1Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Seoul, Korea
2Department of Oncology, University of Ulsan College of Medicine, Seoul, Korea
3Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Copyright © 2022 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
The study protocol was approved by the Institutional Review Board of Asan Medical Center (approval number: 2017-0295) and written informed consent was obtained from all patients.
Author Contributions
Conceived and designed the analysis: Ji WJ, Lee JC, Choi CM.
Collected the data: Ji WJ, Lee JC, Choi CM.
Contributed data or analysis tools: Ji WJ, Lee JC, Chun SM, Choi CM.
Performed the analysis: Kim YJ, Chun SM, Choi CM.
Wrote the paper: Kim YJ, Choi CM.
Conflicts of Interest
This study was funded by Astrazeneca, Inc. (study sponsor). The authors have no conflicts of interest to declare otherwise.
Values are presented as number (%) or median (range). EGFR mutation: T790M, (c.2369C>T; p.Thr790Met); E19del, (c.2235del15; p.E746_ A750del); L858R, (c.2573 T>G; p.Leu858Arg); G719X, (c.2155G>A; p.Gly719Ser); L861Q, (c.2582T>A; p.Leu861Gln); S768I, (c.2303G>T; p.Ser768Ile). Group A, patients who have T790M mutation detected in both tissue and liquid biopsy samples; Group B, patients who have T790M mutation detected only in tissue; Group C, patients who have T790M mutation detected only in liquid biopsy samples. BALF, bronchoalveolar lavage fluid; BWF, bronchial washing fluid; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; RTx, radiotherapy.
EGFR mutation: T790M, (c.2369C>T; p.Thr790Met); E19del, (c.2235del15; p.E746_A750del); L858R, (c.2573 T>G; p.Leu858Arg). BALF, bronchoalveolar lavage fluid; BWF, bronchial washing fluid; CI, confidence interval; EGFR, epidermal growth factor receptor; FN, false negative; FP, false positive; TN, true negative; TP, true positive.
Group A, patients who have T790M mutation detected in both tissue and liquid biopsy samples; Group B, patients who have T790M mutation detected only in tissue; Group C, patients who have T790M mutation detected only in liquid biopsy samples. CI, confidence interval; CR, complete response; NR, not reached to median; PD, progression of disease; PFS, progression-free survival; PR, partial response; SD, stable disease; T790M, (c.2369C>T; p.Thr790Met).
Baseline characteristics
Total | Group A | Group B | Group C | |
---|---|---|---|---|
No. | 63 | 26 | 19 | 18 |
Age (yr) | 63 (45–84) | 60.3 (47–74) | 63.7 (45–84) | 66.9 (54–81) |
Female sex | 38 (60.3) | 15 (57.7) | 11 (57.9) | 15 (66.7) |
ECOG | ||||
0–1 | 59 (93.7) | 25 (96.2) | 17 (89.5) | 17 (94.4) |
2–3 | 4 (6.3) | 1 (3.8) | 2 (10.5) | 1 (5.6) |
Previous surgery | 12 (19.0) | 3 (11.5) | 2 (10.5) | 7 (38.9) |
Previous RTx | 21 (33.3) | 10 (38.5) | 7 (36.8) | 4 (22.2) |
Extrathoracic metastasis | 37 (58.7) | 15 (57.7) | 12 (63.2) | 10 (55.6) |
Brain | 18 (28.6) | 9 (34.6) | 4 (21.1) | 5 (27.8) |
Extrathoracic visceral metastases | 28 (44.4) | 11 (42.3) | 10 (52.6) | 7 (38.9) |
Coexisting EGFR mutation | ||||
E19del | 45 (71.4) | 23 (88.5) | 13 (68.4) | 9 (50.0) |
L858R | 16 (25.4) | 3 (11.5) | 5 (26.3) | 8 (44.4) |
G719X | 2 (3.2) | 1 (3.8) | 1 (5.3) | 0 |
Other (L861Q, S768I) | 1 (1.6) | 0 | 0 | 1 (5.6) |
T790M positivity | ||||
Plasma | 18 | 13 | 0 | 5 |
BALF/BWF | 32 | 19 | 0 | 13 |
Pleural effusion | 8 | 4 | 0 | 4 |
Tissue | 45 | 26 | 19 | 0 |
Reason for absence of EGFR mutation test in tissue sample | ||||
Unable to conduct tissue biopsy | - | - | - | 7 (38.9) |
Inadequate amount of sample | - | - | - | 3 (16.7) |
No malignant cells | - | - | - | 4 (22.2) |
Values are presented as number (%) or median (range). EGFR mutation: T790M, (c.2369C>T; p.Thr790Met); E19del, (c.2235del15; p.E746_ A750del); L858R, (c.2573 T>G; p.Leu858Arg); G719X, (c.2155G>A; p.Gly719Ser); L861Q, (c.2582T>A; p.Leu861Gln); S768I, (c.2303G>T; p.Ser768Ile). Group A, patients who have T790M mutation detected in both tissue and liquid biopsy samples; Group B, patients who have T790M mutation detected only in tissue; Group C, patients who have T790M mutation detected only in liquid biopsy samples. BALF, bronchoalveolar lavage fluid; BWF, bronchial washing fluid; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; RTx, radiotherapy.
