1Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea
2Department of Pathology, Chonnam National University Medical School, Gwangju, Korea
Copyright © 2019 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.
The current study was financially supported by AstraZeneca, Panagene, and Roche Molecular Diagnostics, Korea. However, the funders had no role in the study design, data collection and analysis, decision to publish, or preparation of this manuscript.
Characteristic | ctDNA T790M–positive (n=21) | ctDNA T790M–negative (n=59) | p-value |
---|---|---|---|
Age (yr) | 68.3 (37.4-82.6) | 68.1 (37.8-82.8) | 0.425 |
Female/Male | 15 (71.4)/6 (28.6) | 37 (62.7)/22 (37.8) | 0.472 |
Never smokers | 18 (85.7) | 38 (62.7) | 0.051 |
Histology, ADC | 21 (100) | 59 (100) | - |
Stage IV | 21 (100) | 59 (100) | - |
Brain metastasis | 11 (52.4) | 22 (37.3) | 0.228 |
Brain RT before screening | 7 (33.3) | 13 (22.0) | 0.304 |
Type of progression | |||
Localized | 1 (4.8) | 18 (30.5) | 0.018 |
Systemic | 20 (95.2) | 41 (69.5) | |
No. of treatments before screening | 1 (1-4) | 1 (1-7) | - |
1/2/3/4/5/6/7 | 17/1/2/1/0/0/0 | 37/17/2/1/0/1/1 | |
Prior TKIs therapy | |||
Gefitinib | 11 (52.4) | 33 (55.9) | 0.298 |
Erlotinib | 5 (23.8) | 16 (27.1) | |
Afatinib | 3 (14.3) | 9 (15.3) | |
Gefitinib and afatinib | 1 (4.8) | 0 | |
Erlotinib and afatinib | 1 (4.8) | 1 (1.7) | |
Type of EGFR mutationa) | |||
Exon 19 deletion | 14 (66.7) | 28 (47.5) | 0.130 |
Exon 21 L858R/L861Q | 4 (19.0) | 24 (40.7) | 0.074 |
Exon 19 deletion+exon 21 L858R | 1 (4.8) | 0 | - |
G719X | 1 (4.8) | 2 (3.4) | - |
No activating mutation found | 1 (4.8) | 5 (8.5) | - |
Time point at screening | |||
After cessation of prior EGFR-TKI | 11 (52.4) | 39 (66.1) | 0.265 |
During EGFR-TKI treatment | 10 (47.6) | 20 (33.9) | |
Re-biopsy | |||
Success | 9b) (42.9) | 43 (72.9) | 0.013 |
Failure | 12 (57.1) | 16 (27.1) |
Values are presented as median (range) or number (%). ctDNA, circulating tumor DNA; ADC, adenocarcinoma; RT, radiotherapy; TKI, tyrosine kinase inhibitor; EGFR, epidermal growth factor receptor.
a) Results of tumor genotyping at diagnosis,
b) Re-biopsy after osimertinib treatment (n=4), invalid for analysis (n=5).
ctDNA EGFR mutation tested screening subject | No. (%) (n=80) |
---|---|
T790M-positive | 21 (26.3) |
Known activating EGFR mutation detected | 20 (95.2) |
Activating EGFR mutation not detecteda) | 1 (4.8) |
(1) PANA Mutyper only | 4 |
(2) Cobas EGFR mutation test version 2 only | 4 |
Both (1) and (2) | 13 |
T790M-negative | 59 (73.7) |
Known activating EGFR mutation detected | 32 (54.2) |
Tumor genotyping performed | 20 |
Tumor T790M-positive | 5 (25.0) |
Known activating EGFR mutation not detected | 27 (45.8) |
Tumor genotyping performed | 23 |
Tumor T790M-positive | 7 (30.4) |
Estimated T790M-positive cases in screening subjectsb) | 37=21+[59×(12/43)] |
Sensitivity of tests | |
(1) PANA Mutyper | 17/37 (45.9) |
(2) Cobas EGFR mutation test ver. 2 | 17/37 (45.9) |
Combination of (1) and (2) | 21/37 (56.8) |
ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.
a) In this case, both tests (1) and (2) detected T790M from ctDNA. However, no EGFR mutation was detected in tumor genotyping at diagnosis or in pleural fluid genotyping after failure of first-line EGFR-TKI treatment (case No. 10),
b) As the T790M mutation was detected in 12 of 43 tumor genotyping tests, 27.9% (12/43) of 59 ctDNA-negative cases was assumed to have T790M (n=16). If we added 21 cases with positive ctDNA T790M, a total of 37 patients were estimated to have the T790M EGFR mutation.
