • R. Ibrahim et al.

    Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma

    (2011)
  • F.S. Hodi et al.

    Improved survival with ipilimumab in patients with metastatic melanoma

    N Engl J Med

    (2010)
  • C. Robert et al.

    Ipilimumab plus dacarbazine for previously untreated metastatic melanoma

    N Engl J Med

    (2011)
  • J.S. Weber et al.

    Management of immune-related adverse events and kinetics of response with ipilimumab

    J Clin Oncol

    (2012)
  • N. Rizvi et al.

    A phase I study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus platinum-based doublet chemotherapy (PT-doublet) in chemotherapy-naive non-small cell lung cancer (NSCLC) patients (pts)

    (2013)
  • J.R. Brahmer et al.

    Safety and activity of anti-PD-L1 antibody in patients with advanced cancer

    N Engl J Med

    (2012)
  • S.J. O’Day

    A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma

    • Cited by (43)

    • Development and Validation of a Machine Learning–Based Model Using CT Radiomics for Predicting Immune Checkpoint Inhibitor-related Pneumonitis in Patients With NSCLC Receiving Anti-PD1 Immunotherapy: A Multicenter Retrospective Case[sbnd]Control Study

      2023, Academic Radiology

    • Colitis following the use of immune checkpoint inhibitors: A real-world analysis of spontaneous reports submitted to the FDA adverse event reporting system

      2020, International Immunopharmacology
      Citation Excerpt :

      The ranges of time to onset after ICI therapy are quite broad but generally occurs within weeks to a couple of months after the initiation of therapy, though infrequently can occur even up to a year after the therapy has been discontinued [14]. Immune-mediated colitis and diarrhea typically occur 5–10 weeks after the second or third dose, but they have also been documented to occur as late as 4 months after the last dose and may even recur one to two years after discontinuation of treatment [13,45,46]. The median time of colitis onset following the last dose of ipilimumab was 11 days, ranged from 0 to 59 days [11,33].

    • Imaging manifestations of immune-related adverse effects in checkpoint inhibitor therapies: A primer for the radiologist

      2020, Clinical Imaging
      Citation Excerpt :

      It is important to raise awareness of these cardiac irAE, as the need to initiate steroid therapy and/or halt immunotherapy may prevent progression of cardiac manifestations and further deterioration in the patient's condition. Pulmonary involvement occurs most frequently in the form of pneumonitis, with an incidence of ~9% [80–83]. Decreased lung reserve, preexisting lung disease and radiation therapy may also increase risk of pulmonary irAEs [80,82].

    • Peritumoural ground-glass opacity associated with tumour pseudoprogression in a patient with non-small cell lung cancer treated with nivolumab

      2017, ESMO Open
      Citation Excerpt :

      Recent meta-analyses showed that incidence of anti-PD-1 inhibitor-related pneumonitis in patients with NSCLC was 3.8%–4.1% for all-grade and 1.8% for grade 3 or higher.8 9 Several studies have described distinct clinical and radiographic manifestations of pneumonitis related to anti-PD-1/programmed death ligand 1 (PD-L1) therapy in patients with advanced cancers, including lymphoma, melanoma and NSCLC.7 10–14 In these studies, median time from therapy initiation to pneumonitis was reported to be 2.2–2.8 months.7 11 12

    • Radiological assessment of immunotherapy effects and immune checkpoint-related pneumonitis for lung cancer

      2024, Journal of Cellular and Molecular Medicine

    • Chinese expert consensus on immunotherapy for advanced non-small lung cancer with oncogenic driver mutations (2023 edition)

      2023, Chinese Journal of Oncology
    View all citing articles on Scopus
    View full text
    Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.