Epidermal growth factor receptor (
Between 2009 and 2017, non-small cell lung cancer (NSCLC) patients who showed an exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes, including responses to chemotherapy (CTx) or targeted therapy.
Of 3,539 NSCLC patients who harbored an activating
The incidence of an exon 20 insertion mutation is rare in Korea and occasionally accompanied by other common
Lung cancer is a leading cause of cancer death worldwide [
EGFR tyrosine kinase inhibitors (TKIs) are associated with a highly effective and durable response in NSCLC patients with these common
Between January 2009 and December 2017, histologically confirmed Samsung Medical Center NSCLC patients with activating
Mutational analyses of
All available data were retrospectively collected using a standardized case report form. OS and PFS were calculated using the Kaplan-Meier method. The Cox proportional hazards regression model was used to evaluate the impact of collected variables on PFS and OS. Two-sided p-values were set at a 0.05 significance level. All analyses were performed using SPSS ver. 23.0 software (IBM Corp., Armonk, NY).
Institutional Review Board (IRB) approval was obtained from Samsung Medical Center (SMC, Seoul, Korea, SMC 2018-02-019). The IRB approved waiver of informed consent.
From January 2009 to December 2017, 3,539 patients showed positive results in the
Of the 3,539 total patients, 1,479 had advanced NSCLC. These patients included 752 (50.8%) with an exon 19 deletion, 557 (37.7%) with L858R, 49 (3.3%) with G719X, 49 (3.3%) with L861Q, 27 (1.8%) with an exon 20 insertion, and 17 (1.1%) with S768I (
Among total 3,539 patients, 3,163 patients were identified that having common
Baseline characteristics of 27 advanced NSCLC patients harboring an exon 20 insertion mutation are summarized in
Among 27 patients with exon 20 insertions, only 17 had available data for amino acid position changes. All exon 20 insertions were clustered between Val769 and Val775. His-773_Val774insHis was the most common insertion mutation (n=7, 41.2%), followed by Val774_Cys775insHisVal (n=3, 17.7%) and His773_Val774insProHis (n=2, 11.7%). Each of the following mutations was found one time: His773_Val-774insAsnProHis, Pro772_His773insThrThrPro, Pro772_ His-773insGlyAsnPro, Val769_Asn771insValGlyVal, and Asp-770_Asn771insGly (
Of the 27 patients with exon 20 insertions, 22 received platinum-based systemic chemotherapy. The overall response rate (ORR) was 50.0%, and the disease control rate was 77.2%. The median PFS was 4.2 months (95% confidence interval [CI], 1.7 to 6.6), and the median OS was 29.4 months (95% CI, 9.3 to 49.6) (
Six patients were treated with an EGFR TKI. Three patients received a reversible EGFR TKI (erlotinib), and the other three received an irreversible EGFR TKI (two received afatinib, and one received osimertinib). Among the four patients with only an exon 20 insertion, three had progressive disease and one had stable disease. In contrast, the two doublemutation patients achieved a partial response to treatment (
We found that exon 20 insertion mutations represented 1.6% of all
Amino acid sequencing data from the exon 20 insertion mutations indicated that the majority (88.2%) showed changes after His773. The most frequent amino acid change was His773_Val774insHis (41.1%), followed by Val774_Cys-775insHisVal (17.6%) and His773_Val774insProHis (11.7%). All amino acid changes occurred between Val769 and Val-775, in a region located just after the C-helix of the
It has been suggested that exon 20 insertions and other types of
One patient showed a long duration of stable disease following treatment with an
In general, exon 20 insertion mutation in NSCLC is associated with lack of sensitivity to first-generation
In one pre-clinical study, patient derived xenografts cells harboring an
In this study, the advanced NSCLC patients with exon 20 insertion had median OS of 29.4 months (95% CI, 9.3 to 49.6), which is consistent with median OS of advanced NSCLC with common
The present study has certain limitations. Given the small number of patients and retrospective nature of the analysis, patients analyzed in this cohort might not be representative of all types of advanced NSCLC with
In conclusion, exon 20 insertion mutations are rare in Korea, and are occasionally accompanied by common
Supplementary materials are available at Cancer Research and Treatment website (
Conflict of interest relevant to this article was not reported.
Distribution of epidermal growth factor receptor (
Kaplan-Meier survival curves. (A) Progression-free survival of patients with an exon 20 insertion receiving systemic chemotherapy. (B) Overall survival of patients with an exon 20 insertion. NSCLC, non-small cell lung cancer.
