Predictive Factors Correlated with the Development of Immune-Related Adverse Events in Patients with Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

Figures & data

Table 1 Patient Characteristics

Category	All Patients, N (%)
Patients, (N)	113
Age, years, (range)	70 (29–87)
Sex, male/female	91 (80.5)/22 (19.5)
ECOG performance status, 0–1/2–3	94 (83.2)/19 (16.8)
Body mass index, (range)	21.7 (14.9–34.0)
Body surface area, (range)	1.61 (1.26–2.09)
Smoking history, current plus former/never	88 (77.9)/25 (22.1)
Histologic subtype, non-squamous/squamous	74 (65.5)/39 (34.5)
Staging, advanced/post operative recurrence	96 (85.0)/17 (15.0)
Driver mutation, positive/negative	18 (15.9)/95 (84.1)
PD-L1 TPS (%)
≥ 50	34 (30.1)
1–49	28 (24.8)
< 1	17 (15.0)
Unknown	34 (30.1)
Immune-checkpoint inhibitors treatment
Nivolumab	63 (55.8)
Pembrolizumab	40 (35.4)
Atezolizumab	10 (8.8)
Lines of immunotherapy
First/subsequent	23 (20.4)/90 (79.6)
Alb (g/dL), (range)	3.7 (1.1–4.9)
NLR (range)	4.08 (0.55–48.77)
PLR (range)	238.8 (69.0–965.4)
SII (range)	1021.9 (93.1–10,875.8)
LIPI, 0–1/2	89 (78.8)/24 (21.2)
irAEs, with/without	44 (38.9)/69 (61.1)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed cell death 1-ligand 1; TPS, tumor proportion score; Alb, albumin; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic immune-inflammation index; LIPI, lung immune prognostic index; irAEs, immune-related adverse events.

Table 2 Characteristics and Efficacy of Immunotherapy in Patients with and without Immune-Related Adverse Events

Category	With irAEs, N (%)	Without irAEs, N (%)	p-value
Patients, (N)	44 (38.9)	69 (61.1)
Age, years, (range)	71 (29–87)	68 (42–83)	0.047
Sex, male/female	38 (86.4)/6 (13.6)	56 (81.2)/13 (18.8)	0.211
ECOG performance status, 0–1/2–3	39 (88.6)/5 (11.4)	55 (79.7)/14 (20.3)	0.216
Body mass index, (range)	21.7 (16.4–29.8)	21.9 (14.9–34.0)	0.883
Body surface area, (range)	1.59 (1.35–1.94)	1.63 (1.23–2.09)	0.708
Smoking history, current plus former/never	37 (84.1)/7 (15.9)	51 (73.9)/18 (26.1)	0.204
Histologic subtype, non-squamous/squamous	28 (63.6)/16 (36.4)	46 (66.7)/23 (33.3)	0.888
Staging, advanced/post operative recurrence	40 (90.9)/4 (9.1)	56 (81.2)/13 (18.8)	0.157
Driver mutation, positive/negative	5 (11.4)/39 (88.6)	13 (18.8)/56 (81.2)	0.290
PD-L1 TPS (%)
≥ 50	17 (38.6)	17 (24.6)
1–49	11 (25.0)	17 (24.6)
< 1	6 (13.6)	11 (15.9)
Unknown	10 (22.7)	24 (34.8)
Immunotherapy treatment
Nivolumab	25 (56.8)	38 (55.1)
Pembrolizumab	18 (40.9)	22 (31.9)
Atezolizumab	1 (2.3)	9 (13.0)
Lines of immunotherapy, first/subsequent	14 (31.8)/30 (68.2)	9 (13.0)/60 (87.0)	0.016
Alb (g/dL), (range)	3.8 (2.3–4.9)	3.7 (1.1–4.6)	0.800
NLR (range)	3.84 (1.48–8.67)	4.38 (0.55–48.77)	0.240
PLR (range)	221.4 (74.6–628.8)	240.8 (69.0–965.4)	0.885
SII (range)	1021.6 (349.5–3166.9)	1021.9 (93.1–10,875.8)	0.552
LIPI, 0–1/2	39 (88.6)/5 (11.4)	50 (72.5)/19 (27.5)	0.040
Best overall response
Complete response	2 (4.5)	1 (1.4)
Partial response	22 (50.0)	4 (5.8)
Stable disease	13 (29.5)	20 (29.0)
Progressive disease	7 (15.9)	40 (58.0)
Not evaluable	0 (0.0)	4 (5.8)
Overall response rate, % (95%, CI)	54.5 (39.7–69.4)	7.7 (1.2–14.2)	< 0.001
Disease control rate, % (95%, CI)	84.1 (73.2–95.0)	38.5 (26.5–50.3)	< 0.001

