Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Copyright © 2023 by the Korean Cancer Association
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ethical Statement
This study was reviewed and approved by the institutional review board (IRB) (no. 2022-08-062) at Samsung Medical Center. The need for informed consent was waived by the IRB due to the retrospective nature of this study. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
Author Contributions
Conceived and designed the analysis: Sun JM.
Performed the study and analyzed the data: Jung HA, Park S, Lee SH, Ahn JS, Ahn MJ, Sun JM.
Wrote the paper: Sun JM, Jung HA.
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
Characteristic | First-generation EGFR-TKI therapy | Afatinib | ||||||
---|---|---|---|---|---|---|---|---|
Total (n=155) | No brain RT (n=94) | Brain RT (n=61) | p-value | Total (n=204) | No brain RT (n=126) | Brain RT (n=78) | p-value | |
Age (yr) | ||||||||
< 65 | 79 (51.0) | 49 (62.0) | 30 (38.0) | 0.75 | 148 (72.5) | 92 (62.2) | 56 (37.8) | 0.87 |
≥ 65 | 76 (49.0) | 45 (59.2) | 31 (40.8) | 56 (27.5) | 34 (60.7) | 22 (39.3) | ||
Sex | ||||||||
Male | 44 (28.4) | 22 (50.0) | 22 (50.0) | 0.10 | 87 (42.6) | 49 (56.3) | 38 (43.7) | 0.19 |
Female | 111 (71.6) | 72 (64.9) | 39 (35.1) | 117 (57.4) | 77 (65.8) | 40 (34.2) | ||
ECOG PS | ||||||||
0–1 | 142 (91.6) | 83 (58.5) | 59 (41.5) | 0.08 | 193 (94.6) | 120 (62.2) | 73 (37.8) | 0.75 |
≥ 2 | 13 (8.4) | 11 (84.6) | 2 (15.4) | 11 (5.4) | 6 (54.5) | 5 (45.5) | ||
Smoking status | ||||||||
Never smoker | 142 (91.6) | 86 (60.6) | 56 (39.4) | > 0.99 | 173 (84.8) | 112 (64.7) | 61 (35.3) | 0.05 |
Ex-/Current smoker | 13 (8.4) | 8 (61.5) | 5 (38.5) | 31 (15.2) | 14 (45.2) | 17 (54.8) | ||
Type ofEGFR mutation | ||||||||
Exon 19 deletion | 71 (45.8) | 46 (64.8) | 25 (35.2) | 0.66 | 128 (62.7) | 82 (64.1) | 46 (35.9) | 0.53 |
L858R | 77 (49.7) | 44 (57.1) | 33 (42.9) | 61 (29.9) | 34 (55.7) | 27 (44.3) | ||
Uncommon EGFR mutationa) | 7 (4.5) | 4 (57.1) | 3 (42.9) | 15 (7.4) | 10 (66.7) | 5 (33.3) | ||
No. of brain metastases | ||||||||
1–3 | 73 (47.1) | 38 (52.1) | 35 (47.9) | 0.12 | 74 (36.3) | 40 (54.1) | 34 (45.9) | 0.11 |
4–6 | 27 (17.4) | 18 (66.7) | 9 (33.3) | 35 (17.2) | 21 (60.0) | 14 (40.0) | ||
7–9 | 22 (14.2) | 13 (59.1) | 9 (40.9) | 28 (13.7) | 16 (57.1) | 12 (42.9) | ||
≥ 10 | 33 (21.3) | 25 (75.8) | 8 (24.2) | 67 (32.8) | 49 (73.1) | 18 (26.9) | ||
Maximum diameter of brain metastases (cm) | ||||||||
< 1.0 | 102 (65.8) | 77 (75.5) | 25 (24.5) | < 0.001 | 142 (69.6) | 114 (80.3) | 28 (19.7) | < 0.001 |
1.0–1.9 | 24 (15.5) | 12 (50.0) | 12 (50.0) | 30 (14.7) | 8 (26.7) | 22 (73.3) | ||
2.0–2.9 | 17 (11.0) | 5 (29.4) | 12 (70.6) | 20 (9.8) | 4 (20.0) | 16 (80.0) | ||
≥ 3.0 | 12 (7.7) | 0 | 12 (100) | 12 (5.9) | 0 | 12 (100) | ||
Symptomatic brain metastases | ||||||||
No | 113 (72.9) | 90 (79.6) | 23 (20.4) | < 0.001 | 145 (71.1) | 125 (86.2) | 20 (13.8) | < 0.001 |
Yes | 42 (27.1) | 4 (9.5) | 38 (90.5) | 59 (28.9) | 1 (1.7) | 58 (98.3) |
First-generation EGFR-TKI therapy | Afatinib | ||||||||