Clinical characteristics of total 3,539 patients with NSCLC
Common (n=3,163) | Uncommon (n=376) | p-value | |
---|---|---|---|
61 (19-92) | 62 (27-87) | NS | |
Female | 2,008 (63.5) | 217 (57.7) | 0.032 |
Male | 1,155 (36.5) | 159 (42.3) | |
ADC | 3,077 (97.3) | 335 (89.1) | < 0.001 |
SqCC | 47 (1.5) | 20 (5.3) | |
Others | 39 (1.2) | 21 (5.6) | |
I-IIIA | 1,866 (59.0) | 194 (51.6) | 0.007 |
IIIB-IV | 1,297 (41.0) | 182 (48.4) |
Values are presented as median (range) or number (%). NSCLC, non-small cell lung cancer; NS, non-significant; ADC, adenocarcinoma; SqCC, squamous cell carcinoma.
Baseline characteristics of patients with an exon 20 insertion mutation
Early-stage (n=29) | Refractory NSCLC (n=27) | Total (n=56) | |
---|---|---|---|
60 (36-78) | 60 (43-75) | 60 (36-78) | |
Female | 14 (48.2) | 11 (40.7) | 25 (44.6) |
Male | 15 (51.8) | 16 (59.3) | 33 (55.4) |
ADC | 29 (100) | 26 (96.3) | 55 (98.2) |
SqCC | 0 | 1 (3.7) | 1 (1.8) |
0 | 8 (27.6) | 1 (3.8) | 9 (16.1) |
1 | 21 (72.4) | 19 (70.3) | 40 (71.4) |
2 | 0 | 7 (25.9) | 7 (12.5) |
Never | 19 (65.5) | 21 (77.8) | 40 (71.4) |
Current | 6 (20.7) | 3 (11.1) | 9 (16) |
Ex | 4 (13.8) | 3 (11.1) | 7 (12.6) |
CNS | - | 11 | - |
Bone | - | 9 | - |
Liver | - | 5 | - |
Lung | - | 9 | - |
Insertion only | 25 (8-6.2) | 23 (85.2) | - |
Insertion+S768I | - | 1 (3.7) | - |
Insertion+G719S | - | 1 (3.7) | - |
Insertion+Deletion 19 | 4 (13.8) | - | - |
Insertion+L858R | - | 2 (7.4) | - |
Values are presented as median (range) or number (%). NSCLC, non-small cell lung cancer; ADC, adenocarcinoma; SqCC, squamous cell carcinoma; ECOG, Eastern Cooperative Oncology Group; CNS, central nervous system.
Amino acid sequences of 17 NSCLC patients with an exon 20 insertion
No. | Sex | Age (yr) | Smoking Hx | ECOG | Initial stage | Exon 20 mutation | EGFR TKI | Chemotherapy | Best response | PFS | OS |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | F | 58 | Never | 1 | IIIA | c.2319_2320 ins CAC (p.H773_V774insH) | N/A | Premetrexed+cisplatin | SD | 17.0 | 46.4 |
2 | M | 73 | Never | 2 | IA | c.2319_2320 ins CAC (p.H773_V774insH) | N/A | N/A | 44.8 | ||
3 | M | 75 | Never | 1 | IV | C.2316_2317 ins GGCAACCCC (p.P772_H773insGNP) | N/A | Premetrexed+cisplatin | SD | 2.7 | 3.8 |
4 | M | 63 | Never | 1 | IIIA | c.2319_2320 ins CCCCAC (p.H773_V774insH) | N/A | Paclitaxel+cisplatin | PD | 0.9 | 9.7 |
5 | M | 50 | Never | 1 | IB | c.2305_2313 ins GTGGGGGTC (p.V769_N771insVGV) | N/A | N/A | 22.5 | ||
6 | F | 55 | Never | 1 | IV | c.2310_2311 ins GGT (p.D770_N771insG) | N/A | Premetrexed+cisplatin | PD | 1.9 | 6.1 |
7 | F | 63 | Never | 2 | IV | c.2322_2323 ins CACGTG (p.V774_C775insHV) | N/A | Premetrexed+cisplatin | SD | 2.1 | 18.4 |
8 | F | 55 | Never | 1 | IA | c.2322_2323 ins CACGTG (p.V774_C775insHV) | N/A | Premetrexed+cisplatin | PR | 13.0 | 26.2 |
9 | F | 56 | Never | 1 | IIIA | c.2319_2320 ins AACCCCCAC (p.H773_V774insNPH) | N/A | Docetaxel+cisplatin | PR | 2.7 | 29.5 |
10 | M | 60 | Never | 2 | IB | c.2319_2320 ins CCCCAC (p.H773_V774insPH | N/A | Premetrexed+cisplatin | PR | 2.6 | 46.4 |
