Tables
- TABLE 1
Demographic features of the study cohorts
Before propensity score matching After propensity score matching# n FV-positive (n=142) FV-negative (n=105) Combined (n=247) p-value n FV-positive (n=105) FV-negative (n=105) Combined (n=210) p-value Race 247 0.921 210 0.448 White 129 (91) 95 (90) 224 (91) 98 (93) 95 (90) 193 (92) Non-White 13 (9) 10 (10) 23 (9) 7 (7) 10 (10) 17 (8) Gender 247 0.393 210 0.889 Male 72 (51) 59 (56) 131 (53) 60 (57) 59 (56) 119 (57) Female 70 (49) 46 (44) 116 (47) 45 (43) 46 (44) 91 (43) Age, years 247 0.550 210 0.537 <60 47 (33) 31 (30) 78 (32) 27 (26) 31 (30) 58 (28) ≥60 95 (67) 74 (70) 169 (68) 78 (74) 74 (70) 152 (72) Smoking status 247 0.219 210 1 Ever-smoker 126 (89) 98 (93) 224 (91) 98 (93) 98 (93) 196 (93) Never-smoker 16 (11) 7 (7) 23 (9) 7 (7) 7 (7) 14 (7) Cancer type 247 0.126 210 0.260 NSCLC 124 (87) 86 (82) 210 (85) 89 (85) 86 (82) 175 (83) SCLC 10 (7) 16 (15) 26 (11) 9 (9) 16 (15) 25 (12) Mixed NSCLC/ SCLC 3 (2) 2 (2) 5 (2) 3 (3) 2 (2) 5 (2) Others 5 (4) 1 (1) 6 (2) 4 (4) 1 (1) 5 (2) Malignant mesothelioma 4 (3) 0 (0) 4 (2) 4 (4) 0 (0) 4 (2) Thymic cancer 1 (1) 1 (1) 2 (1) 0 (0) 1 (1) 1 (0) Stage 247 0.479 210 1 III 13 (9) 7 (7) 20 (8) 7 (7) 7 (7) 14 (7) IV 129 (91) 98 (93) 227 (92) 98 (93) 98 (93) 196 (93) Trial patient 247 0.326 210 0.471 Yes 56 (39) 35 (33) 91 (37) 40 (38) 35 (33) 75 (36) No 86 (61) 70 (67) 156 (63) 65 (62) 70 (67) 135 (64) ICI received¶ 247 0.163 210 0.284 PD-1 inhibitor 111 (78) 81 (77) 192 (78) 83 (79) 81 (77) 164 (78) PD-L1 inhibitor 19 (13) 11 (10) 30 (12) 10 (10) 11 (10) 21 (10) CTLA-4 inhibitor 3 (2) 0 (0) 3 (1) 3 (3) 0 (0) 3 (1) CTLA-4 combination 9 (6) 13 (12) 22 (9) 9 (9) 13 (12) 22 (10) Best ICI response 247 0.396 210 0.474 PD 48 (34) 41 (39) 89 (36) 36 (34) 41 (39) 77 (37) Responses other than PD 94 (66) 64 (61) 158 (64) 69 (66) 64 (61) 133 (63) Comorbidities, n 234 0.905 210 0.719 0 2 (2) 1 (1) 3 (1) 3 (3) 1 (1) 4 (2) 1 39 (30) 29 (28) 68 (29) 33 (31) 30 (29) 63 (30) 2 33 (25) 30 (29) 63 (27) 28 (27) 31 (30) 59 (28) ≥3 57 (44) 43 (42) 100 (43) 41 (39) 43 (41) 84 (40) Comorbidity Cardiovascular 234 85 (65) 68 (66) 153 (65) 0.856 210 68 (65) 69 (66) 137 (65) 0.885 Pulmonary 234 53 (40) 50 (49) 103 (44) 0.216 210 50 (48) 50 (48) 100 (48) 1 Metabolic 234 53 (40) 47 (46) 100 (43) 0.427 210 43 (41) 47 (45) 90 (43) 0.577 Second primary cancers 234 34 (26) 17 (17) 51 (22) 0.082 210 18 (17) 17 (16) 35 (17) 0.853 Autoimmune 234 25 (19) 27 (26) 52 (22) 0.193 210 23 (22) 28 (27) 51 (24) 0.421 Nephrology/ urology 234 16 (12) 15 (15) 31 (13) 0.599 204 11 (11) 15 (15) 26 (13) 0.432 Cerebrovascular 234 13 (10) 11 (11) 24 (10) 0.850 204 8 (8) 11 (11) 19 (9) 0.498 Neurological 234 6 (5) 8 (8) 14 (6) 0.308 204 4 (4) 8 (8) 12 (6) 0.248 Influenza prodromes 247 0.830 210 0.313 Yes 2 (1) 3 (3) 5 (2) 1 (1) 3 (3) 4 (2) No 140 (99) 102 (97) 