Efficacy | ITT (n=19) | Both Pana and Cobas (n=11)a) | Pana only (n=4) | Cobas only (n=4) | p-value | Without BM (n=9) | With BM (n=10) | p-value |
---|---|---|---|---|---|---|---|---|
Type of response | ||||||||
Not evaluable | 4 (21.0) | 2 (18.2) | 1 (25.0) | 1 (25.0) | 0.702 | 2 (22.2) | 2 (20.0) | 0.289 |
Complete | 1 (5.3) | 1 (9.1) | 0 | 0 | 0 | 1 (10.0) | ||
Partial | 9 (47.4) | 5 (45.4) | 3 (75.0) | 1 (25.0) | 6 (66.7) | 3 (30.0) | ||
Stable disease | 5 (26.3) | 3 (27.3) | 0 | 2 (50.0) | 1 (11.1) | 4 (40.0) | ||
Progression | 0 | 0 | 0 | 0 | 0 | 0 | ||
ORRb) | 10/15 (66.7) | 6/9 (66.7) | 3/3 (100) | 1/3 (33.3) | 0.223 | 6/7 (85.7) | 4/8 (50.0) | 0.282 |
DCRb) | 15/15 (100) | 9/9 (100) | 3/3 (100) | 3/3 (100) | - | 7/7 (100) | 8/8 (100) | - |
PFS (mo) | 8.3 (7.9-8.7) | - | - | - | - | 5.1 (0.0-13.9) | 8.4 (6.5-10.3) | 0.431 |
TTR (mo) | 1.6 (1.6-1.7) | - | - | - | - | 1.6 (1.6-1.7) | 1.6 (1.6-1.7) | 0.789 |
DoR (mo) | 6.8 (5.3-8.3) | - | - | - | - | 6.7 (0.9-12.5) | 6.8 (1.1-12.5) | 0.782 |
Values are presented as number (%) or median (95% confidence interval). ITT, intention-to-treat population; Pana, PANA Mutyper; Cobas, Cobas EGFR mutation test ver. 2; BM, brain metastasis; ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; TTR, time to response; DoR, duration of response.
a) Thirteen patients were positive for both Pana and Cobas at screening, but two patients failed to enroll in this study,
b) Evaluated in response evaluable population.
Case No. | ctDNA T790M Pana/Cobas | Known activating mutation | Sources of re-biopsy | Time point of re-biopsya) | Re-biopsy T790M | Re-biopsy activating mutation | Prior EGFR-TKI | Treatment line | Best response | PFS (mo) |
---|---|---|---|---|---|---|---|---|---|---|
1 | +/+ | L858R | Tissue | After | + | L858R | Afatinib | 2 | CR | 13.4 |
2 | +/+ | E19del | Tissue | After | – | E19del | Erlotinib | 2 | PR | 11.0 |
3 | +/+ | L858R | Tissue | Beforeb) | + | L858R | Gefitinib | 2 | PR | 5.1 |
4 | +/+ | E19del | - | - | NA | - | Gefitinib | 2 | PR | Ongoing |
5 | +/+ | E19del | - | - | NA | - | Gefitinib | 2 | PR | 3.7 |
6 | +/+ | E19del | - | - | NA | - | Erlotinib | 2 | PR | 12.7 |
7 | +/+ | E19del | Tissue | After | – | E19del | Gefitinib | 2 | SD | 8.2 |
8 | +/+ | E19del | Bone marrow | Before | – | Wild | Gefitinib | 4 | SD | 12.3 |
9 | +/+ | L858R | - | - | NA | - | Gefitinib | 2 | SD | Ongoing |
10 | +/+ | Unknown | Pleural fluid | Before | – | Wild | Gefitinib | 3 | NE | 1.0 |
11 | +/+ | L858R | - | - | NA | - | Gefitinib | 2 | NE | 2.5 |
12 | +/+ | E19del | - | - | NA | - | Gefitinib | - | Screening fail | - |
13 | +/+ | E19del | - | - | NA | - | Erlotinib | - | Screening fail | - |
14 | +/– | E19del | - | - | NA | - | Gefitinib, afatinib | 5 | PR | 8.4 |
15 | +/– | E19del | - | - | NA | - | Afatinib | 2 | PR | 9.4 |
16 | +/– | E19del L858R | - | - | NA | - | Erlotinib | 2 | PR | 8.3 |
17 | +/– | G719X | - | - | NA | - | Afatinib | 2 | NE | 0.3 |
18 | –/+ | E19del | Tissue | Before | Not requested | Not requested | Gefitinib | 2 | PR | Ongoing |
19 | –/+ | E19del | Tissue | After | + | E19del | Gefitinib, afatinib | 4 | SD | 18.5 |
20 | –/+ | E19del | Tissue | Before | Invalid | Invalid | Erlotinib | 2 | SD | 9.9 |
21 | –/+ | E19del | - | - | NA | - | Gefitinib | 2 | NE | 0.5 |
ctDNA, circulating tumor DNA; Pana, PANA Mutyper; Cobas, Cobas EGFR mutation test ver. 2; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PFS, progression-free survival; CR, complete response; PR, partial response; NA, not available; SD, stable disease; NE, not evaluable.