11 | M | 48 | Never | 2 | IV | c.2315_2316 ins GACAACCCC (p.P772_H773insTTP) | N/A | Premetrexed+cisplatin | PR | 2.4 | 12.4 |
12 | F | 62 | Never | 1 | IA | c.2321_2322 ins CCACGT (p.V774_C775insHV) | N/A | N/A | 44.1 | ||
13 | F | 52 | Never | 1 | IA | c.2319_2320insCAC (p.H773_V774insH) | N/A | N/A | 35.2 | ||
14 | M | 60 | Never | 1 | IIIA | c.2319_2320insCAC (p.H773_V774insH) | N/A | Etoposide+cisplatin | PD | 2.6 | 25.9 |
15 | M | 60 | Never | 1 | IIIA | c.2319_2320insCAC (p.H773_V774insH) | N/A | Etoposide+cisplatin | SD | 17.2 | 26.2 |
16 | F | 66 | Never | 1 | IIIA | c.2318_2319 ins TAACCCCAG (p.H773_V774insPH) | N/A | Premetrexed+cisplatin | SD | 2.8 | 62.4 |
17 | M | 65 | Never | 1 | IA | c.2319_2320insCAC (p.H773_V774insH) | N/A | Premetrexed+cisplatin | PR | 2.9 | 36.9 |
The most frequent amino acid change was His773_Val774insHis (41.1%), followed by Val774_Cys775insHisVal (17.6%) and His773_Val774insProHis (11.7%).
NSCLC, non-small cell lung cancer; ECOG, Eastern Cooperative Oncology Group; ECOG, Eastern Cooperative Oncology Group; EGFR TKI, epidermal growth factor receptor tyrosine kinase inhibitor; PFS, progression-free survival; OS, overall survival; F, female; N/A, not available; M, male; SD, stable disease; PD, progressive disease; PR, partial response.
Clinical information and treatment outcomes of six patients who received EGFR TKIs
Sex | Age (yr) | Exon 20 type | ECOG | Smoking history | Initial stage | TKI type | EGFR TKI response | PFS |
---|---|---|---|---|---|---|---|---|
F | 44 | Insertion | 1 | Never-smoker | IV | Erlotinib | PD | 0.7 |
M | 65 | Insertion | 2 | Never-smoker | IV | Afatinib | PD | 0.9 |
M | 60 | Insertion | 1 | Current smoker 30PY | IV | Erlotinib | PD | 2.6 |
M | 48 | Insertion | 0 | Ex-smoker 20PY | IV | Erlotinib | SD | 11.4 |
M | 62 | Insertion+L858R | 1 | Ex-smoker 10PY | IIB | Afatinib | PR | 1.9 |
F | 43 | Insertion+G719S | 1 | Never-smoker | IV | Osimertinib | PR | 2.8 |
EGFR TKI, epidermal growth factor receptor tyrosine kinase inhibitor; ECOG, Eastern Cooperative Oncology Group; PFS, progression-free survival; F, female; M, male; PD, progressive disease; SD, stable disease; PR, partial response.
Published studies evaluating clinical response to EGFR TKIs in NSCLC patients with exon 20 insertion
Study | Type of EGFR Exon 20 mutation | Patients treated with EGFR TKIs | ORR to TKI (%) | PFS to TKI | OS |
---|---|---|---|---|---|
Tu et al. [ |
Insertion 20 | 12 | 0 | 3.0 (1.3-4.7) | 12.5 (0-25.5) |
Lund-Iversen et al. [ |
Insertion 20 | 3 | 0 | - | - |
Arcila et al. [ |
Insertion 20 | 5 | 40 | 2.5 | > 48 mo |
Naidoo et al. [ |
Insertion 20 | 11 | 27 | - | - |
Yasuda et al. [ |
Insertion 20 | 19 | 11 | - | - |
Kuiper et al. [ |
Insertion 20 | 16 | 0 | 2.9 (2.3-3.6) | 9.7 |
Current study | Insertion 20 | 4 | 25 | 2.6 (0.7-11.4) | 29.4 (9.3-49.6) |
EGFR TKI, epidermal growth factor receptor tyrosine kinase inhibitor; NSCLC, non-small cell lung cancer; ORR, objective response rate; PFS, progression free survival; OS, overall survival.