Background
Methods
Data collection
Eligibility and exclusion criteria
Patients’ characteristics and treatment course
Treatment and response evaluation
Adverse events
Statistical analysis
Results
Patient characteristics
Characteristics | Total (N = 62) | Response | p-value | |
---|---|---|---|---|
CR/PR/SD (N = 47) | PD/NA (N = 15) | |||
Age, median (IQR) | 66.7 (18.1) | 65.1 (19.5) | 71.2 (16.1) | 0.42 |
≤ 65 | 27 (43.5%) | 23 (85.2%) | 4 (14.8%) | 0.13 |
> 65 | 35 (56.5%) | 24 (68.6%) | 11 (31.4%) | |
Sex | ||||
Male | 22 (35.5%) | 16 (72.7%) | 6 (27.3%) | 0.675 |
Female | 40 (64.5%) | 31 (77.5%) | 9 (22.5%) | |
Stage | ||||
Stage 3B | 1 (1.6%) | 1 (100.0%) | 0 (0.0%) | 0.569 |
Stage 4 | 61 (98.4%) | 46 (75.4%) | 15 (24.6%) | |
Smoking statusa | ||||
Smoker | 9 (14.8%) | 8 (88.9%) | 1 (11.1%) | 0.36 |
Never smoker | 52 (85.2%) | 39 (75.0%) | 13 (25.0%) | |
Histology | ||||
Adenocarcinoma | 62 (100.0%) | 47 (75.8%) | 15 (24.2%) | – |
Performance status, PS | ||||
PS 2 | 38 (61.3%) | 28 (73.7%) | 10 (26.3%) | 0.623 |
PS 3/4 | 24 (38.7%) | 19 (79.2%) | 5 (20.8%) | |
Mutation | ||||
L858R | 30 (48.4%) | 24 (80.0%) | 6 (20.0%) | 0.097 |
19del | 25 (40.3%) | 20 (80.0%) | 5 (20.0%) | |
Uncommon | 7 (11.3%) | 3 (42.9%) | 4 (57.1%) | |
Starting dose | ||||
40 mg | 39 (62.9%) | 31 (79.5%) | 8 (20.5%) | 0.378 |
30 mg | 23 (37.1%) | 16 (69.6%) | 7 (30.4%) | |
Metastatic sites | ||||
Lung | ||||
Yes | 27 (43.5%) | 19 (70.4%) | 8 (29.6%) | 0.38 |
No | 35 (56.5%) | 28 (80.0%) | 7 (20.0%) | |
Liver | ||||
Yes | 14 (22.6%) | 10 (71.4%) | 4 (28.6%) | 0.664 |
No | 48 (77.4%) | 37 (77.1%) | 11 (22.9%) | |
Brain | ||||
Yes | 27 (43.5%) | 19 (70.4%) | 8 (29.6%) | 0.38 |
No | 35 (56.5%) | 28 (80.0%) | 7 (20.0%) | |
Bone | ||||
Yes | 32 (51.6%) | 28 (87.5%) | 4 (12.5%) | 0.026 |
No | 30 (48.4%) | 19 (63.3%) | 11 (36.7%) | |
Pleura | ||||
Yes | 21 (33.9%) | 16 (76.2%) | 5 (23.8%) | 0.96 |
No | 41 (66.1%) | 31 (75.6%) | 10 (24.4%) | |
Adrenal gland | ||||
Yes | 4 (6.5%) | 3 (75.0%) | 1 (25.0%) | 0.969 |
No | 58 (93.5%) | 44 (75.9%) | 14 (24.1%) | |
Distant lymphadenopathy | ||||
Yes | 6 (9.7%) | 4 (66.7%) | 2 (33.3%) | 0.582 |
No | 56 (90.3%) | 43 (76.8%) | 13 (23.2%) | |
Dose reduction/interruption | ||||
Yes | 23 (37.1%) | 21 (91.3%) | 2 (8.7%) | 0.029 |
No | 39 (62.9%) | 26 (66.7%) | 13 (33.3%) | |
Discontinuation, AE-related | ||||
Yes | 8 (12.9%) | 5 (62.5%) | 3 (37.5%) | 0.346 |
No | 54 (87.1%) | 42 (77.8%) | 12 (22.2%) | |
BMI, median (IQR) | 23.11 (4.50) | 22.68 (3.75) | 25.98 (8.46) | 0.059 |
BSA, median (IQR) | 1.57 (0.17) | 1.57 (0.17) | 1.60 (0.20) | 0.48 |
Prognostic factors for PFS
Parameters | Univariate | Multivariate | ||||||
