Safety and Efficacy of Immunotherapy Rechallenge Following Checkpoint Inhibitor-Related Pneumonitis in Advanced Lung Cancer Patients: a Retrospective Multi-Center Cohort Study

Background: Checkpoint inhibitor-related pneumonitis (CIP) induced by immune checkpoint inhibitors (ICIs) is one of the most fatal immune-related adverse events (irAE). However, only limited data are available on rechallenge with ICIs after CIP. We evaluated the efficacy and safety of rechallenge after CIP in patients with advanced lung cancer to identify the potential populations that would benefit. Methods: We conducted a multicenter retrospective study of advanced lung cancer patients who received further ICI treatment (rechallenge) or did not undergo re-administration after grade >_1 CIP between May 2017 and May 2021. Progression-free survival (PFS) and overall survival (OS) were estimated from first or second ICI initiation to disease progression (PFS1 and PFS2, respectively), death, or last follow-up (OS1 and OS2, respectively). The recurrence of CIP and new irAEs in these patients after ICI rechallenge were calculated.Results: Among 107 patients afflicted with CIP, 45 (42.1%) received ICI rechallenge. Multivariate analysis showed that severe grade (grades >_3) and ground-glass opacity of pneumonitis lesions were negatively associated with rechallenge. Following rechallenge, 9 (20.0%) patients developed recurrent pneumonitis, and 11 (24.4%) developed a new irAE. Severe grade of CIP and poor performance status at initial CIP as well as levels of interleukin (IL)-6 and C-reactive protein (CRP), and absolute white blood cell and neutrophil counts at the time of ICI rechallenge were associated with a higher recurrence rate. The median (95% confidence interval) PFS1 and PFS2 were 17.9 (9.9-24.2) and 15.5 (5.5-25.6) months, respectively. The median (95% confidence interval) OS1 and OS2 were 23.5 (16.5-30.5) and 18.4 (10.1-26.7) months, respectively. Lower OS2 was observed in patients with severe grade of CIP and poor performance status at the initial CIP, recurrence of CIP, and in patients with high levels of CRP and IL-6 at rechallenge. Only IL-6 was found to affect OS2 on multivariate analysis.Conclusions: ICI rechallenge following CIP may be a promising treatment for patients with advanced lung cancer, particularly in those with low-grade of CIP and good performance status at initial CIP, and low levels of IL-6 and CRP at the time of initial challenge. Prospective studies are needed for further verification.