242 (98) 104 (99) 102 (97) 206 (98) Influenza-related hospitalisation 247 0.419 210 0.316 Yes 1 (1) 1 (1) 2 (1) 0 (0) 1 (1) 1 (0) No 141 (99) 104 (99) 245 (99) 105 (100) 104 (99) 209 (100) Data are presented as n (%), unless otherwise stated. FV: influenza vaccination; NSCLC: nonsmall cell lung cancer; SCLC: small cell lung cancer; ICI: immune checkpoint inhibitor; PD-1: programmed cell death 1; PD-L1: PD-1 ligand 1; CTLA-4: cytotoxic T-lymphocyte antigen 4; PD: progressive disease. #: one of the five propensity score matching model runs after multiple imputations (numbers change very slightly among five runs); ¶: PD-1 inhibitors include nivolumab and pembrolizumab; PD-L1 inhibitors include atezolizumab and durvalumab; CTLA-4 inhibitor here indicates ipilimumab; CTLA-4 combinations include ipilimumab plus nivolumab and tremelimumab plus durvalumab.
- TABLE 2
Immune-related adverse events (IRAEs) in the study cohorts
Before propensity score matching After propensity score matching# n FV-positive (n=142) FV-negative (n=105) Combined (n=247) p-value n FV-positive (n=105) FV-negative (n=105) Combined (n=210) p-value IRAEs 247 0.419 210 0.49 Yes 67 (47) 55 (52) 122 (49) 50 (48) 55 (52) 105 (50) No 75 (53) 50 (48) 125 (51) 55 (52) 50 (48) 105 (50) IRAE severity grading 247 0.004* 210 0.004* Grade 5 1 (1) 0 (0) 1 (0) 1 (1) 0 (0) 1 (0) Grade 4 2 (1) 1 (1) 3 (1) 1 (1) 1 (1) 2 (1) Grade 3 26 (18) 38 (36) 64 (26) 18 (17) 38 (36) 56 (27) Grade 2 27 (19) 16 (15) 43 (17) 22 (21) 16 (15) 38 (18) Grade 1 11 (8) 0 (0) 11 (4) 8 (8) 0 (0) 8 (4) No IRAEs 75 (53) 50 (48) 125 (51) 55 (52) 50 (48) 105 (50) IRAE severity group 247 0.006* 210 0.005* Grade 3–5 29 (20) 39 (37) 68 (28) 20 (19) 39 (37) 59 (28) Grade 1–2 38 (27) 16 (15) 54 (22) 30 (29) 16 (15) 46 (22) No IRAEs 75 (53) 50 (48) 125 (50) 55 (52) 50 (48) 105 (50) IRAE type Endocrinopathy 247 27¶ (19) 16+ (15) 43 (17) 0.440 210 22§ (21) 16ƒ (15) 38 (18) 0.282 Hypothyroidism 21 (15) 12 (11) 33 (13) 17 (16) 12 (11) 29 (28) Adrenal insufficiency 8 (6) 4 (4) 12 (5) 6 (6) 4 (4) 10 (10) Hypophysitis 1 (1) 1 (1) 2 (1) 1 (1) 1 (1) 2 (2) Pneumonitis 247 17 (12) 18 (17) 35 (14) 0.250 210 12 (11) 18 (17) 30 (14) 0.237 Dermatological 247 17 (12) 7 (7) 24 (10) 0.160 210 14 (13) 7 (7) 21 (10) 0.107 Hepatitis/colitis 247 16 (11) 8 (8) 24 (10) 0.340 210 8 (8) 8 (8) 16 (8) 1 Hepatitis 9 (6) 6 (6) 15 (6) 5 (5) 6 (6) 11 (5) Colitis 7 (5) 2 (2) 9 (4) 3 (3) 2 (2) 5 (2) Neuromuscular 247 5 (3) 10 (10) 15 (6) 0.051 210 4 (4) 10 (10) 14 (7) 0.097 Severe fatigue 247 4 (3) 4 (4) 8 (3) 0.660 210 3 (3) 4 (4) 7 (3) 0.701 Myocarditis 247 1 (1) 4 (4) 5 (2) 0.087 210 1 (1) 4 (4) 5 (2) 0.174 Haematological 247 0 (0) 2 (2) 2 (2) 1 210 0 (0) 2 (2) 2 (1) 0.155 Nephritis 247 1 (1) 0 (0) 1 (0) 0.390 210 1 (1) 0 (0) 1 (0) 0.316 Immunosuppressive agents for IRAEs 247 0.005* 210 0.004* Yes 32 (23) 41 (39) 