Background
Methods
Patients and settings
Data availability
Clinical and laboratory findings
Assessment of and response to AEs
Statistical analysis
Results
Characteristics
Present study (n = 30) | Nintedanib group in INPULSIS trials | ||
---|---|---|---|
Japanese (n = 76) | Overall (n = 638) | ||
Baseline characteristics | |||
Age | 72.0 [68.0, 74.8] | 68.4 ± 7.6a | 66.6 ± 8.1a |
Gender (male/female) | 24/6 | 62/14 | 507/131 |
Current or former smoker (%) | 26 (86.7%) | 66 (86.8%) | 464 (72.7%) |
Physique | |||
Body weight (kg) | 54.9 [49.7, 64.4] | 63.8 ± 11.6a | 79.2 ± 16.6a |
Body mass index | 21.0 [19.0, 23.6] | 24.4 ± 3.4a | 28.1 ± 4.6a |
Body surface area (DuBois, m2) | 1.59 [1.48, 1.72] | – | – |
Concomitant therapy | |||
Prednisolone (%) | 3 (10.0%) | 9 (11.8%) | 136 (21.3%) |
Tacrolimus (%) | 1 (3.3%) | 0 | 0 |
Laboratory data | |||
Aspartate aminotransferase (IU/L) | 21.5 [18.0, 24.8] | – | – |
Alanine aminotransferase (IU/L) | 16.0 [11.0, 24.3] | – | – |
Total bilirubin (mg/dL) | 0.50 [0.30, 0.60] | – | – |
γ-glutamyl transpeptidase (IU/L) | 31.0 [21.3, 48.0] | – | – |
Creatinine (mg/dL) | 0.80 [0.68, 0.87] | – | – |
Krebs von den Lungen-6 (U/mL) | 1021 [829, 1903] | – | – |
Surfactant protein D (ng/dL) | 382 [259, 452] | – | – |
Lung function test | |||
Forced vital capacity (L) | 1.68 [1.34, 1.99] | 2.42 ± 0.67a | 2.71 ± 0.76a |
% Forced vital capacity (%) | 52.9 [43.7, 69.7] | 80.9 ± 16.6a | 79.7 ± 17.6a |
% DLco (%) | 44.2 [40.9, 58.5] | 44.6 ± 11.4a | 47.4 ± 13.5a |
Administration history of pirfenidone | |||
Administration period (months) | 8.30 [4.23, 13.9] | – | – |
Time from discontinuation to nintedanib initiation | |||
0 (direct switch) | 20 (66.6%) | – | – |
< 1 month | 3 (10.0%) | – | – |
≥ 1 month | 7 (23.3%) | – | – |
Reason for discontinuation (%) | |||
Decline of FVC | 15 (50.0%) | – | – |
Adverse events | 15 (50.0%) | – | – |
Maintenance dose (%) | |||
< 1200 mg | 10 (33.3%) | – | – |
1200 mg | 16 (53.3%) | – | – |
1800 mg | 4 (13.3%) | – | – |
Adverse events
During the pirfenidone administration period (n = 30) | During the nintedanib administration period (n = 30) | |||||||
---|---|---|---|---|---|---|---|---|
Subjects | CTCAE grade | Subjects | CTCAE grade | |||||
1 | 2 | 3 | 1 | 2 | 3 | |||
Gastrointestinal | ||||||||
Anorexia | 19 (63.3%) | 3 | 14 | 2 | 14 (46.7%) | 3 | 8 | 3 |
Weight loss | 17 (56.7%) | 10 | 5 | 2 | 6 (20.0%) | 3 | 3 | 0 |
Diarrhea | 0 | 0 | 0 | 0 | 14 (46.7%) | 6 | 7 | 1 |
Dyspepsia | 5 (16.7%) | 1 | 4 | 0 | 0 | 0 | 0 | 0 |
Nausea | 0 | 0 | 0 | 0 | 2 (6.7%) | 0 | 2 | 0 |
Vomiting | 0 | 0 | 0 | 0 | 2 (6.7%) | 2 | 0 | 0 |
Other | ||||||||
AST/ALT elevation | 1 (3.3%) | 0 | 0 | 1 | 19 (63.3%) | 12 | 5 | 2 |
Fatigue | 5 (16.7%) | 1 | 4 | 0 | 3 (10.0%) | 1 | 1 | 1 |
Photosensitivity | 3 (10.0%) | 2 | 0 | 1 | 0 | 0 | 0 | 0 |
Rash | 2 (6.7%) | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
Abdominal pain | 0 | 0 | 0 | 0 | 3 (10.0%) | 2 | 1 | 0 |
Back pain | 2 (6.7%) | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
Non-cardiac chest pain | 1 (3.3%) | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
Fever | 0 | 0 | 0 | 0 | 2 (6.7%) | 2 | 0 | 0 |
Acute exacerbation | 0 | 0 | 0 | 0 | 2 (6.7%) | 0 | 0 | 2 |