---|---|---|---|---|---|---|---|---|---|
No. of patients | No brain RT | Brain RT | No. of patients | No brain RT | Brain RT | p-valuea) | |||
GKS | WBRT | GKS | WBRT | ||||||
Total | 155 (100) | 94 (60.6) | 46 (29.7) | 15 (9.7) | 204 (100) | 126 (61.8) | 64 (31.4) | 14 (6.9) | 0.62 |
No. of brain metastases | |||||||||
1–3 | 73 (47.1) | 38 (52.1) | 32 (43.8) | 3 (4.1) | 74 (36.3) | 40 (54.1) | 34 (45.9) | 0 | 0.31 |
4–6 | 27 (17.4) | 18 (66.7) | 8 (29.6) | 1 (3.7) | 35 (17.2) | 21 (60.0) | 13 (37.1) | 1 (2.9) | 0.80 |
7–9 | 22 (14.2) | 13 (59.1) | 6 (27.3) | 3 (13.6) | 28 (13.7) | 16 (57.1) | 11 (39.3) | 1 (3.6) | 0.38 |
≥ 10 | 33 (21.3) | 25 (75.8) | 0 | 8 (24.2) | 67 (32.8) | 49 (73.1) | 6 (9.0) | 12 (17.9) | 0.21 |
Maximum dimension of brain metastases (cm) | |||||||||
< 1.0 | 102 (65.8) | 77 (75.5) | 22 (21.6) | 3 (2.9) | 142 (69.6) | 114 (80.3) | 26 (18.3) | 2 (1.4) | 0.50 |
1.0–1.9 | 24 (15.5) | 12 (50.0) | 7 (29.2) | 5 (20.8) | 30 (14.7) | 8 (26.7) | 17 (56.7) | 5 (16.7) | > 0.99 |
2.0–2.9 | 17 (11.0) | 5 (29.4) | 8 (47.1) | 4 (23.5) | 20 (9.8) | 4 (20.0) | 12 (60.0) | 4 (20.0) | 0.75 |
≥ 3.0 | 12 (7.7) | 0 | 9 (75.0) | 3 (25.0) | 12 (5.9) | 0 | 9 (75.0) | 3 (25.0) | > 0.99 |
Symptomatic brain metastases | |||||||||
No | 113 (72.9) | 90 (79.6) | 21 (18.6) | 2 (13.3) | 145 (71.1) | 125 (86.2) | 17 (11.7) | 3 (2.1) | 0.31 |
Yes | 42 (27.1) | 4 (9.5) | 25 (59.5) | 13 (31.0) | 59 (28.9) | 1 (1.7) | 47 (79.7) | 11 (18.6) | 0.05 |
Values are presented as number (%). EGFR-TKI, epidermal growth factor receptor–tyrosine kinase inhibitor; GKS, gamma knife radiosurgery; RT, radiotherapy; WBRT, whole-brain radiotherapy.
a) p-values were calculated by comparing the proportions of patients who received brain RT between the first-generation EGFR-TKI and afatinib groups, using the chi-square test.
Baseline characteristics
Characteristic | First-generation EGFR-TKI therapy | Afatinib | ||||||
---|---|---|---|---|---|---|---|---|
Total (n=155) | No brain RT (n=94) | Brain RT (n=61) | p-value | Total (n=204) | No brain RT (n=126) | Brain RT (n=78) | p-value | |
Age (yr) | ||||||||
< 65 | 79 (51.0) | 49 (62.0) | 30 (38.0) | 0.75 | 148 (72.5) | 92 (62.2) | 56 (37.8) | 0.87 |
≥ 65 | 76 (49.0) | 45 (59.2) | 31 (40.8) | 56 (27.5) | 34 (60.7) | 22 (39.3) | ||
Sex | ||||||||
Male | 44 (28.4) | 22 (50.0) | 22 (50.0) | 0.10 | 87 (42.6) | 49 (56.3) | 38 (43.7) | 0.19 |
Female | 111 (71.6) | 72 (64.9) | 39 (35.1) | 117 (57.4) | 77 (65.8) | 40 (34.2) | ||
ECOG PS | ||||||||
0–1 | 142 (91.6) | 83 (58.5) | 59 (41.5) | 0.08 | 193 (94.6) | 120 (62.2) | 73 (37.8) | 0.75 |
≥ 2 | 13 (8.4) | 11 (84.6) | 2 (15.4) | 11 (5.4) | 6 (54.5) | 5 (45.5) | ||
Smoking status | ||||||||
Never smoker | 142 (91.6) | 86 (60.6) | 56 (39.4) | > 0.99 | 173 (84.8) | 112 (64.7) | 61 (35.3) | 0.05 |
Ex-/Current smoker | 13 (8.4) | 8 (61.5) | 5 (38.5) | 31 (15.2) | 14 (45.2) | 17 (54.8) | ||
Type ofEGFR mutation | ||||||||
Exon 19 deletion | 71 (45.8) | 46 (64.8) | 25 (35.2) | 0.66 | 128 (62.7) | 82 (64.1) | 46 (35.9) | 0.53 |
L858R | 77 (49.7) | 44 (57.1) | 33 (42.9) | 61 (29.9) | 34 (55.7) | 27 (44.3) | ||