Abbreviations: ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed cell death 1-ligand 1; TPS, tumor proportion score; Alb, albumin; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic immune-inflammation index; LIPI, lung immune prognostic index; irAEs, immune-related adverse events; CI, confidence interval.

Figure 1 Evaluation of survival for patients with and without immune-related adverse events (irAEs). Kaplan–Meier curves for (A) progression-free survival (B) and overall survival in patients with and without irAEs.

Figure 2 Evaluation of survival for patients with LIPI 0 or 1 and LIPI 2. Kaplan–Meier curves for (A) progression-free survival (B) and overall survival in patients with LIPI 0 or 1 and LIPI 2.

Table 3 Analyses Based on Multivariate Logistic Regression of Predictive Factors Correlated with the Development of Immune-Related Adverse Events

Variable	Odds Ratio	95%, CI	P-value
Age	1.010	0.969–1.053	0.637
Lines of immunotherapy	0.209	0.066–0.656	0.007
LIPI	0.200	0.088–0.693	0.011

Abbreviations: CI, confidence interval; LIPI, lung immune prognostic index.

Table 4 Categorization of Immune-Related Adverse Events

Immune-Related Adverse Events	Any Grade, N (%)	Grade 1, N (%)	Grade 2, N (%)	Grade 3, N (%)	Grade 4, N (%)
Hypothyroidism	14 (12.4)	5 (4.4)	9 (8.0)	0 (0.0)	0 (0.0)
Interstitial lung disease	8 (7.1)	2 (1.8)	0 (0.0)	6 (5.3)	0 (0.0)
Skin rash	8 (7.1)	1 (0.9)	5 (4.4)	2 (1.8)	0 (0.0)
Aminotransferase increased	5 (4.4)	2 (1.8)	1 (0.9)	1 (0.9)	1 (0.9)
Arthralgia	4 (3.5)	1 (0.9)	2 (1.8)	1 (0.9)	0 (0.0)
Adrenal insufficiency	3 (2.7)	0 (0.0)	1 (0.9)	1 (0.9)	1 (0.9)
Hyperthyroidism	2 (1.8)	2 (1.8)	0 (0.0)	0 (0.0)	0 (0.0)
Uveitis	2 (1.8)	0 (0.0)	1 (0.9)	1 (0.9)	0 (0.0)
Creatinine increased	1 (0.9)	0 (0.0)	0 (0.0)	1 (0.9)	0 (0.0)
Neutropenia	1 (0.9)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.9)
Myalgia	1 (0.9)	0 (0.0)	1 (0.9)	0 (0.0)	0 (0.0)
Peripheral sensory neuropathy	1 (0.9)	0 (0.0)	1 (0.9)	0 (0.0)	0 (0.0)
Malaise	1 (0.9)	0 (0.0)	1 (0.9)	0 (0.0)	0 (0.0)
Anorexia	1 (0.9)	0 (0.0)	1 (0.9)	0 (0.0)	0 (0.0)
Pyrexia	1 (0.9)	1 (0.9)	0 (0.0)	0 (0.0)	0 (0.0)