a) Re-biopsy “before” or “after” administration of the third-generation EGFR-TKI,
b) Reports of EGFR mutation genotyping on re-biopsy was delayed and confirmed after enrollment of this trial.
Any grade (n=19) | Grade ≥ 3 (n=19) | ||
---|---|---|---|
Adverse events | 17 (89.5) | 6 (31.6) | |
Drug-related adverse events | 10 (52.6) | 1 (5.3) | |
AEs leading to dose reduction | 0 | ||
AEs leading to drug discontinuationa) | 1 (5.3) | ||
Serious adverse events | 8 (42.1) | ||
Serious adverse events, drug-related | 1 (5.3) | ||
Common events | |||
Gastritis | 4 (21.0) | 0 | |
Paronychia | 4 (21.0) | 0 | |
Diarrhea | 3 (15.8) | 0 | |
Nausea | 3 (15.8) | 0 | |
Constipation | 3 (15.8) | 0 | |
Rash or Acne | 3 (15.8) | 0 | |
Headache | 3 (15.8) | 0 | |
Back pain | 3 (15.8) | 1 (5.3) | |
Pruritus | 2 (10.5) | 0 | |
Mucositis | 2 (10.5) | 0 | |
LFTb) elevation | 2 (10.5) | 1 (5.3) | |
Sepsis | 2 (10.5) | 2 (10.5) | |
Vomiting | 1 (5.3) | 1 (5.3) | |
Anemia | 1 (5.3) | 0 | |
Pneumonitisa) | 1 (5.3) | 1 (5.3) |
Characteristic | ctDNA T790M–positive (n=21) | ctDNA T790M–negative (n=59) | p-value |
---|---|---|---|
Age (yr) | 68.3 (37.4-82.6) | 68.1 (37.8-82.8) | 0.425 |
Female/Male | 15 (71.4)/6 (28.6) | 37 (62.7)/22 (37.8) | 0.472 |
Never smokers | 18 (85.7) | 38 (62.7) | 0.051 |
Histology, ADC | 21 (100) | 59 (100) | - |
Stage IV | 21 (100) | 59 (100) | - |
Brain metastasis | 11 (52.4) | 22 (37.3) | 0.228 |
Brain RT before screening | 7 (33.3) | 13 (22.0) | 0.304 |
Type of progression | |||
Localized | 1 (4.8) | 18 (30.5) | 0.018 |
Systemic | 20 (95.2) | 41 (69.5) | |
No. of treatments before screening | 1 (1-4) | 1 (1-7) | - |
1/2/3/4/5/6/7 | 17/1/2/1/0/0/0 | 37/17/2/1/0/1/1 | |
Prior TKIs therapy | |||
Gefitinib | 11 (52.4) | 33 (55.9) | 0.298 |
Erlotinib | 5 (23.8) | 16 (27.1) | |
Afatinib | 3 (14.3) | 9 (15.3) | |
Gefitinib and afatinib | 1 (4.8) | 0 | |
Erlotinib and afatinib | 1 (4.8) | 1 (1.7) | |
Type of EGFR mutation |
|||
Exon 19 deletion | 14 (66.7) | 28 (47.5) | 0.130 |
Exon 21 L858R/L861Q | 4 (19.0) | 24 (40.7) | 0.074 |
Exon 19 deletion+exon 21 L858R | 1 (4.8) | 0 | - |
G719X | 1 (4.8) | 2 (3.4) | - |
No activating mutation found | 1 (4.8) | 5 (8.5) | - |
Time point at screening | |||
After cessation of prior EGFR-TKI | 11 (52.4) | 39 (66.1) | 0.265 |
During EGFR-TKI treatment | 10 (47.6) | 20 (33.9) | |
Re-biopsy | |||
Success | 9 |
43 (72.9) | 0.013 |
Failure | 12 (57.1) | 16 (27.1) |
ctDNA EGFR mutation tested screening subject | No. (%) (n=80) |
---|---|
T790M-positive | 21 (26.3) |
Known activating EGFR mutation detected | 20 (95.2) |
Activating EGFR mutation not detected |
1 (4.8) |
(1) PANA Mutyper only | 4 |
(2) Cobas EGFR mutation test version 2 only | 4 |