Diagnostic performance of liquid biopsy according to EGFR mutation
T790M | E19del | L858R | All EGFR mutations | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
| |||||||||
Plasma | BALF/BWF | p-value | Plasma | BALF/BWF | p-value | Plasma | BALF/BWF | p-value | Plasma | BALF/BWF | p-value | |
Sensitivity (95% CI) | 28.9 (16.4–44.3) | 42.2 (27.7–57.9) | 0.083 | 52.8 (35.5–69.6) | 80.6 (64.0–91.8) | 0.026 | 40.0 (12.2–73.8) | 80.0 (44.4–97.5) | 0.381 | 54.2 (39.2–68.6) | 81.3 (67.4–91.1) | 0.012 |
| ||||||||||||
Specificity (95% CI) | 75.0 (19.4–99.4) | 25.0 (0.63–80.6) | 92.3 (64.0–99.8) | 92.3 (64.0–99.8) | 97.4 (86.5–99.9) | 100.0 (91.0–100.0) | 0.0 (0.0–97.5) | 0.0 (0.0–97.5) | ||||
| ||||||||||||
Accuracy, n (%) | 16/49 (32.7) | 20/49 (40.8) | 63.3 (31/49) | 83.7 (41/49) | 42/49 (85.7) | 47/49 (95.9) | 26/49 (53.1) | 39/49 (79.6) | ||||
| ||||||||||||
TP | 13 | 19 | 19 | 29 | 4 | 8 | 26 | 39 | ||||
| ||||||||||||
TN | 3 | 1 | 12 | 12 | 38 | 39 | 0 | 0 | ||||
| ||||||||||||
FP | 1 | 3 | 1 | 1 | 1 | 0 | 1 | 1 | ||||
| ||||||||||||
FN | 32 | 26 | 17 | 7 | 6 | 2 | 22 | 9 |
EGFR mutation: T790M, (c.2369C>T; p.Thr790Met); E19del, (c.2235del15; p.E746_A750del); L858R, (c.2573 T>G; p.Leu858Arg). BALF, bronchoalveolar lavage fluid; BWF, bronchial washing fluid; CI, confidence interval; EGFR, epidermal growth factor receptor; FN, false negative; FP, false positive; TN, true negative; TP, true positive.
Clinical efficacy of osimertinib treatment by T790M positivity status in tissue or liquid biopsy samples
Total | Group A | Group B | Group C | |
---|---|---|---|---|
No. | 63 | 26 | 19 | 18 |
Type of response | ||||
CR | 0 | 0 | 0 | 0 |
PR | 40 | 16 | 13 | 11 |
SD | 21 | 10 | 6 | 5 |
PD | 2 | 0 | 0 | 2 |
Response rate (CR+PR) (95% CI, %) | 63.5 (51.3–75.7) | 61.5 (42.4–80.6) | 68.4 (46.9–89.9) | 61.1 (37.9–84.3) |
PFS (95% CI, mo) | 15.6 (10.7–24.2) | 10.7 (7.2–16.7) | NR | 20.3 (11.1–24.4) |
Group A, patients who have T790M mutation detected in both tissue and liquid biopsy samples; Group B, patients who have T790M mutation detected only in tissue; Group C, patients who have T790M mutation detected only in liquid biopsy samples. CI, confidence interval; CR, complete response; NR, not reached to median; PD, progression of disease; PFS, progression-free survival; PR, partial response; SD, stable disease; T790M, (c.2369C>T; p.Thr790Met).
Adverse events with CTCAE grade ≥ 3 related to osimertinib treatment
Adverse events | No. (%) | Grade | Action taken | Outcome |
---|---|---|---|---|
Hyponatremia | 1 (1.6) | 3 | Drug interrupted | Resolved |
Neutropenia | 2 (3.2) | 3 | Drug interrupted | Resolved |
QTc prolongation | 1 (1.6) | 3 | Drug withdrawn | Resolved |
Pneumonia | 2 (3.2) | 5 | Drug withdrawn | Death |
CTCAE, Common Terminology Criteria for Adverse Events.
Values are presented as number (%) or median (range).
Group A, patients who have T790M mutation detected in both tissue and liquid biopsy samples; Group B, patients who have T790M mutation detected only in tissue; Group C, patients who have T790M mutation detected only in liquid biopsy samples. CI, confidence interval; CR, complete response; NR, not reached to median; PD, progression of disease; PFS, progression-free survival; PR, partial response; SD, stable disease; T790M, (c.2369C>T; p.Thr790Met).
CTCAE, Common Terminology Criteria for Adverse Events.