Uncommon EGFR mutation |
7 (4.5) | 4 (57.1) | 3 (42.9) | 15 (7.4) | 10 (66.7) | 5 (33.3) | ||
No. of brain metastases | ||||||||
1–3 | 73 (47.1) | 38 (52.1) | 35 (47.9) | 0.12 | 74 (36.3) | 40 (54.1) | 34 (45.9) | 0.11 |
4–6 | 27 (17.4) | 18 (66.7) | 9 (33.3) | 35 (17.2) | 21 (60.0) | 14 (40.0) | ||
7–9 | 22 (14.2) | 13 (59.1) | 9 (40.9) | 28 (13.7) | 16 (57.1) | 12 (42.9) | ||
≥ 10 | 33 (21.3) | 25 (75.8) | 8 (24.2) | 67 (32.8) | 49 (73.1) | 18 (26.9) | ||
Maximum diameter of brain metastases (cm) | ||||||||
< 1.0 | 102 (65.8) | 77 (75.5) | 25 (24.5) | < 0.001 | 142 (69.6) | 114 (80.3) | 28 (19.7) | < 0.001 |
1.0–1.9 | 24 (15.5) | 12 (50.0) | 12 (50.0) | 30 (14.7) | 8 (26.7) | 22 (73.3) | ||
2.0–2.9 | 17 (11.0) | 5 (29.4) | 12 (70.6) | 20 (9.8) | 4 (20.0) | 16 (80.0) | ||
≥ 3.0 | 12 (7.7) | 0 | 12 (100) | 12 (5.9) | 0 | 12 (100) | ||
Symptomatic brain metastases | ||||||||
No | 113 (72.9) | 90 (79.6) | 23 (20.4) | < 0.001 | 145 (71.1) | 125 (86.2) | 20 (13.8) | < 0.001 |
Yes | 42 (27.1) | 4 (9.5) | 38 (90.5) | 59 (28.9) | 1 (1.7) | 58 (98.3) |
Values are presented as number (%). ECOG PS, European Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; RT, radiotherapy; TKI, tyrosine kinase inhibitor.
a)Uncommon EGFR mutations include G719X, L861Q, and S768I.
Pattern of brain RT according to clinical features related to brain metastases
First-generation EGFR-TKI therapy | Afatinib | ||||||||
---|---|---|---|---|---|---|---|---|---|
No. of patients | No brain RT | Brain RT | No. of patients | No brain RT | Brain RT | p-value | |||
GKS | WBRT | GKS | WBRT | ||||||
Total | 155 (100) | 94 (60.6) | 46 (29.7) | 15 (9.7) | 204 (100) | 126 (61.8) | 64 (31.4) | 14 (6.9) | 0.62 |
No. of brain metastases | |||||||||
1–3 | 73 (47.1) | 38 (52.1) | 32 (43.8) | 3 (4.1) | 74 (36.3) | 40 (54.1) | 34 (45.9) | 0 | 0.31 |
4–6 | 27 (17.4) | 18 (66.7) | 8 (29.6) | 1 (3.7) | 35 (17.2) | 21 (60.0) | 13 (37.1) | 1 (2.9) | 0.80 |
7–9 | 22 (14.2) | 13 (59.1) | 6 (27.3) | 3 (13.6) | 28 (13.7) | 16 (57.1) | 11 (39.3) | 1 (3.6) | 0.38 |
≥ 10 | 33 (21.3) | 25 (75.8) | 0 | 8 (24.2) | 67 (32.8) | 49 (73.1) | 6 (9.0) | 12 (17.9) | 0.21 |
Maximum dimension of brain metastases (cm) | |||||||||
< 1.0 | 102 (65.8) | 77 (75.5) | 22 (21.6) | 3 (2.9) | 142 (69.6) | 114 (80.3) | 26 (18.3) | 2 (1.4) | 0.50 |
1.0–1.9 | 24 (15.5) | 12 (50.0) | 7 (29.2) | 5 (20.8) | 30 (14.7) | 8 (26.7) | 17 (56.7) | 5 (16.7) | > 0.99 |
2.0–2.9 | 17 (11.0) | 5 (29.4) | 8 (47.1) | 4 (23.5) | 20 (9.8) | 4 (20.0) | 12 (60.0) | 4 (20.0) | 0.75 |
≥ 3.0 | 12 (7.7) | 0 | 9 (75.0) | 3 (25.0) | 12 (5.9) | 0 | 9 (75.0) | 3 (25.0) | > 0.99 |
Symptomatic brain metastases | |||||||||
No | 113 (72.9) | 90 (79.6) | 21 (18.6) | 2 (13.3) | 145 (71.1) | 125 (86.2) | 17 (11.7) | 3 (2.1) | 0.31 |
Yes | 42 (27.1) | 4 (9.5) | 25 (59.5) | 13 (31.0) | 59 (28.9) | 1 (1.7) | 47 (79.7) | 11 (18.6) | 0.05 |
Values are presented as number (%). EGFR-TKI, epidermal growth factor receptor–tyrosine kinase inhibitor; GKS, gamma knife radiosurgery; RT, radiotherapy; WBRT, whole-brain radiotherapy.