Both (1) and (2) | 13 |
T790M-negative | 59 (73.7) |
Known activating EGFR mutation detected | 32 (54.2) |
Tumor genotyping performed | 20 |
Tumor T790M-positive | 5 (25.0) |
Known activating EGFR mutation not detected | 27 (45.8) |
Tumor genotyping performed | 23 |
Tumor T790M-positive | 7 (30.4) |
Estimated T790M-positive cases in screening subjects |
37=21+[59×(12/43)] |
Sensitivity of tests | |
(1) PANA Mutyper | 17/37 (45.9) |
(2) Cobas EGFR mutation test ver. 2 | 17/37 (45.9) |
Combination of (1) and (2) | 21/37 (56.8) |
Efficacy | ITT (n=19) | Both Pana and Cobas (n=11) |
Pana only (n=4) | Cobas only (n=4) | p-value | Without BM (n=9) | With BM (n=10) | p-value |
---|---|---|---|---|---|---|---|---|
Type of response | ||||||||
Not evaluable | 4 (21.0) | 2 (18.2) | 1 (25.0) | 1 (25.0) | 0.702 | 2 (22.2) | 2 (20.0) | 0.289 |
Complete | 1 (5.3) | 1 (9.1) | 0 | 0 | 0 | 1 (10.0) | ||
Partial | 9 (47.4) | 5 (45.4) | 3 (75.0) | 1 (25.0) | 6 (66.7) | 3 (30.0) | ||
Stable disease | 5 (26.3) | 3 (27.3) | 0 | 2 (50.0) | 1 (11.1) | 4 (40.0) | ||
Progression | 0 | 0 | 0 | 0 | 0 | 0 | ||
ORR |
10/15 (66.7) | 6/9 (66.7) | 3/3 (100) | 1/3 (33.3) | 0.223 | 6/7 (85.7) | 4/8 (50.0) | 0.282 |
DCR |
15/15 (100) | 9/9 (100) | 3/3 (100) | 3/3 (100) | - | 7/7 (100) | 8/8 (100) | - |
PFS (mo) | 8.3 (7.9-8.7) | - | - | - | - | 5.1 (0.0-13.9) | 8.4 (6.5-10.3) | 0.431 |
TTR (mo) | 1.6 (1.6-1.7) | - | - | - | - | 1.6 (1.6-1.7) | 1.6 (1.6-1.7) | 0.789 |
DoR (mo) | 6.8 (5.3-8.3) | - | - | - | - | 6.7 (0.9-12.5) | 6.8 (1.1-12.5) | 0.782 |
Case No. | ctDNA T790M Pana/Cobas | Known activating mutation | Sources of re-biopsy | Time point of re-biopsy |
Re-biopsy T790M | Re-biopsy activating mutation | Prior EGFR-TKI | Treatment line | Best response | PFS (mo) |
---|---|---|---|---|---|---|---|---|---|---|
1 | +/+ | L858R | Tissue | After | + | L858R | Afatinib | 2 | CR | 13.4 |
2 | +/+ | E19del | Tissue | After | – | E19del | Erlotinib | 2 | PR | 11.0 |
3 | +/+ | L858R | Tissue | Before |
+ | L858R | Gefitinib | 2 | PR | 5.1 |
4 | +/+ | E19del | - | - | NA | - | Gefitinib | 2 | PR | Ongoing |
5 | +/+ | E19del | - | - | NA | - | Gefitinib | 2 | PR | 3.7 |
6 | +/+ | E19del | - | - | NA | - | Erlotinib | 2 | PR | 12.7 |
7 | +/+ | E19del | Tissue | After | – | E19del | Gefitinib | 2 | SD | 8.2 |
8 | +/+ | E19del | Bone marrow | Before | – | Wild | Gefitinib | 4 | SD | 12.3 |
9 | +/+ | L858R | - | - | NA | - | Gefitinib | 2 | SD | Ongoing |
10 | +/+ | Unknown | Pleural fluid | Before | – | Wild | Gefitinib | 3 | NE | 1.0 |
11 | +/+ | L858R | - | - | NA | - | Gefitinib | 2 | NE | 2.5 |
12 | +/+ | E19del | - | - | NA | - | Gefitinib | - | Screening fail | - |
13 | +/+ | E19del | - | - | NA | - | Erlotinib | - | Screening fail | - |