73 (30) 22 (21) 41 (39) 63 (30) No 110 (77) 64 (61) 174 (70) 83 (79) 64 (61) 147 (70) ICI discontinuation due to IRAEs 247 0.018* 210 0.014* Yes 25 (18) 32 (30) 57 (23) 17 (16) 32 (30) 49 (23) No 117 (82) 73 (70) 190 (77) 88 (84) 73 (70) 161 (77) Grade 3–5 IRAEs## 247 0.004* 210 0.004* Yes 29 (20) 39 (37) 68 (28) 20 (19) 39 (37) 59 (28) No 113 (80) 66 (63) 179 (72) 85 (81) 66 (63) 151 (72) Data are presented as n (%), unless otherwise stated. FV: influenza vaccination; ICI: immune checkpoint inhibitor. #: one of the five propensity score matching models run after multiple imputations (the numbers varied very slightly among the five runs); ¶: three patients had both hypothyroidism and adrenal insufficiency; +: one patient had both hypothyroidism and adrenal insufficiency; §: two patients had both hypothyroidism and adrenal insufficiency; ƒ: one patient had both hypothyroidism and adrenal insufficiency; ##: denominator: cases with positive IRAE (annotated as IRAE=Yes in the table). *: p<0.05.
- TABLE 3
Seasonal distribution of immune-related adverse event (IRAE) occurrence
Before propensity score matching After propensity score matching# n FV-positive (n=67) FV-negative (n=55) Combined (n=122) p-value n FV-positive (n=50) FV-negative (n=55) Combined (n=105) p-value Season of IRAEs 122 0.620 105 0.464 Spring 15 (22) 9 (16) 24 (20) 12 (24) 9 (16) 21 (20) Summer 17 (25) 16 (29) 33 (27) 15 (30) 16 (29) 31 (30) Fall 12 (18) 14 (25) 26 (21) 7 (14) 14 (25) 21 (20) Winter 23 (35) 16 (30) 39 (32) 16 (32) 16 (30) 32 (30) Influenza season of IRAEs 122 0.799 105 0.382 Fall/winter 35 (52) 30 (55) 65 (53) 23 (46) 30 (55) 53 (50) Spring/ summer 32 (48) 25 (45) 57 (47) 27 (54) 25 (45) 52 (50) Data are presented as n (%), unless otherwise stated. FV: influenza vaccination. #: one of the five propensity score matching models run after multiple imputations (the numbers varied very slightly among the five runs).
- TABLE 4
Associations between clinical features and immune-related adverse events (IRAEs) using ordinal logistic regression analysis: grade 3–5 IRAEs versus grade 1–2 IRAEs versus no IRAEs
OR (90% CI) p-value FV: positive versus negative (reference) 0.63 (0.40–0.99) 0.046* Race: White versus non-White (reference) 3.27 (1.13–9.47) 0.034* Gender: male versus female (reference) 0.93 (0.57–1.53) 0.406 Smoking status: ever versus never (reference) 2.86 (0.97–8.42) 0.055 Age: <60 versus ≥60 years (reference) 0.86 (0.49–1.52) 0.335 Trial: yes versus no (reference) 1.23 (0.73–2.07) 0.254 ICI received: PD-L1 versus PD-1 (reference) 2.36 (0.94–5.90) 0.062 CTLA-4/CTLA-4 combinations versus PD-1 (reference) 2.06 (0.97–4.38) 0.057 FV: influenza vaccination; ICI: immune checkpoint inhibitor; PD-L1: PD-1 ligand 1; PD-1: programmed cell death 1; CTLA-4: cytotoxic T-lymphocyte antigen 4. Harrell's C-statistic=0.642. *: p<0.05.