Treatment status of nintedanib during the observation period
(n = 30) | |
---|---|
Administration period of nintedanib (months) | 5.30 [2.84, 11.8] |
Discontinued | 18 (60.0%) |
Discontinued within 6 months | 16 (53.3%) |
Reason for discontinuation | |
Liver injury | 3 (10.0%) |
Anorexia + weight loss | 3 (10.0%) |
Deterioration of physical condition | 3 (10.0%) |
Death | 3 (10.0%) |
Acute exacerbation of IPF | 3 (10.0%) |
Diarrhea | 1 (3.3%) |
Nausea | 1 (3.3%) |
Rash | 1 (3.3%) |
Continued | 12 (40.0%) |
Continued without interruption/dose reduction | 7 (23.3%) |
Need at least ≥1 interruption and/or dose reduction | 5 (16.7%) |
Reason for interruption and/or dose reduction | |
Liver injury | 2 (6.7%) |
Diarrhea | 2 (6.7%) |
Fever | 1 (3.3%) |
Efficacy of nintedanib in patients switched from pirfenidone
Risk factors for the early termination of nintedanib
Early termination group (n = 16) | Continuous treatment group (n = 14) | p value | |
---|---|---|---|
Baseline characteristics | |||
Age | 73.0 [67.5, 76.5] | 71.5 [68.0, 74.0] | 0.601 |
Gender (male/female) | 13/3 | 11/3 | 1.00 |
Physique | |||
Body weight (kg) | 52.6 [47.7, 57.8] | 58.5 [54.5, 66.3] | 0.048 |
Body mass index | 19.1 [17.2, 21.1] | 21.9 [21.0, 24.2] | 0.007 |
Body surface area (DuBois, m2) | 1.58 [1.47, 1.66] | 1.65 [1.51, 1.77] | 0.19 |
Laboratory data | |||
Creatinine (mg/dL) | 0.81 [0.68, 0.87] | 0.74 [0.68, 0.86] | 0.852 |
Krebs von den Lungen-6 (U/mL) | 1021 [732, 1518] | 1047 [845, 2106] | 0.678 |
Surfactant protein D (ng/dL) | 315 [186, 393] | 420 [273, 553] | 0.081 |
Lung function test | |||
% Forced vital capacity (%) | 48.5 [36.5, 58.6] | 56.6 [50.1, 69.7] | 0.212 |
% DLco (%) | 45.1 [41.9, 58.6] | 42.4 [37.8, 53.3] | 0.499 |
Administration history of pirfenidone | |||
Administration period (day) | 238 [146, 468] | 262 [127, 397] | 0.934 |
Reason for discontinuation (%) | |||
decline of forced vital capacity | 6 (37.5%) | 9 (64.3%) | 0.272 |
adverse events | 10 (62.5%) | 5 (35.7%) | |
Maintenance dose (%) | |||
< 1200 mg | 8 (50.0%) | 2 (14.3%) | 0.099 |
1200 mg | 5 (31.2%) | 11 (78.6%) | |
1800 mg | 3 (18.8%) | 1 (7.1%) |
Univariate | Multivariate | |||||
---|---|---|---|---|---|---|
Odds ratio | 95% CI | p value | Odds ratio | 95% CI | p value | |
Age | 1.02 | 0.885–1.18 | 0.751 | |||
Gender (male/female) | 1.18 | 0.197–7.08 | 0.855 | |||
Never smoker (%) | 0.857 | 0.104–7.04 | 0.886 | |||
Body weight (kg) | 0.931 | 0.861–1.01 | 0.0702 | |||
Body mass index | 0.704 | 0.519–0.955 | 0.0239 | 0.487 | 0.280–0.849 | 0.0111 |
Body surface area (DuBois, m2) | 0.0418 | 0.000541–3.22 | 0.152 | |||
Creatinine (mg/dL) | 1.07 | 0.0280–40.7 | 0.972 | |||
Krebs von den Lungen-6 (U/mL) | 1 | 0.999–1.00 | 0.348 | |||
Surfactant protein D (ng/dL) | 0.995 | 0.989–1.00 | 0.08 | 0.997 | 0.990–1.00 | 0.315 |
Forced vital capacity (L) | 0.561 | 0.150–2.1 | 0.391 | |||
% Forced vital capacity (%) | 0.967 | 0.918–1.02 | 0.213 | |||
% DLco (%) | 1.01 | 0.9580–1.06 | 0.739 | |||
Administration period of Pirfenidone | 1 | 0.999–1.00 | 0.329 | |||
Time from pirfenidone discontinuation to nintedanib initiation | 1.01 | 0.994–1.02 | 0.355 | |||
