Shinshu Med J, 70⑹：397～405, 2022

Treatment Outcomes in Patients with Atypical EGFR-positive
Non-small Cell Lung Cancer in Nagano Prefecture, Japan
Toshihiko Agatsuma1）, Shintaro Kanda2）＊, Ryouhei Yamamoto3）
Yasushi Ono4）, Kenichi Nishie5）, Hozumi Tanaka6）, Akemi Matsuo7）
Mio Shibutani8） and Tomonobu Koizumi2）
1） Department of Pulmonary Medicine, National Hospital Organization Shinshu Ueda Medical Center2） Department of Hematology and Medical Oncology, Shinshu University School of Medicine
3） Department of General Thoracic Surgery, Saku Central Hospital Advanced Care Center4） Department of Pulmonary Medicine, Aizawa Hospital5） Department of Pulmonary Medicine, Iida Municipal Hospital6） Department of Surgery, Iida Hospital
7） Department of Pulmonary Medicine, Minami Nagano Medical Center, Shinonoi General Hospital8） Undergraduate School of Medicine, Shinshu University School of Medicine

Background : This study was performed to evaluate clinical practices in patients with atypical epidermal growth
factor receptor (EGFR)-positive inoperable non-small cell lung cancer (NSCLC) in Nagano Prefecture, Japan.
Patients and methods : Patients with newly diagnosed atypical EGFR-positive inoperable NSCLC in 14 hospitals
in Nagano, Japan, between May 2016 and March 2019 were enrolled in this study. Atypical EGFR mutations
included G719X, S768I, L861Q, compound mutations, and coexistence of de novo T790N in this study. After reg­istering baseline clinical characteristics and initial treatment, serial data were recorded every 4 months in eachpatient. Initial and serial therapies were at the discretion of the attending physician.
Results : The study population consisted of 24 patients with atypical EGFR-positive NSCLC (12 men and 12
women ; median age : 78.5 years ; range : 49-89 years). Fourteen patients had single G719X, S768I, or L861Q muta­tion and 10 had compound EGFR mutations. Performance statuses 0/1/2/3/4 were seen in 11/7/3/2/1 cases andclinical stage I/II/III/IV/ recurrence occurred in 1/0/0/15/8 cases, respectively. One patient with clinical stage
IA was treated with radiotherapy. Other patients were treated with EGFR-tyrosine kinase inhibitors (TKIs) as
first (n＝21) or second (n＝2)-line therapy, and the response rate to TKIs was 56.5 ％. Median overall survival
was 23.9 months (95 ％ confidence interval［CI］: 10.2 months to NA) in atypical EGFR-positive cases.
Conclusion : The present results reveal that clinical outcomes in patients with atypical EGFR- positive NSCLCs
in Nagano prefecture were comparable with those in other clinical trials and studies. Shinshu Med J 70 : 397―
405, 2022(Received for publication July 12, 2022 ; accepted in revised form August 18, 2022)
Key words : EGFR-TKI, non-small cell lung cancer, compound mutation, uncommon mutation, T790M

Ⅰ

Introduction

Lung cancer is the most common type of cancer

and the leading cause of cancer mortality worldwide1）,
including Japan2）3）. Non-small cell lung cancer (NSCLC)
is the most frequent histological type, and non-squa­mous NSCLC is the predominant histological subtype3）.

＊

Corresponding author : Shintaro Kanda
Department of Hematology and Medical Oncology,
Shinshu University School of Medicine, 3-1-1 Asahi,
Matsumoto, Nagano 390-8621, Japan
E-mail : skanda@shinshu-u.ac.jp

No. 6, 2022

Molecular targeted agents, such as epidermal growth
factor receptor (EGFR) tyrosine kinase inhibitors(TKIs) have markedly improved overall survival
in populations harboring these targetable genetic
397

Agatsuma・Kanda・Yamamoto et al.