---|---|---|---|---|---|---|---|---|
Median (months) | 95% CI | HR | 95% CI | p-value | HR | 95% CI | p-value | |
Age | ||||||||
≤ 65 | 9.9 | 7.8–12.0 | 0.95 | 0.54–1.66 | 0.862 | |||
> 65 | 8.1 | 1.2–15.0 | ||||||
Sex | ||||||||
Male | 11.6 | 7.2–16.1 | 0.66 | 0.37–1.16 | 0.15 | |||
Female | 6.7 | 3.2–10.2 | ||||||
Smoking statusa | ||||||||
Smoker | 14.8 | 10.1–19.5 | 0.54 | 0.25–1.16 | 0.113 | |||
Never smoker | 8.1 | 5.5–10.6 | ||||||
Performance status, PS | ||||||||
PS 2 | 9.9 | 8.4–11.4 | 0.94 | 0.52–1.69 | 0.826 | |||
PS 3/4 | 6.2 | 5.0–7.5 | ||||||
Mutation | 0.446 | |||||||
L858R | 8.4 | 5.2–11.5 | 0.77 | 0.33–1.80 | 0.548 | |||
19del | 10.2 | 7.3–13.1 | 0.59 | 0.25–1.41 | 0.235 | |||
Uncommon | 3.5 | 0.5–6.6 | ||||||
Starting dose | ||||||||
40 mg | 10.8 | 8.6–13.1 | 0.55 | 0.31–0.98 | 0.043 | 0.92 | 0.49–1.75 | 0.806 |
30 mg | 6.7 | 1.9–11.5 | ||||||
Metastatic sites | ||||||||
Lung | ||||||||
Yes | 8.1 | 5.5–10.6 | 1.41 | 0.81–2.46 | 0.222 | |||
No | 9.9 | 8.5–11.3 | ||||||
Liver | ||||||||
Yes | 3.1 | 0.0–13.3 | 1.94 | 1.02–3.69 | 0.044 | 2.17 | 1.11–4.26 | 0.023 |
No | 9.9 | 6.5–13.3 | ||||||
Brain | ||||||||
Yes | 9.8 | 7.6–12.0 | 1.16 | 0.66–2.04 | 0.615 | |||
No | 8.6 | 5.8–11.5 | ||||||
Bone | ||||||||
Yes | 9.8 | 8.1–11.5 | 0.65 | 0.38–1.14 | 0.133 | |||
No | 5.9 | 1.4–10.2 | ||||||
Pleura | ||||||||
Yes | 8.1 | 0.8–15.3 | 1.92 | 1.07–3.45 | 0.03 | 1.58 | 0.84–2.98 | 0.157 |
No | 10.2 | 6.8–13.6 | ||||||
Adrenal gland | ||||||||
Yes | 8.6 | 0.0–21.1 | 1.13 | 0.35–3.64 | 0.842 | |||
No | 8.9 | 5.4–12.3 | ||||||
Distant lymphadenopathy | ||||||||
Yes | 6.7 | 0.0–15.9 | 1.91 | 0.74–4.94 | 0.183 | |||
No | 8.9 | 7.0–10.8 | ||||||
Dose reduction/interruption | ||||||||
Yes | 11.6 | 9.0–14.3 | 0.65 | 0.36–1.16 | 0.143 | |||
No | 6.2 | 0. 0–12.7 | ||||||
Discontinuation, AE-related | ||||||||
Yes | 6.7 | 0.6–12.8 | 0.64 | 0.20–2.07 | 0.457 | |||
No | 8.9 | 6.9–10.8 | ||||||
Clinical tumor response | < 0.001 | < 0.001 | ||||||
CR/PR | 11.8 | 9.2–14.4 | 0.05 | 0.02–0.13 | < 0.001 | 0.05 | 0.02–0.13 | < 0.001 |
SD | 18.4 | 4.7–32.1 | 0.04 | 0.01–0.14 | < 0.001 | 0.05 | 0.01–0.19 | < 0.001 |
PD/NA | 1.4 | 0.9–1.8 | ||||||
BMI | 1.05 | 0.97–1.13 | 0.244 | |||||
BSA | 0.1 | 0.01–2.02 | 0.132 |
Prognostic factors for OS
Parameters | Univariate | Multivariate | ||||||
---|---|---|---|---|---|---|---|---|
Median (months) | 95% CI | HR | 95% CI | p-value | HR | 95% CI | p-value | |
Age | ||||||||
≤ 65 | 15.8 | 10.3–21.4 | 0.91 | 1.59–0.52 | 0.744 | |||
> 65 | 8.2 | 1.1–15.3 | ||||||
Sex | ||||||||
Male | 13.3 | 3.8–22.9 | 0.77 | 0.43–1.38 | 0.375 | |||
Female | 11.6 | 5.3–17.8 | ||||||
