Rapid temporal improvement of pembrolizumab-induced pneumonitis using the anti-TNF-α antibody infliximab

Abstract

Pembrolizumab monotherapy has shown survival benefit as a first-line therapy for patients with metastatic non-small cell cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or greater and without epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma receptor tyrosine kinase (ALK) translocation (1). The addition of pembrolizumab to pemetrexed and a platinum-based chemotherapy also prolongs overall survival in patients with metastatic non-squamous NSCLC without EGFR or ALK alterations regardless of the tumor proportion score (2). Although pembrolizumab is generally well-tolerated compared to cytotoxic chemotherapy, immune-related adverse events (irAEs) are sometimes severe or even fatal. The severity of irAEs is graded according to the Common Terminology Criteria for Adverse Events (CTCAE) (3). The incidence of immune-mediated pneumonitis of any grade was 5.8% and that of grade ≥ 3 was 2.6% in the phase 3 KEYNOTE-024 trial (1). For grade ≥ 3 pneumonitis, the guidelines of the European Society for Medical Oncology (ESMO) (4) and American Society of Clinical Oncology (5) recommend intravenous methylprednisolone at 2-4 mg/kg/day and Summary Immune checkpoint inhibitors are associated with a wide spectrum of immune-related adverse events (irAEs) that are typically transient but are sometimes severe or even fatal. No consensus exists for the treatment of severe immune-mediated pneumonitis that is refractory to corticosteroids. Here, we report an autopsy case of pembrolizumab-induced pneumonitis that was transiently improved using infliximab. A 67-year-old male with advanced lung adenocarcinoma developed pneumonitis two weeks after a single dose of first-line pembrolizumab. The pneumonitis was refractory to corticosteroids, and the patient required mechanical ventilation. Addition of a single dose of infliximab rapidly improved the respiratory status and chest CT showed resolution of ground-glass opacities in the right upper and middle lobes. However, the patient died from re-exacerbation of pneumonitis 17 days after infliximab administration. The autopsy confirmed organizing phase diffuse alveolar damage in the right lower lobe, while the right upper lobe remained almost intact consistent with the CT findings, which is suggestive of the therapeutic effect of infliximab. The half-life of infliximab is 7-12 days, and a second dose of infliximab two weeks after the first dose is sometimes required for the treatment of gastrointestinal toxicity induced by anti-CTLA4 antibodies. Although the current guidelines do not recommend repeated administration of infliximab for immune-mediated pneumonitis, the present case suggests that repeated infliximab therapy may be beneficial in the treatment of immunemediated pneumonitis.

Pneumonitis Induced by Immune Checkpoint Inhibitors: From Clinical Data to Translational Investigation

“…Guacimara et al reported that a case of mycophenolate-resistant CIP was successfully treated with infliximab, and they thought that infliximab might be preferable than other classical immunosuppressants ( 46 ). Another case report pointed out that repeated administration of infliximab for a certain period may be beneficial in the treatment of steroid-refractory CIP ( 47 ). However, after these treatments, there are still some cases that are reported to be deteriorating.…”

Treatment of steroid‐resistant checkpoint inhibitor pneumonitis with pirfenidone: A case report

“…Common treatments previously reported include shock steroid therapy, intravenous immunoglobulin (IVIG), IL-6 receptor inhibitors, TNF-inhibitors, or immunosuppressants. [9][10][11] In the case reported here, we immediately discontinued pembrolizumab and the patient was treated with medranone, IVIG, tacrolimus and noninvasive ventilator-assisted ventilation. Due to the severe shortness of breath in our patient, high-flow oxygen was also administered together with tosilizumab during hospitalization.…”

Improvement in recurring nivolumab-induced pneumonitis with repetitive administration of infliximab in a patient with head and neck cancer: A case report

“…Several studies reported that infliximab is effective for anti-CTLA-4 Ab-induced enterocolitis that is refractory to corticosteroids ( 21 , 22 ). Infliximab also improves ICI-induced pneumonitis that is refractory to corticosteroids ( 15 , 23 ). TNF-α is involved in the onset of pneumonitis associated with autoimmune diseases ( 24 ).…”