Abstract
Simple SummaryLung cancer immunotherapy has many complications and hospitalizations that often occur in non-small cell lung cancer (NSCLC) while on immunotherapy due to adverse events or other factors. The molecular and clinical profiles of these patients are often not well-defined, and the aim of our retrospective study is to better understand these clinical and molecular features. We evaluated a cohort of 90 stage IV thoracic malignancy patients who had hospital admissions after treatment with immune checkpoint inhibitors. We identified a relationship between immune-related adverse events (irAEs) and molecular markers that showed unique survival outcomes, as well as a significant overall survival improvement in patients who required discontinuation or interruption of immunotherapy due to irAEs. Lung cancer patients undergoing systemic treatment with immune checkpoint inhibitors (ICIs) can lead to severe immune-related adverse events (irAEs) that may warrant immediate hospitalization. Patients with thoracic malignancies hospitalized at City of Hope while undergoing treatment with ICIs were identified. Pathology and available next-generation sequencing (NGS) data, including the programmed death-ligand 1 (PD-L1) status and clinical information, including hospitalizations, invasive procedures, and the occurrence of irAEs, were collected. Unpaired T-tests, Chi-square/Fisher’s exact test, and logistic regression were used to analyze our cohort. The overall survival (OS) was calculated and compared using univariate and multivariate COX models. Ninety patients with stage IV lung cancer were admitted after ICI treatment. Of those patients, 28 (31.1%) had documented irAEs. Genomic analyses showed an enrichment of LRP1B mutations (n = 5/6 vs. n = 7/26, 83.3% vs. 26.9%; odds ratio (OR) (95% confidence interval (CI): 13.5 (1.7–166.1); p < 0.05) and MLL3 mutations (n = 4/6, 66.7% vs. n = 5/26, 19.2%; OR (95% CI): 8.4 (1.3–49.3), p < 0.05) in patients with irAE occurrences. Patients with somatic genomic alterations (GAs) in MET (median OS of 2.7 vs. 7.2 months; HR (95% CI): 3.1 (0.57–17.1); p < 0.05) or FANCA (median OS of 3.0 vs. 12.4 months; HR (95% CI): 3.1 (0.70–13.8); p < 0.05) demonstrated a significantly shorter OS. Patients with irAEs showed a trend toward improved OS (median OS 16.4 vs. 6.8 months, p = 0.19) compared to hospitalized patients without documented irAEs. Lung cancer patients who required treatment discontinuance or interruption due to irAEs (n = 19) had significantly longer OS (median OS 18.5 vs. 6.2 months; HR (95% CI): 0.47 (0.28–0.79); p < 0.05). Our results showed a significant survival benefit in lung cancer patients hospitalized due to irAEs that necessitated a treatment interruption. Patients with positive somatic GAs in MET and FANCA were associated with significantly worse OS compared to patients with negative GAs.
Highlights
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) have transformed the landscape of lung cancer treatment
The dates of ICI treatment initiation were between 6 May 2015, and 6 August 2018
28 patients (31.1%) experienced immune-related adverse events (irAEs) with the most common irAE being pneumonitis (n = 10/90, 11.1%). This is consistent with other reports demonstrating that 12% of emergency room visits and inpatient care were associated with irAE development in metastatic solid tumor patients undergoing ICI treatment [30]
Summary
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) have transformed the landscape of lung cancer treatment. Pembrolizumab, an anti-PD-1 monoclonal antibody, was approved by the US Food and Drug Administration (FDA) as a monotherapy first-line treatment of metastatic non-small cell lung cancer (NSCLC) with PD-L1 expression ≥ 1, and in combination with chemotherapy regardless of PD-L1 status [1,2,3,4]. Atezolizumab and durvalumab, anti-PD-L1 monoclonal antibodies, were approved as a first-line treatment in combination with chemotherapy for small cell lung cancer (SCLC) [5,6,7]. Other severe adverse events not related to ICIs can emerge as well during treatment and lead to hospitalization. In a meta-analysis of 35 clinical trials involving ICIs, irAEs of grade 3 and above were reported in 14% of patients treated with monotherapy ICIs, 34% with anti-CTLA-4 antibodies, 46% with combination ICI-chemotherapy, and 55% with ICIs combinations [17]
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