Discontinued pirfenidone due to FVC decline | 0.333 | 0.0751–1.48 | 0.148 | |||
Anorexia during the period of pirfenidone | 1.65 | 0.370–7.37 | 0.512 | |||
Weight loss during the period of pirfenidone | 2.93 | 0.657–13.1 | 0.159 | |||
Weight loss with grade ≥ 2 during the period of pirfenidone | 7.8 | 0.804–75.6 | 0.0764 | 3.29 | 0.184–58.8 | 0.418 |
Comparison between the switch and pirfenidone-naïve groups
Switch-group (n = 30) | Pirfenidone-naïve group (n = 64) | p value | ||
---|---|---|---|---|
Just before initiation of pirfenidone | Just before initiation of nintedanib | |||
Characteristics | ||||
Age | 71.0 [67.0, 75.0] | 72.0 [68.0, 74.8] | 72.0 [65.8, 75.3] | 0.903* |
Gender (male/female) | 24 / 6 | 24 / 6 | 53 / 11 | 0.778* |
Physique | ||||
Height (cm) | 165 [158, 169] | 165 [158, 169] | 164 [160, 170] | 0.958* |
Body weight (kg) | 61.4 [59.2, 66.0] | 54.9 [49.7, 64.4] | 63.2 [54.2, 73.1] | 0.01* |
Body mass index | 22.6 [21.0, 24.9] | 21.0 [19.0, 23.6] | 23.9 [20.7, 26.2] | 0.001* |
Body surface area (DuBois, m2) | 1.69 [1.62, 1.76] | 1.59 [1.48, 1.72] | 1.68 [1.54, 1.82] | 0.063* |
Lung function test | ||||
Forced vital capacity (L) | 2.36 [1.78, 3.52] | 1.68 [1.34, 1.99] | 2.21 [1.74, 2.66] | 0.001* |
% Forced vital capacity (%) | 62.5 [51.0, 76.6] | 52.9 [43.7, 69.7] | 67.7 [55.9, 79.0] | 0.001* |
% DLco (%) | 58.4 [46.7, 65.7] | 44.2 [40.9, 58.5] | 54.8 [47.6, 67.9] | 0.009* |
Nintedanib | ||||
Administration period (month) | – | 5.30 [2.84, 11.8] | 6.13 [3.02, 14.5] | 0.415 |
Discontinue within 6 months | – | 16 (53.3%) | 21 (32.8%) | 0.072 |
Adverse events | ||||
AST/ALT elevation | – | 19 (63.3%) | 46 (71.9%) | 0.475 |
Diarrhea | – | 14 (46.7%) | 34 (53.1%) | 0.659 |
Anorexia | – | 14 (46.7%) | 14 (21.9%) | 0.028 |
Weight loss | – | 6 (20.0%) | 6 (9.3%) | 0.188 |
Nausea | – | 2 (6.7%) | 11 (17.1%) | 0.213 |
Fatigue | – | 3 (10.0%) | 5 (7.8%) | 0.707 |
Switch-group (n = 30) | Pirfenidone-naïve group (n = 64) | |||||||
---|---|---|---|---|---|---|---|---|
Subjects | CTCAE grade | Subjects | CTCAE grade | |||||
1 | 2 | 3 | 1 | 2 | 3 | |||
Gastrointestinal | ||||||||
Anorexia | 14 (46.7%) | 3 | 8 | 3 | 14 (21.9%) | 8 | 2 | 4 |
Diarrhea | 14 (46.7%) | 6 | 7 | 1 | 34 (53.1%) | 20 | 10 | 4 |
Weight loss | 6 (20.0%) | 3 | 3 | 0 | 6 (9.3%) | 2 | 3 | 1 |
Nausea | 2 (6.7%) | 0 | 2 | 0 | 11 (17.1%) | 5 | 5 | 1 |
Vomiting | 2 (6.7%) | 2 | 0 | 0 | 3 (4.7%) | 3 | 0 | 0 |
Dyspepsia | 0 | 0 | 0 | 0 | 1 (1.6%) | 0 | 1 | 0 |
Other | ||||||||
AST/ALT elevation | 19 (63.3%) | 12 | 5 | 2 | 46 (71.9%) | 28 | 12 | 6 |
Fatigue | 3 (10.0%) | 1 | 1 | 1 | 5 (7.8%) | 2 | 3 | 0 |
Abdominal pain | 3 (10.0%) | 2 | 1 | 0 | 3 (4.7%) | 3 | 0 | 0 |
Fever | 2 (6.7%) | 2 | 0 | 0 | 4 (6.3%) | 4 | 0 | 0 |
Acute exacerbation | 2 (6.7%) | – | – | – | 3 (4.7%) | – | – | – |
Pneumothorax | 0 | – | – | – | 3 (4.7%) | – | – | – |
Rash | 0 | 0 | 0 | 0 | 2 (3.1%) | 0 | 2 | 0 |
Hemoptysis | 0 | – | – | – | 1 (1.6%) | – | – | – |
Cerebral infarction | 0 | – | – | – | 1 (1.6%) | – | – | – |
Eosinophilia | 0 | – | – | – | 1 (1.6%) | – | – | – |
Pneumatosis intestinalis | 0 | – | – | – | 1 (1.6%) | – | – | – |
Hematochezia | 0 | – | – | – | 1 (1.6%) | – | – | – |
Thrombocytopenia | 0 | – | – | – | 1 (1.6%) | 1 | 0 | 0 |