14 | +/– | E19del | - | - | NA | - | Gefitinib, afatinib | 5 | PR | 8.4 |
15 | +/– | E19del | - | - | NA | - | Afatinib | 2 | PR | 9.4 |
16 | +/– | E19del L858R | - | - | NA | - | Erlotinib | 2 | PR | 8.3 |
17 | +/– | G719X | - | - | NA | - | Afatinib | 2 | NE | 0.3 |
18 | –/+ | E19del | Tissue | Before | Not requested | Not requested | Gefitinib | 2 | PR | Ongoing |
19 | –/+ | E19del | Tissue | After | + | E19del | Gefitinib, afatinib | 4 | SD | 18.5 |
20 | –/+ | E19del | Tissue | Before | Invalid | Invalid | Erlotinib | 2 | SD | 9.9 |
21 | –/+ | E19del | - | - | NA | - | Gefitinib | 2 | NE | 0.5 |
Any grade (n=19) | Grade ≥ 3 (n=19) | ||
---|---|---|---|
Adverse events | 17 (89.5) | 6 (31.6) | |
Drug-related adverse events | 10 (52.6) | 1 (5.3) | |
AEs leading to dose reduction | 0 | ||
AEs leading to drug discontinuation |
1 (5.3) | ||
Serious adverse events | 8 (42.1) | ||
Serious adverse events, drug-related | 1 (5.3) | ||
Common events | |||
Gastritis | 4 (21.0) | 0 | |
Paronychia | 4 (21.0) | 0 | |
Diarrhea | 3 (15.8) | 0 | |
Nausea | 3 (15.8) | 0 | |
Constipation | 3 (15.8) | 0 | |
Rash or Acne | 3 (15.8) | 0 | |
Headache | 3 (15.8) | 0 | |
Back pain | 3 (15.8) | 1 (5.3) | |
Pruritus | 2 (10.5) | 0 | |
Mucositis | 2 (10.5) | 0 | |
LFT |
2 (10.5) | 1 (5.3) | |
Sepsis | 2 (10.5) | 2 (10.5) | |
Vomiting | 1 (5.3) | 1 (5.3) | |
Anemia | 1 (5.3) | 0 | |
Pneumonitis |
1 (5.3) | 1 (5.3) |
Values are presented as median (range) or number (%). ctDNA, circulating tumor DNA; ADC, adenocarcinoma; RT, radiotherapy; TKI, tyrosine kinase inhibitor; EGFR, epidermal growth factor receptor. Results of tumor genotyping at diagnosis, Re-biopsy after osimertinib treatment (n=4), invalid for analysis (n=5).
ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor. In this case, both tests (1) and (2) detected T790M from ctDNA. However, no As the T790M mutation was detected in 12 of 43 tumor genotyping tests, 27.9% (12/43) of 59 ctDNA-negative cases was assumed to have T790M (n=16). If we added 21 cases with positive ctDNA T790M, a total of 37 patients were estimated to have the T790M
Values are presented as number (%) or median (95% confidence interval). ITT, intention-to-treat population; Pana, PANA Mutyper; Cobas, Cobas Thirteen patients were positive for both Pana and Cobas at screening, but two patients failed to enroll in this study, Evaluated in response evaluable population.
ctDNA, circulating tumor DNA; Pana, PANA Mutyper; Cobas, Cobas Re-biopsy “before” or “after” administration of the third-generation EGFR-TKI, Reports of
Values are presented as number (%). LFT, liver function test. Interstitial pneumonia, Aspartate aminotransferase or alanine aminotransferase.