Smoking status | ||||||||
Smoker | 22.3 | 16.7–27.9 | 0.62 | 0.28–1.39 | 0.244 | |||
Never smoker | 11.3 | 5.5–17.0 | ||||||
Performance status, PS | ||||||||
PS 2 | 15.8 | 8.8–22.9 | 0.86 | 0.49–1.53 | 0.615 | |||
PS ¾ | 8.4 | 2.3–14.6 | ||||||
Mutation | 0.52 | |||||||
L858R | 11.7 | 7.7–15.6 | 0.67 | 0.27–1.65 | 0.382 | |||
19del | 18.1 | 9.1–27.1 | 0.59 | 0.24–1.46 | 0.253 | |||
Uncommon | 3.5 | 0.5–6.6 | ||||||
Starting dose | ||||||||
40 mg | 17.5 | 11.6–23.4 | 0.59 | 0.34–1.05 | 0.073 | 0.93 | 0.51–1.72 | 0.827 |
30 mg | 8.1 | 2.6–13.5 | ||||||
Metastatic sites | ||||||||
Lung | ||||||||
Yes | 10.1 | 4.9–15.2 | 1.26 | 0.72–2.19 | 0.422 | |||
No | 15.8 | 11.0–20.7 | ||||||
Liver | ||||||||
Yes | 3.1 | 0.0–18.5 | 1.85 | 0.97–3.52 | 0.061 | 2.15 | 1.1–4.18 | 0.024 |
No | 13.8 | 8.9–18.6 | ||||||
Brain | ||||||||
Yes | 17.5 | 11.6–23.4 | 0.94 | 0.54–1.64 | 0.838 | |||
No | 10.8 | 6.7–15.0 | ||||||
Bone | ||||||||
Yes | 18.1 | 11.5–24.8 | 0.66 | 0.38–1.15 | 0.147 | |||
No | 8.4 | 1.7–15.2 | ||||||
Pleura | ||||||||
Yes | 8.1 | 0.0–17.8 | 1.59 | 0.90–2.81 | 0.112 | |||
No | 15.5 | 8.2–22.8 | ||||||
Adrenal gland | ||||||||
Yes | 10.1 | 0.0–29.7 | 1.28 | 0.46–3.55 | 0.641 | |||
No | 12.9 | 8.4–17.3 | ||||||
Distant lymphadenopathy | ||||||||
Yes | 15.5 | 0.0–39.8 | 1.11 | 0.47–2.62 | 0.804 | |||
No | 11.7 | 8.1–15.2 | ||||||
Dose reduction/interruption | ||||||||
Yes | 20.3 | 15.8–24.8 | 0.65 | 0.37–1.15 | 0.138 | |||
No | 8.1 | 0.1–16.1 | ||||||
Discontinuation, AE-related | ||||||||
Yes | 17.5 | 0.0–38.6 | 0.59 | 0.23–1.48 | 0.261 | |||
No | 11.7 | 8.2–15.2 | ||||||
Clinical tumor response | < 0.001 | < 0.001 | ||||||
CR/PR | 18.1 | 13.6–22.7 | 0.15 | 0.08–0.3 | < 0.001 | 0.14 | 0.05–0.42 | < 0.001 |
SD | 20.3 | 0.0–43.5 | 0.14 | 0.05–0.39 | < 0.001 | 0.14 | 0.07–0.30 | < 0.001 |
PD/NA | 1.5 | 0.0–3.1 | ||||||
BMI | 1.01 | 0.93–1.10 | 0.867 | |||||
BSA | 0.33 | 0.02–5.99 | 0.451 |
Predictive factors for tumor response
Adverse events and association with the starting dose of afatinib
AEs | Any grade | Grade 3–4 | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
All (N = 62) | % | Afatinib 40 mg (N = 39) | % | Afatinib 30 mg (N = 23) | % | p-value | All (N = 62) | % | Afatinib 40 mg (N = 39) | % | Afatinib 30 mg (N = 23) | % | p-value | |
Any adverse effects | 60 | 96.8% | 39 | 100.0% | 21 | 91.3% | 0.061 | 14 | 22.6% | 12 | 30.8% | 2 | 8.7% | 0.045 |
Diarrhea | 54 | 87.1% | 36 | 92.3% | 18 | 78.3% | 0.111 | 7 | 11.3% | 6 | 15.4% | 1 | 4.3% | 0.185 |
Acneiform | 8 | 12.9% | 6 | 15.4% | 2 | 8.7% | 0.448 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | – |
Paronychia | 28 | 45.2% | 20 | 51.3% | 8 | 34.8% | 0.207 | 6 | 9.7% | 5 | 12.8% | 1 | 4.3% | 0.276 |
