Pulmonary complications of immune checkpoint inhibitors in patients with nonsmall cell lung cancer

Abstract

Immune checkpoint inhibitor-related pneumonitis (ICI-P) during cancer treatment is rarely observed (<5%). ICI-P is more often observed in patients with nonsmall cell lung cancer (NSCLC) than in those with other cancers. Likewise, it is more common in those receiving programmed cell death (PD)-1/PD-1 ligand inhibitors rather than cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors alone. The frequency of ICI-P is higher when anti-PD-1 and anti-CTLA-4 are administered concomitantly. Despite the low fatality rate (≈13%), ICI-P is the leading cause of ICI-related deaths. This narrative review focuses on the epidemiology, clinical and radiological presentation and prognosis of ICI-P occurring in patients, especially those with advanced NSCLC. Emphasis is placed on the differences in terms of frequency or clinical picture observed depending on whether the ICI is used as monotherapy or in combination with another ICI or chemotherapy. Other pulmonary complications observed in cancer patients, yet not necessarily immune-related, are reviewed, such as sarcoid-like granulomatosis, tuberculosis or other infections. A proposal for pragmatic management, including differential diagnosis and therapeutic strategies, is presented, based on the ICI-P series reported in the literature and published guidelines.

FIGURE 1

Frequency of immune checkpoint inhibitor (ICI)-related pneumonitis in published phase III trials. a) Frequency of ICI-related pneumonitis observed in all published phase III trials; b) frequency of pneumonitis observed in ICI and chemotherapy arms in published lung cancer phase III trials. SCLC: small cell lung carcinoma. ^#: pneumonitis of any cause.

FIGURE 2

Thoracic computed tomography (CT) findings in patients with immune checkpoint inhibitor (ICI)-related pneumonitis and sarcoid-like granulomatosis. a) Transverse CT scan showing ground-glass opacity in the right upper lobe; b) transverse CT scan showing multifocal air-space consolidations with subpleural and basal distribution suggestive of an organising pneumonitis (note small ground-glass opacity surrounding consolidations); c and d) transverse CT scan in a patient with histologically proven ICI-related sarcoid-like granulomatosis showing mediastinal and bilateral and symmetric lymphadenopathies (c, mediastinal window) associated with unusual diffuse and bilateral ground-glass opacities (d, parenchymal window).

FIGURE 3

Multiple relapsing immune checkpoint inhibitor-related pneumonitis (ICI-P) after immunotherapy cessation and corticosteroids treatment. A 72-year-old female with an advanced lung adenocarcinoma experienced an ICI-P 54 weeks after second-line treatment using nivolumab (3 mg·kg⁻¹ every 2 weeks). She complained of dyspnoea and cough without fever. Thoracic computed tomography (CT) scanning showed bilateral multifocal air-space consolidations. Lung cancer evaluation confirmed the persistence of a partial response. Bronchioloalveolar lavage identified a CD8 T-lymphocytic alveolitis, with no pathogens identified. The diagnosis of nivolumab-related organising pneumonitis was considered. Nivolumab was interrupted, and prednisone 3 mg·kg⁻¹ per day initiated. The patient improved clinically and radiologically. However, two attempts to discontinue corticosteroids were associated with a clinical or radiological relapse, whereas the lung cancer remained controlled.

FIGURE 4

Proposed algorithm for the management of suspected immune checkpoint inhibitor-related pneumonitis (ICI-P). Schematically, two settings may present in a patient treated with ICI for a nonsmall cell lung carcinoma: either new images occur on the cancer follow-up computed tomography (CT) scan or the CT scan is performed because of new respiratory (cough and dyspnoea) or general symptoms (fevers and extrathoracic signs). In each case, CT scan analysis should focus on cancer progression (probable progression) or the occurrence of new parenchymal abnormalities; particularly ground-glass opacities or condensation(s) (possible ICI-P or infection), pleurisy or mediastinal lymphadenopathy being more rarely observed. In case of respiratory or general symptoms, their severity must be graded and a hospitalisation considered in view of the appropriate diagnostic tests and symptomatic treatment initiation. In case of a fever, an extensive microbial investigation must be carried out, particularly if the patient is under immunosuppresants. ICI must be stopped and the initiation of high-dose corticosteroid therapy discussed. In the absence of tumour progression, the discussion between ICI-P or infectious pneumonia is likely to depend on concomitant respective risk factors and on the documentation of an infection. ICU: intensive care unit; BNP: bone natriuretic protein; CPK: creatine phosphokinase; BAL: bronchioloalveolar lavage; ir: immune-related; AE: adverse events; ARDS: acute respiratory distress syndrome; ILD: interstitial lung disease: S_aO2: arterial oxygen saturation; PD-1: programmed cell death protein; PD-L1: programmed cell death ligand 1; CTLA: cytotoxic T-lymphocyte associated antigen.