alterations4）-7）. Indeed, gefitinib and erlotinib (first-

Ⅱ

generation EGFR-TKI), afatinib (second-generation
EGFR-TKI), and osimertinib (third-generation
EGFR-TKI) have been widely used in clinical prac­Ａ

Materials and Methods

Patients and data collection
Registration of eligible patients for this prospective

study was conducted centrally at the Shinshu Cancer

tice.
L858R mutations and exon 19 deletions represent

Center, Shinshu University Hospital. Patients withthe most common classical EGFR mutations in pa­

histologically or cytologically proven EGFR-positivetients with NSCLC, accounting for 80 ％-90 ％ of EGFR

and inoperable NSCLC newly diagnosed between

8）9）, and numerous clinical studies haveMay 6, 2016, and March 31, 2019, with no history of

demonstrated the usefulness of EGFR-TKIs in theseprior therapy or recurrence after thoracic surgery

mutations4）-7）. Other EGFR mutations are designatedwere eligible for inclusion in the study. To avoid se­

as uncommon mutations, and account for 10 ％-20 ％lection bias at the time of enrollment, patients whopatients

9）-13）

of all EGFR mutations. The sensitivity of uncom­

were eligible for this study were enrolled in a con­mon EGFR mutations to EGFR-TKIs is highly het­

secutive and sequential manner in each participating

erogeneous. Patients harboring one group of uncom­

hospital. Patients were anonymized before registra­mon, recurrent EGFR mutations (G719X, S768I, L861Q)

tion in participating hospitals, and their anonymous

respond to EGFR-TKIs, referred to as sensitive un­data were collected from serial case report forms.

9）
-13）

. However, it has been

Data were collected on baseline demographic andshown that the efficacy of EGFR-TKIs in patients withclinical characteristics, including age, sex, smoking

sensitive uncommon EGFR mutations is low com­

history, performance status (PS), histology, and clini­9）-13）,

cal stage. Fourteen hospitals in Nagano prefecture

Furthermore, uncommon EGFR mutations were ob­participated in the present study (Table 1). The

14）
-16）

.

study protocol was approved by the institutional

Compound EGFR mutations have also been observed

review board of Shinshu University (Approval No.

even in cases of common L858R mutations and exon 19

3407, 10/May/2016, UMIN000003645) and the ethics

common EGFR mutations

pared with classical common EGFR mutations
served as single and compound EGFR mutations

15）
16）

. In particular, the combination of T790M

committee of each participating hospital. The histo­

mutations, acquired resistance to first- or second-

logical diagnosis and stage of NSCLC were based ondeletions17）

generation EGFR-TKIs , accounts for 0.5 ％ of TKI-

the World Health Organization (WHO) classificationnaïve NSCLC patients, and survival data for such(version 7 until 2016 and version 8 from 2017). PS

18）

cases are lacking . Thus, information about the clin­

was estimated according to the Eastern Cooperative

ical efficacy and/or practice data in these atypical

Oncology Group (ECOG) classification.

EGFR mutations are still insufficient, and therapeuticstrategies are still challenging for this population.

EGFR mutations were analyzed by polymerase
chain reaction (PCR) or direct sequencing methods in

We performed a prospective and multicenter ob­

each hospital or laboratory center. Patients with any

servational study to determine the treatment pat­type of EGFR mutation were registered and a flow

terns and outcomes of treatment-naïve patients withdiagram for selection of patients for enrollment in the

newly diagnosed inoperable EGFR-positive NSCLC

study is shown in Fig. 1. Patients with G719X, S768I,

14）

in Nagano prefecture, Japan . Here, we selected andand L861Q single mutations and combined withsummarized daily practice data on clinical and treat­common exon 19 deletion and exon 21 L858R werement outcomes of patients with sensitive uncommon

selected for inclusion in the present study. In addition,

and/or combined EGFR-positive NSCLCs in Nagano

those with combined EGFR mutation and T790M in

prefecture, Japan.

exon 20 and other rare types were also enrolled into
the present study. These EGFR mutations wereclassified as atypical in this study. Treatment and398

Shinshu Med J

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Clinical outcome of atypical EGFR-positive NSCLCs

choice of TKI were determined at the discretion ofval from the initial date of induction therapy to thethe attending physician. The types of drugs given asdate of death or the last follow-up visit. Kaplan-

initial treatment were also registered at baseline.

