The Long Half-Life of Programmed Cell Death Protein 1 Inhibitors May Increase the Frequency of Immune-Related Adverse Events After Subsequent EGFR Tyrosine Kinase Inhibitor Therapy

Abstract

Introduction: EGFR tyrosine kinase inhibitors are one of the key drugs for treatment of NSCLC with EGFR mutations. In recent times, immune check-point inhibitors (ICIs) have also been widely used for patients with NSCLC. Although a subset of patients obtain benefit from ICIs, adverse events (AEs) that are different from those of cytotoxic chemotherapies may occur. Moreover, some patients develop AEs, which seem to be caused by the previously discontinued nivolumab.

Methods: We identified patients with NSCLC who developed AEs, which started shortly after discontinuation of nivolumab and during treatment with osimertinib. We conducted liquid chromatography-mass spectrometry analyses to estimate the concentration of serum nivolumab.

Results: Three patients with AEs were identified. Two patients developed interstitial lung disease (cases 1 and 2) and one developed hepatotoxicity (case 3) during osimertinib therapy initiated after nivolumab administration. They received several treatments, including cytotoxic chemotherapies or EGFR tyrosine kinase inhibitors other than osimertinib, followed by nivolumab for three to five cycles; nevertheless, the disease progressed. After discontinuation of nivolumab, osimertinib was administered from day 22 to 46; but treatment-related toxicities developed 56 to 96 days later. Liquid chromatography-mass spectrometry analyses revealed that the remaining levels of nivolumab in the blood (2.1 μg/mL, 12.8 μg/mL, and 31.1 μg/mL, respectively, for cases 1, 2, and 3) were enough to induce an immune response.

Conclusion: The presence of the ICI antibody that persists even after drug discontinuation may account not only for the prolonged efficacy of these agents but also for the late onset of AEs, especially when the antibodies may have interacted during subsequent treatments.

Keywords: EGFR; Immune-related adverse events; Non−small cell lung cancer; Osimertinib; programmed cell death protein 1.

Figure 1

Clinical course of case 1. A computed tomography scan taken 15 days after three cycles of nivolumab revealed disease progression (A). After 50 days of administration, the efficacy of osimertinib was confirmed, although abnormal findings indicating interstitial lung disease were found (B). Seven days later, the symptoms and computed tomography findings of drug–induced interstitial lung disease worsened and prednisolone was started (C). The graph exhibits the treatment timeline and longitudinal changes in the nivolumab concentrations in the blood (D).

Figure 2

Clinical course of case 2. A computed tomography scan taken 15 days after three cycles of nivolumab revealed disease progression (A). After 34 days of administration, the efficacy of osimertinib was confirmed, although ground-glass opacities indicating interstitial lung disease were found (B). Although the patient continued osimertinib treatment, the abnormal shadow in computed tomography disappeared spontaneously (C). The graph exhibits the treatment timeline and longitudinal changes in the nivolumab concentrations in the blood (D).

Figure 3

Clinical course of case 3. The graph exhibits the treatment timeline and longitudinal changes in the nivolumab concentrations in the blood and serum ALT activities. ALT, alanine transaminase.