Grade 3-4 Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer (NSCLC) Patients Are Correlated with Better Outcome: A Real-Life Observational Study

Abstract

Background: Immune checkpoint inhibitors (ICIs) have been a major advance in treating non-small-cell lung cancer (NSCLC). Programmed cell death protein-1/programmed death-ligand 1 blockade enhances immune function, mediating anti-tumor activity, yet causing immune-related adverse events (irAEs). We investigated the prognostic role of Grade 3−4 irAEs on overall survival (OS). Methods: This observational study recruited advanced NSCLC patients who received ICIs at Bichat-Claude Bernard University Hospital and in a community hospital, Saint-Joseph Foundation (Paris), between 1 January 2016 and 31 December 2019. Immunotherapy as a single-agent or double-drug combination was applied in the first and later lines. Univariable and multivariable analyses were instrumental in evaluating the prognostic impact of irAEs. Results: Overall, 201 consecutive ICI-treated patients were enrolled. High-grade irAEs (Grades 3−4) occurred in 36 patients (17.9%), including 11 (30.5%) cases of pneumonitis, 8 (22.2%) of colitis, 4 (11.1%) hepatic, 3 (8.3%) dermatological, 2 (5.5%) neurological events, and 2 cases (5.5%) of poly-arthralgia. The median OS was 10.4 ± 1.36 months (95% CI:7.7−13.1), being significantly higher in patients with high-grade irAEs than those without, 27.8 months vs. 8.1 months, respectively (HR = 2.5; p < 0.0001). Multivariable analysis revealed an independent association between high-grade irAEs and longer OS (HR = 0.29, 95% CI: 0.2−0.6, p < 0.0001). Conclusions: Our real-life study confirms that high-grade irAEs predict longer OS in advanced NSCLC.

Keywords: immune checkpoint inhibitors; immune-related adverse events; immunotherapy; ipilimumab; nivolumab; non-small-cell lung cancer; pembrolizumab; prognosis.

Figure 1

Type and incidence of Grade 3–4 irAEs. Grade 3–4 irAEs occurring in the series of 201 consecutive patients receiving ICI from 1 January 2016 to 31 December 2019 are summarized in a pie chart, showing that the most prevalent Grade 3–4 irAEs are respiratory (31%) and gastrointestinal (22%) while endocrine Grade 3–4 irAEs are rare (3%), linked to non-thyroid irAEs.

Figure 2

Overall survival in the entire population. Overall survival curve from day 1 of ICI, according to the Kaplan–Meier method is shown for the 201 accrued patients. Median OS for the whole series was 10.4 months (95%CI: 7.7–13.1).

Figure 3

Overall survival according to the incidence of Grade 3–4 irAEs. Kaplan–Meier overall survival plots according to the incidence of Grade 3–4 irAEs are shown. Orange OS curve: patients with Grade 3–4 irAEs (n = 165), median OS: 27.8 months (95%CI: 17.0–38.7). Green OS curve: patients without Grade 3–4 irAEs (n = 36), median OS: 8.1 (95% CI: 5.9–10.4). (p < 0.0001, log-rank test).

Figure 4

Overall survival according to treatment with antibiotics (A), corticosteroids (B), and LIPI score (C). (A) Kaplan–Meier overall survival curves according to treatment with antibiotics the month preceding ICI initiation or the first three months of ICI treatment (n = 79), or not (n = 114). Median OS in case of antibiotics intake history was 7.2 months (95%CI: 4.9–9.5) vs. 13.5 months (95%CI: 9.1–17.9) in patients without identified antibiotic intake (p = 0.004, log-rank test). (B) Kaplan–Meier overall survival curves according to treatment with corticosteroids within the previous month before ICI initiation (n = 33) or not (n = 168). Median OS in case of corticosteroid treatment the month preceding ICI was 4.7 months (95%CI: 2.0–7.4) vs. 12.0 (95%CI: 8.5–15.4) in patients who did not receive corticosteroids before ICI (p < 0.0001, log-rank test). (C) Kaplan–Meier overall survival curves according to LIPI score (low vs. intermediate vs. high score). The median OS for low, intermediate, and high LIPI scores were 15.3 months (95%CI: 9.8–20.8), 9.9 (95%CI: 6.6–13.2), and 5.8 (95%CI: 0.1–12.1), respectively (p = 0.017, log-rank test).

Figure 4

Overall survival according to treatment with antibiotics (A), corticosteroids (B), and LIPI score (C). (A) Kaplan–Meier overall survival curves according to treatment with antibiotics the month preceding ICI initiation or the first three months of ICI treatment (n = 79), or not (n = 114). Median OS in case of antibiotics intake history was 7.2 months (95%CI: 4.9–9.5) vs. 13.5 months (95%CI: 9.1–17.9) in patients without identified antibiotic intake (p = 0.004, log-rank test). (B) Kaplan–Meier overall survival curves according to treatment with corticosteroids within the previous month before ICI initiation (n = 33) or not (n = 168). Median OS in case of corticosteroid treatment the month preceding ICI was 4.7 months (95%CI: 2.0–7.4) vs. 12.0 (95%CI: 8.5–15.4) in patients who did not receive corticosteroids before ICI (p < 0.0001, log-rank test). (C) Kaplan–Meier overall survival curves according to LIPI score (low vs. intermediate vs. high score). The median OS for low, intermediate, and high LIPI scores were 15.3 months (95%CI: 9.8–20.8), 9.9 (95%CI: 6.6–13.2), and 5.8 (95%CI: 0.1–12.1), respectively (p = 0.017, log-rank test).

Figure 5

TTNT according to the occurrence of Grade 3–4 irAE. Time to next treatment (TTNT) Kaplan–Meier curves, according to the occurrence of Grade 3–4 irAEs. Median TNT was 27.5 months (95%CI: 16.2–38.8) in the case of Grade 3–4 irAEs, but only 2.1 months (95%CI: 1.1–3.1) in absence of Grade 3–4 irAEs (p < 0.0001, Log-Rank test).