Meier plots were used for OS analyses and the medi­

The response, toxicities, subsequent therapy, andan and 95 ％ confidence interval (CI) were deter­clinical outcomes were recorded every 4 months. Pa­

mined. Statistical analysis was performed using NZR

tient privacy was protected when using individual

Statistics.

information.
Ｂ

Ⅲ

Analysis and statistics

The analysis of survival was locked on May 31,
2022. Overall survival (OS) was defined as the inter­
Table 1

Ａ

Results

Clinical characteristics
There were 281 EGFR＋ NSCLC patients in Nagano

Participating hospitals

Hospital

Department

Nagano Municipal Hospital

Department of Pulmonary Medicine

Nagano Red Cross Hospital

Department of Pulmonary Medicine

Nagano Prefectural Shinshu Medical Center

Department of Thoracic Surgery

Nagano Matsushiro General Hospital

Department of Pulmonary Medicine

Minami Nagano Iryou Center, Shinonoi Hospital

Department of Pulmonary Medicine

Shinshu Ueda Medical Center

Department of Pulmonary Medicine

Saku Central Hospital Advanced Care Center

Department of Pulmonary Medicine

Aizawa Hospital

Department of Pulmonary Medicine

Shinshu University HospitalFirst Department of Internal Medicine, Medical Oncology

Suwa Red Cross Hospital

Department of Pulmonary Medicine

Ina Central Hospital

Department of Pulmonary Medicine, Department ofThoracic Surgery

Showa Inan General Hospital

Department of Thoracic Surgery

Iida Municipal Hospital

Department of Pulmonary Medicine

Iida Hospital

Department of Thoracic Surgery

EGFR-mutated non-small cell lung cancer (n = 281)
exon 19 deletion (n = 132)
L858R in exon 21 (n = 125)

uncommon EGFR mutations (n = 14)
compound EGFR mutations (n = 10)
Fig. 1
No. 6, 2022

Flow diagram in the present study
399

Agatsuma・Kanda・Yamamoto et al.
Table 2 Characteristics of patients with atypical epidermal growth factor receptor (EGFR)positive inoperable non-small cell lung cancer (NSCLC) in the present study
Patients (N＝24)
Median age

78.5 years(49 - 89)

Type of Atypical EGFR mutations

Sex

G719X

8

Male

12

L861Q

4

Female

12

S768I

2

Performance Status
0/1/2/3/4

11/7/3/2/1

Smoking status
Never smokedEx-smoker

14
9
BI 962(400-1720)

Current smoker

1
BI 210

Histology

L858R ＋ S768I

2

L858R ＋ T790M

3

Del19 ＋ G719X

1

Del19 ＋ T790M

2

Del19＋E746-A750del(2236-2250)

1

Exon19-duplication(K739-1744duplication)

1

Site of metastasis

Adenocarcinoma

22

Bone

8

Adenosquamous cell cacinoma

2

Pleura

8

Lung

4

Brain

3

Adrenal gland

2

Liver

2

Muscle1

Pancreas

1

Skin

1

prefecture between May 6, 2016, and March 31, 2019.

Ｂ

First-line treatment choice and serial treatments

Among them, 24 patients with atypical EGFR-

The first-line therapy in atypical EGFR-positive

positive NSCLC (12 men and 12 women ; median

NSCLCs is summarized in Table 3. In first-line ther­age : 78.5 years ; range : 49-89 years) were analyzed

apy, EGFR-TKI was used in 21 cases. Gefitinib andin this study (Fig. 1). Fourteen patients had single

afatinib were used in 8 cases, respectively and follow­

G719X, S768I, or L861Q mutation and 10 had com­ed by osimertinib in 4, and erlotinib in 1. One patient

bined EGFR mutations. The clinical characteristics

with stage I disease was treated with radiotherapy.