- TABLE 5
Associations between clinical features and severe immune-related adverse events (IRAEs) using logistic regression analysis: grade 3–5 IRAEs versus grade 1–2 IRAEs plus no IRAEs#
OR (90% CI) p-value FV: positive versus negative (reference)¶ 0.42 (0.24–0.73) 0.005* Race: White versus non-White (reference) 1.94 (0.60–6.25) 0.175 Gender: male versus female (reference) 0.90 (0.51–1.58) 0.378 Smoking status: ever versus never (reference) 4.34 (0.73–25.76) 0.088 Age: <60 versus ≥60 years (reference) 0.99 (0.53–1.85) 0.489 Trial: yes versus no (reference) 0.78 (0.41–1.46) 0.257 ICI received: PD-L1 versus PD-1 (reference) 2.24 (0.87–5.79) 0.081 CTLA-4/CTLA-4 combinations versus PD-1 (reference) 2.89 (1.22–6.87) 0.022* FV: influenza vaccination; ICI: immune checkpoint inhibitor; PD-L1: PD-1 ligand 1; PD-1: programmed cell death 1; CTLA-4: cytotoxic T-lymphocyte antigen 4. #: comparisons made between patients with grade 3–5 IRAEs and patients with no IRAEs plus patients with grade 1–2 IRAEs; ¶: OR 0.45 by elastic-net logistic regression with α=0.5 and OR 0.61 by Bayesian logistic regression with horseshoe prior. Harrell's C-statistic=0.695. *: p<0.05.
- TABLE 6
Subset analysis for the associations between clinical features and immune-related adverse events (IRAEs): grade 3–5 IRAEs versus no IRAEs
OR (90% CI) p-value FV: positive versus negative (reference) 0.46 (0.26–0.84) 0.016* Race: White versus non-White (reference) 2.70 (0.79–9.25) 0.092 Gender: male versus female (reference) 0.89 (0.48–1.67) 0.382 Smoking status: ever versus never (reference) 4.97 (0.82–30.18) 0.072 Age: <60 versus ≥60 years (reference) 0.86 (0.43–1.72) 0.357 Trial: yes versus no (reference) 0.94 (0.48–1.85) 0.439 ICI received: PD-L1 versus PD-1 (reference) 2.80 (0.91–8.61) 0.065 CTLA-4/CTLA-4 combinations versus PD-1 (reference) 2.95 (1.13–7.72) 0.032* FV: influenza vaccination; ICI: immune checkpoint inhibitor; PD-L1: PD-1 ligand 1; PD-1: programmed cell death 1; CTLA-4: cytotoxic T-lymphocyte antigen 4. Harrell's C-statistic=0.691. *: p<0.05.
- TABLE 7
Associations between clinical features and survival (progression-free survival (PFS) and overall survival (OS))
PFS OS HR (90% CI) p-value HR (90% CI) p-value FV: positive versus negative (reference) 0.96 (0.73–1.26) 0.395 1.06 (0.79–1.43) 0.371 Race: White versus non-White (reference) 0.70 (0.45–1.11) 0.100 1.03 (0.59–1.80) 0.465 Gender: male versus female (reference) 0.81 (0.62–1.05) 0.091 0.97 (0.72–1.30) 0.427 Smoking status: ever versus never (reference) 0.80 (0.48–1.33) 0.235 1.14 (0.61–2.15) 0.363 Age: <60 versus ≥60 years (reference) 1.19 (0.88–1.60) 0.176 0.96 (0.68–1.37) 0.428 Trial: yes versus no (reference) 0.71 (0.53–0.95) 0.026* 0.60 (0.43–0.83) 0.005* ICI received: PD-L1 versus PD-1 (reference) 0.60 (0.34–1.07) 0.074 0.56 (0.28–1.12) 0.083 CTLA-4/CTLA-4 combinations versus PD-1 (reference) 1.17 (0.77–1.78) 0.264 1.26 (0.80–1.99) 0.202 FV: influenza vaccination; ICI: immune checkpoint inhibitor; PD-L1: PD-1 ligand 1; PD-1: programmed cell death 1; CTLA-4: cytotoxic T-lymphocyte antigen 4. Harrell's C-statistic for PFS=0.541 and for OS=0.542.
Supplementary Materials
Supplementary Material
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Supplementary material 00684-2021.SUPPLEMENT