Skin lesions | 39 | 62.9% | 28 | 71.8% | 11 | 47.8% | 0.059 | 3 | 4.8% | 3 | 7.7% | 0 | 0.0% | 0.173 |
Pruritus | 1 | 1.6% | 1 | 2.6% | 0 | 0.0% | 0.439 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | – |
Nausea and vomiting | 5 | 8.1% | 3 | 7.7% | 2 | 8.7% | 0.889 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | – |
Constipation | 3 | 4.8% | 3 | 7.7% | 0 | 0.0% | 0.173 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | – |
Dry skin | 5 | 8.1% | 2 | 5.1% | 3 | 13.0% | 0.269 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | – |
Mucositis | 24 | 38.7% | 18 | 46.2% | 6 | 26.1% | 0.117 | 4 | 6.5% | 4 | 10.3% | 0 | 0.0% | 0.112 |
Hand foot syndrome | 2 | 3.2% | 2 | 5.1% | 0 | 0.0% | 0.270 | 1 | 1.6% | 1 | 2.6% | 0 | 0.0% | 0.439 |
Eye | 2 | 3.2% | 2 | 5.1% | 0 | 0.0% | 0.270 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | – |
Edema | 1 | 1.6% | 1 | 2.6% | 0 | 0.0% | 0.439 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | – |
Onycholysis | 1 | 1.6% | 1 | 2.6% | 0 | 0.0% | 0.439 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | – |
Subsequent treatment after afatinib
Subsequent treatment | Overall (N = 62) | % | Starting dose | Clinical response | ||||||||
Afatinib 40 mg (N = 39) | % | Afatinib 30 mg (N = 23) | % | p-value | CR/PR/SD (N = 47) | % | PD/NA (N = 15) | % | p-value | |||
Yes | 25 | 40.3% | 15 | 38.5% | 10 | 43.5% | 0.697 | 20 | 42.6% | 5 | 33.3% | 0.526 |
No | 37 | 59.7% | 24 | 61.5% | 13 | 56.5% | 27 | 57.4% | 10 | 66.7% | ||
Patients receiving subsequent treatment | Overall (n = 25) | % | Afatinib 40 mg (N = 39) | % | Afatinib 30 mg (N = 23) | % | p-value | CR/PR/SD (N = 47) | % | PD/NA (N = 15) | % | p-value |
Chemotherapy | ||||||||||||
Yes | 14 | 56.0% | 7 | 46.7% | 7 | 70.0% | 0.256 | 11 | 23.4% | 3 | 20.0% | 0.784 |
No | 11 | 44.0% | 8 | 53.3% | 3 | 30.0% | 36 | 76.6% | 12 | 80.0% | ||
TKI other than osimertinib | ||||||||||||
Yes | 14 | 56.0% | 9 | 60.0% | 5 | 50.0% | 0.903 | 11 | 23.4% | 3 | 20.0% | 0.784 |
No | 11 | 44.0% | 6 | 40.0% | 5 | 50.0% | 36 | 76.6% | 12 | 80.0% | ||
Osimertinib | ||||||||||||
Yes | 4 | 16.0% | 2 | 13.3% | 2 | 20.0% | 0.581 | 3 | 6.4% | 1 | 6.7% | 0.969 |
No | 21 | 84.0% | 13 | 86.7% | 8 | 80.0% | 44 | 93.6% | 14 | 93.3% | ||
Bevacizumab | ||||||||||||
Yes | 3 | 12.0% | 2 | 13.3% | 1 | 10.0% | 0.89 | 3 | 6.4% | 0 | 0.0% | 0.316 |
No | 22 | 88.0% | 13 | 86.7% | 9 | 90.0% | 44 | 93.6% | 15 | 100.0% | ||
Immune checkpoint inhibitors | ||||||||||||
Yes | 2 | 8.0% | 1 | 6.7% | 1 | 10.0% | 0.701 | 1 | 2.1% | 1 | 6.7% | 0.386 |
No | 23 | 92.0% | 14 | 93.3% | 9 | 90.0% | 46 | 97.9% | 14 | 93.3% |