are summarized in Table 2. Eleven patients were

Two patients with compound EGFR mutation wereclassified as PS 0, 7 as PS 1, 3 as PS 2, 2 as PS 3, andinitially treated with platinum-based chemotherapy

1 as PS 4. Histological type was adenocarcinoma infollowed by EGFR-TKI as second-line therapy.

most cases (22 cases), and two cases had adenosqua­

Twenty-three patients, with the exclusion of one

mous carcinoma. The clinical stages were metastatic

patient with stage I disease, received EGFR-TKIs.

stage (stage IV : 15 cases, 62.5 ％), recurrence after

Complete response was achieved in two cases andsurgery (8 cases, 24.9 ％), and stage 1 (stage 1A, one

partial response was obtained in 11 cases, resultingcase). Metastatic sites included bone (n＝8), pleura (nin an overall response rate (ORR) of 56.5 ％. Gefitinib＝8), intrapulmonary (n＝4), and brain (n＝3), etc.

and afatinib were used in two cases each after cisplat­400

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Clinical outcome of atypical EGFR-positive NSCLCs
Table 3 Initial therapy in patients with atypical epidermal growth factor receptor (EGFR)positive inoperable non-small cell lung cancer (NSCLC) in the present study
Single mutation (n＝14)
Gefitinib

3

Erlotinib

1

Afatinib

7

Osimertinib

2

Radiation

1
Compound mutation (n＝10)

with T790M (n＝5)

Gefitinib

52Afatinib

1

1

Osimertinib

2

1

Cytotoxic chemotherapy

21

in-based chemotherapy, but the response was stablewith atypical EGFR-positive NSCLCs in Nagano pre­disease in both cases.

fecture, Japan. A total of 281 patients with EGFR-

The sequences of serial treatment in each case arepositive NSCLCs were treated between May 2016

shown in Fig. 2. Ten patients received only first-line

and March 2019. In the present study, we selected

EGFR-TKI and six of these patients died. First-line

14 sensitive uncommon and 10 compound EGFR mu­

EGFR-TKI treatment has been continued in four

tations, including those combined with de novo

cases, both of whom remain alive without recurrence.

T790M, and reviewed their clinical outcomes. The

Second-line therapy after front line EGFR-TKIs was

population (24/281 cases, 8.5 ％) and median OS were

performed in 10 cases, with a switch to anothersimilar to previous studies10）-13）.

EGFR-TKI in 5 cases, platinum-doublet cytotoxic

Wu et al.11） reported that objective responses tochemotherapy in 3 cases, monotherapy in 1 case, andgefitinib or erlotinib (first-generation EGFR-TKIs)

immune checkpoint inhibitor in 1 case (Fig. 2).

were observed in 57.1 ％ of patients with Gly719 orFive patients were treated with third- and fourth-

Leu861 mutations, with an OS of 16.4 months. Yangline therapy, respectively. One patient was treated

et al.12） reported post hoc analysis of afatinib data

until eighth-line therapy.

from the LUX-Lung 2, LUX-Lung 3, and LUX-LungＣ

6 trial populations. The ORR of afatinib was 71 ％Survival
The median observation time was 23.9 months

and the median progression free survival (PFS) and(range : 6.0-62.3 months). Survival curves in all cases

OS were 11 months and 19.4 months, respectively.

of atypical EGFR-positive NSCLC are shown in Fig. 3.

Furthermore, a phase II study in Korea13） showed an

Median OS in all subjects was 23.9 months (95 ％ORR of osimertinib for uncommon EGFR-positive

CI : 10.2 to NA months) and there was no significant

NSCLC of 50 ％ (18 of 36 patients) and median PFS ofdifference between uncommon and compound EGFR

8.2 months, although the study included four EGFR-＋NSCLC (27.9 months［95 ％CI ; 7.4 to NA months］

positive mutations in addition to G719X, S768I, andvs. 20.7 months［95 ％ CI, 8.7 to NA months］; P＝

L861Q. Thus, the higher response rate and prolonged

0.54, log-rank test).

survival with afatinib was validated in a larger num­Ⅳ

Discussion

This study examined clinical practice in patients
No. 6, 2022

ber of patients using real-world data. However, theoptimal TKI for uncommon EGFR-positive NSCLC
was still unclear because of the small sample sizes
401

Agatsuma・Kanda・Yamamoto et al.

♰♰♰

Each case of
singlemutation＃＃
Each case ofcompoundmutation

0

♰

♰
♰

geﬁ�nib,elro�nib
afa�nibosimer�nib

♰

10

♰

ICI

♰

♰

20

♰

♰

30

♰

Pla�num-based
chemotherapy
Monotherapy

♰

40

RT

50
60
geﬁ�nib,elro�nib
afa�nib♰osimer�nib

♰

ICI

♰

＃
＃

Pla�num-based
chemotherapy
Monotherapy

＃

♰
0

10

20

30

40

50

Months60

Fig. 2 Serial treatment and outcomes in each case. Each colored bar indicates the treatment intervals of various
therapies in each case.
＋ ; time of death. # ; case of compound epidermal growth factor receptor (EGFR) mutation with T790M. ICI ; immunecheck point inhibitors, RT ; radiotherapy.

1.00

Probability

0.80

0.60

0.40

0.20

0.00

0

10

20

30

40

50

60

70

Fig. 3 Kaplan-Meier plot of overall
survival after initial therapy inpatients with atypical epidermal
growth factor receptor mutatednon-small cell lung cancer.

Months402

Shinshu Med J

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Clinical outcome of atypical EGFR-positive NSCLCs

and different patient backgrounds in each study. In­

NDCLCs5）, it may be considered the first choice for

deed, afatinib was used in the present study in first-

treatment in patients with de novo T790M mutation.

line and subsequent therapy. The response rate ofHowever, this agent became available in Japan for

56.5 ％ in the present study was similar to previous

first-line therapy in 2018. Therefore, various therapies

studies10）-13）. Although six cases were treated with

were selected in our case series with de novo T790M-

only first-line therapy, subsequent therapies werepositive NSCLC. Initial therapy was as follows : gefi­

continued in 14 cases. Clinical practice analysis re­tinib in two cases, afatinib in one case, osimertinib

vealed that OS in the present study was 23.9 months,

in one case, and cytotoxic chemotherapy includingwhich was longer than in previous studies, sug­

cisplatin, pemetrexed, and bevacizumab in one casegesting that patients with atypical EGFR positive

each. Osimertinib was used as second-line (n＝2) and

NSCLCs in Nagano prefecture were appropriately

third-line (n＝2) line therapy. In addition, re-challenge

treated in terms of clinical practice.

with osimertinib was performed in two cases. Five

Several clinical studies indicated that patients har­patients showed survival of 7.3 months (dead), 10.0

boring compound mutations or double uncommon

months (dead), 33.3 months (dead), 40.9 months

mutations showed better clinical outcomes than(currently alive), and 57.7 months (currently alive). A

10）those with a single uncommon mutation. Si et al.

recent study showed that patients who received se­summarized the treatment outcomes in 132 cases ofquential treatment with first- and second-generation

uncommon EGFR-positive NSCLC and reported that

EGFR-TKIs followed by osimertinib had longer me­patients with compound mutations and double un­dian OS (37.3 months) than patients without subse­

common EGFR mutations had longer OS than thosequent osimertinib treatment (23.0 months) or thosewith a single uncommon EGFR mutation, althoughtreated with osimertinib alone (8.2 months)23）. Further

the difference was not significant. Chiu et al.19） ana­

clinical experience is needed to verify the best se­lyzed 19 patients with double uncommon EGFR mu­

quence of TKIs for treatment of de novo T790M-

tations and found significant differences in PFS be­

positive NSCLC.

tween those with double uncommon EGFR mutations

This study had several limitations. First, there

and those with a single uncommon mutation (11.9 vs.

were no detailed data regarding molecular biomarker

6.5 months, respectively ; P＝0.010). There was no

testing rates in participating hospitals and EGFR

significant difference in OS between duplicated andtesting methods differed between participating hos­single mutation in the present study. Recently, next-

pitals. The detection rates of de novo T790M andgeneration sequencing (NGS)-based molecular tests

uncommon EGFR mutation depend on the sensitive­

have become available in clinical practice, and theirly of methods used for EGFR testing. Therefore, oursensitivity may facilitate the application of single

results do not reflect actual clinical practice withcompanion diagnostics (CDx) methods

19）
20）

. Severalatypical EGFR-positive NSCLC, including molecularcase reports and studies indicated the presence ofprofile testing rate. Second, we did not have data on

compound EGFR mutation by NGS-based profilingdose reduction and/or suspension of each TKI. There­that were negative by single CDx, suggesting thefore, physician treatment bias may have affected ourlimitation of single CDx for detecting compound

clinical outcomes. Nevertheless, the present results

mutations

20）
-22）

. We would like to emphasize the sub­mission of NGS-based molecular tests in cases with­out known biomarkers in NSCLC using companion
tests.

provide references for clinical practice in treatmentof patients with atypical EGFR-positive NSCLC.
In conclusion, the results presented here reveal
the clinical outcome data in patients with atypical

There were five cases with primary EGFR T790M

EGFR-positive NSCLC in Nagano prefecture, Japan.

mutation in the present study. As osimertinib was

Although these clinical results were based on obser­

developed to overcome the acquired T790M mutatedvational analyses, our clinical practice for atypicalNo. 6, 2022

403

Agatsuma・Kanda・Yamamoto et al.

EGFR-positive NSCLC in Nagano prefecture was

Municipal Hospital ; Takeshi Masubuchi, Department ofcomparable to those in other clinical studies.

Respiratory Medicine, Nagano Red Cross Hospital ;Mineyuki Hama, Department of Respiratory Medicine,Acknowledgments

Japanese Red Cross Suwa Hospital ; Takasuna Kei­

The authors are grateful to Fumie Miyasaka, re­ichiro, Department of Thoracic Surgery, Ina Central

search assistant at Shinshu Cancer Center, for col­Hospital ; and all members of the Nagano Lung Cancer

lecting and summarizing the data.

Research Group for their support.

The authors thank Munetaka Takada, Department

Disclosure of Potential Conflicts of Interestof Respiratory Medicine, Aizawa Hospital ; Fumiaki
Yoshiike, Department of Respiratory Medicine, Nagano

The authors have no conflicts of interest to disclose.

References
1） Siegel RL, Miller KD, Fuchs HE, Jemal A : Cancer Statistics, 2021. CA Cancer J Clin 71 : 7-33, 2021
2） National Cancer Registry (Ministry of Health, Labour and Welfare), tabulated by Cancer Information Service,
National Cancer Center, Japan. https://ganjoho.jp/reg_stat/statistics/data/dl/en.html
3） Cancer Statistics in Japan 2021. https://ganjoho.jp/public/qa_links/report/statistics/2021_en.html
4） Okamoto I, Morita S, Tashiro N, et al : Real world treatment and outcomes in EGFR mutation-positive non-small celllung cancer : Long-term follow-up of a large patient cohort. Lung Cancer 117 : 14-19, 2018
5） Sonehara K, Kobayashi T, Tateishi K, et al : Clinical analysis of EGFR-positive non-small cell lung cancer patientstreated with first-line afatinib -A Nagano Lung Cancer Research Group- Thorac Cancer 10 : 1078-1085, 20196） Mok TS, Wu Y-L, Ahn M-J, et al : Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N
Engl J Med 376 : 629-640, 2017
7） Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al : Osimertinib in untreated
EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378 : 113-125, 20188） Mitsudomi T, Morita S, Yatabe Y, et al : Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lungcancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405) : an open label, randomised
phase 3 trial. Lancet Oncol 11 : 121-128, 20109） Evans M, O’Sullivan B, Smith M, et al : Large-Scale EGFR Mutation Testing in Clinical Practice : Analysis of a Seriesof 18,920 Non-Small Cell Lung Cancer Cases. Pathol Oncol Res 25 : 1401-1409, 201910） Si J, Gu X, Wang W, Ying S, Song Z : Clinical outcomes of lung adenocarcinoma patients harboring uncommon
epidermal growth factor receptor (EGFR) mutations treated with EGFR-tyrosine kinase inhibitors (TKIs). Ann
Palliat Med 11 : 1624-1634, 2022
11） Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC : Effectiveness of tyrosine kinase inhibitors on “uncommon”
epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin
Cancer Res 17 : 3812-3821, 201112） Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al : Clinical activity of afatinib in patients withadvanced non-small-cell lung cancer harbouring uncommon EGFR mutations : A combined post-hoc analysis of
LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 16 : 830-838, 201513） Cho JH, Lim SH, An HJ, Kim KH, Park KU, Kang EJ, et al : Osimertinib for patients with non-small-cell lung cancer
harboring uncommon EGFR mutations : a multicenter, open-label, phase II trial (KCSG-LU15-09). J Clin Oncol
38 : 488-495, 202014） Kobayashi T, Kanda S,Tateishi K, et al : Multi-institutional cohort study of patients with EGFR-and ALK positive
non-small-cell lung cancer in Nagano prefecture, Japan. (submission).
15） Kim EY, Cho EN, Park HS, et al : Compound EGFR mutation is frequently detected with co-mutations of actionable
404

Shinshu Med J

Vol. 70

Clinical outcome of atypical EGFR-positive NSCLCs
genes and associated with poor clinical outcome in lung adenocarcinoma. Cancer Biol Ther 17 : 237-245, 201616） Kohsaka S, Nagano M, Ueno T, et al : A method of high-throughput functional evaluation of EGFR gene variants of
unknown significance in cancer. Sci Transl Med 9 : eaan6566, 201717） Yu HA, Arcila ME, Rekhtman N, et al : Analysis of tumor specimens at the time of acquired resistance to EGFRTKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 19 : 2240-2247, 201318） Li W, Qiu T, Guo L, Ling Y, Gao Y, Ying J, He J : Primary and acquired EGFR T790M-mutant NSCLC patients
identified by routine mutation testing show different characteristics but may both respond to osimertinib treatment.
Cancer Lett 423 : 9-15, 201819） Chiu CH, Yang CT, Shih JY, et al : Epidermal growth factor receptor tyrosine kinase inhibitor treatment response inadvanced lung adenocarcinomas with G719X/ L861Q/S768I mutations. J Thorac Oncol 10 : 793-799, 201520） Ikemura S, Yasuda H, Matsumoto S, et al : Molecular dynamics simulation-guided drug sensitivity prediction forlung cancer with rare EGFR mutations. Proc Natl Acad Sci U S A 116 : 10025-10030, 201921） Sunami K, Ichikawa H, Kubo T, Kato M, Fujiwara Y, Shimomura A, et al : Feasibility and utility of a panel testingfor 114 cancer-associated genes in a clinical setting : A hospital-based study. Cancer Sci 110 : 1480-1490, 201922） Onozawa H, Saito H, Sunami K, et al : Lung adenocarcinoma in a patient with a cis EGFR L858R-K860I doublet
mutation identified using NGS-based profiling test : Negative diagnosis on initial companion test and successfultreatment with osimertinib. Thorac Cancer 11 : 3599-3604, 2020
23） Chang JW, Huang CY, Fang YF, et al : Epidermal growth factor receptor tyrosine kinase inhibitors for de novo
T790M mutation : A retrospective study of 44 patients. Thorac Cancer 13 : 1888-1897, 2022

（2022. 7. 12 received ; 2022. 8. 18 accepted）

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