a)p-values were calculated by comparing the proportions of patients who received brain RT between the first-generation EGFR-TKI and afatinib groups, using the chi-square test.
Multivariate analysis for overall survival
First-generation EGFR-TKI therapy (n=155) | Afatinib (n=204) | |||||
---|---|---|---|---|---|---|
HR | 95% CI | p-value | HR | 95% CI | p-value | |
Age (≥ 65 yr vs. < 65 yr) | 1.10 | 0.68–1.78 | 0.71 | 1.17 | 0.69–2.00 | 0.56 |
Sex (male vs. female) | 1.40 | 0.83–2.37 | 0.21 | 1.21 | 0.78–1.87 | 0.40 |
ECOG PS (≥ 2 vs. 0–1) | 1.94 | 0.25–15.17 | 0.53 | 1.24 | 0.46–3.36 | 0.67 |
Brain RT (no brain RT vs. brain RT) | 1.92 | 1.15–3.22 | 0.01 | 0.91 | 0.53–1.54 | 0.72 |
Type of EGFR mutation (L858R or uncommon EGFR mutation vs. exon 19 deletion) | 1.83 | 1.11–3.02 | 0.02 | 1.70 | 1.08–2.69 | 0.02 |
No. of brain metastases (≥ 7 vs. 1–6) | 1.31 | 0.79–2.16 | 0.30 | 1.99 | 1.26–3.13 | < 0.01 |
Maximum dimension of brain metastases (≥ 1 cm vs. < 1 cm) | 1.07 | 0.77–1.49 | 0.67 | 0.70 | 0.46–1.05 | 0.09 |
Subsequential treatment (others vs. third-G EGFR-TKI) | 2.16 | 1.29–3.59 | < 0.01 | 1.85 | 1.19–2.89 | < 0.01 |
CI, confidence interval; ECOG PS, European Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HR, hazard ratio; RT, radiotherapy; TKI, tyrosine kinase inhibitor.
Subsequent treatment in patients who progressed to first-line EGFR-TKI therapy (n=330)
First-generation EGFR-TKI (n=146) | Afatinib (n=184) | p-value | |
---|---|---|---|
The first subsequent chemotherapy | 58 (39.7) | 62 (33.7) | 0.11 |
Pemetrexed/Platinum | 9 (6.2) | 19 (10.3) | |
Gemcitabine/Platinum | 13 (8.9) | 24 (13.0) | |
Taxane/Patinum | 6 (4.1) | 1 (0.5) | |
Pemetrexed | 25 (17.1) | 11 (6.0) | |
Atezolizumab/Bevacizumab/Paclitaxel/Carboplatin | 5 (3.4) | 7 (3.8) | |
Third-generation EGFR-TKI | 47 (32.2) | 76 (41.3) | 0.08 |
Osimertinib | 39 (26.7) | 70 (38.0) | |
Lazertinib | 1 (0.7) | 4 (2.2) | |
Olmutinib | 7 (4.8) | 2 (1.1) | |
No subsequent treatment | 41 (28.1) | 46 (25.0) | 0.98 |
Values are presented as number (%). EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor.
Values are presented as number (%). ECOG PS, European Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; RT, radiotherapy; TKI, tyrosine kinase inhibitor. Uncommon
Values are presented as number (%). EGFR-TKI, epidermal growth factor receptor–tyrosine kinase inhibitor; GKS, gamma knife radiosurgery; RT, radiotherapy; WBRT, whole-brain radiotherapy. p-values were calculated by comparing the proportions of patients who received brain RT between the first-generation EGFR-TKI and afatinib groups, using the chi-square test.
CI, confidence interval; ECOG PS, European Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HR, hazard ratio; RT, radiotherapy; TKI, tyrosine kinase inhibitor.
Values are presented as number (%). EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor.