上⽪性増殖因⼦受容体変異陽性（EGFRm+）肺癌に対するチロシンキナーゼ阻害剤での初回治療の観察研究

10137

⾦ 永学1，棚井 千春2，細⾒ 幸⽣3，葉 清隆4，後藤 悌5，⼤橋 靖雄5，國頭 英夫6
京都⼤学⼤学院医学研究科 呼吸器内科1，NTT東⽇本関東病院 呼吸器内科2，がん・感染症センター
都⽴駒込病院 呼吸器内科3，国⽴がん研究センター東病院 呼吸器内科4，東京⼤学 医学部5
三井記念病院 呼吸器内科6BackgroundResults• Although NSCLC with activating EGFR mutation is generally sensitive to
EGFR‐TKI, such as gefitinib or erlotinib, it eventually gets acquiredresistance.
• In the prospective trials of first‐line EGFR‐TKI, the progression‐freesurvival generally ranges in 9‐14 months. On the other hand, the overall
survival are approximately 3 years, thus the prognosis of those patients isfavorable after radiological “PD”.
• The clinical course after radiological (RECIST‐based) “progressive disease(PD) judgment" is highly variable, and some patients are reported to dowell with continuation of TKI beyond PD, with or without local therapy.
Those reports are anecdotal, and based only on selected patients.
• There is a concern for “disease flare” after discontinuation of EGFR‐TKI.

Study design and purpose• Multicentre cooperative, prospective cohort study.
• To survey actual treatment pattern after PD judgment according toRECIST criteria as well as the clinical course after discontinuation of thetreatment in patients with EGFRm+ advanced or recurrent NSCLC who
receive first‐line therapy with EGFR‐tyrosine kinase inhibitor (EGFR‐TKI).

Treatment outline
Advance stage NSCLC with EGFR mutation
9 ‐ 14m

EGFR TKI
PD by RECISTEGFR TKI
Beyond PD
Stop EGFR TKI
by doctor discretion

ComprehensiveSupportProject?

Clinical PD

Patient accrual status as of Sep.30/2013• Participating Institutions, which registered at least 1 patient: 25 (planned participation: 34)• Registered patients: 450 (planned registry: 500 ‐ 800)
• Initial CRF received: 284

Patient characteristics
Characteristics%
No. of patients (n=450)
TKI agent Gefitinib/Erlotinib
417/3392.7/7.3
Registration for clinical studies Yes/No
24/426
5.3/94.7
Gender Male/Female
139/31130.9/69.1
Age 20‐49/50‐69/70‐
157/257/36
34.9/57.1/8.0
ECOG PS 0/1/2/3‐4/unknown
150/190/67/42/1
33.3/42.2/14.9/9.3/0.2
EGFR mutation
223/210/1749.6/46.7/3.8
Ex19Del/Ex21 L858R/Other
Smoking history
298/34/116/2
66.2/7.6/25.8/0.4
Never/Current/Past/unknown

EGFR‐TKI beyond RECIST‐PDTotal No. of patients who received EGFR‐TKI “beyond PD”
Median time from RECIST‐PD to Clinical PD
Patients with termination of EGFR‐TKI
EGFR‐TKI continued beyond RECIST‐PD (without Clinical PD)
Time from RECIST‐PD to Clinical PD
1‐30days
31‐90days
91‐days
Patients with continued administration of EGFR‐TKI
Without RECIST‐PD
With RECIST‐PD and Clinical PD
With RECIST‐PD, no Clinical PD
Time from RECIST‐PD to Clinical PD

4196 days(N=246)32
7‐403 days
10814(N=38)
28
1949‐573 days

Reasons for discontinuation

Study endpoints– Time from RECIST‐based radiological PD to clinical PD, inpatients who were continuously received EGFR‐TKI
beyond “RECIST‐PD”.

• Primary• Secondary – Proportion of patients who continued to receive EGFR‐TKI
beyond “RECIST‐ PD”, with or without concomitanttherapy.
– Proportion of patients in which “disease flare” developed
after
discontinuation of treatment with EGFR‐TKI.
– Organ at the time of judgment as RECIST‐based PD– Overall duration of treatment with EGFR‐TKI– Survival time after discontinuation of EGFR‐TKI.
– Survival time after RECIST‐based PD to EGFR‐TKI wasjudged.
– Survival time after clinical PD to EGFR‐TKI was judged.
– Overall duration of treatment with EGFR‐TKI.
– Reason of discontinuation of EGFR‐TKI therapy.
– Overall survival.

Definition of specific terms– Symptomatic progression• Clinical PD(disease progression) – Declining of PS due to progression– Threat to major organ(s)– Unequivocal multi‐organ progression• Disease flare– Death or exacerbation of disease which
necessitated hospitalization and made it
impossible to go on to the next treatment,
within 1month after discontinuation ofEGFR‐TKI.

ReasonRECIST‐PD w/ or w/o Clinical PD
Clinical PD w/ or w/o AE
AE or patient’s pref.
OthersTreatment on‐going

Efficacy of EGFR‐TKI
Best response
No. of patients (n = 284)
CR
5PR
182
SD59
PD
9NE
22Not reported
7
Median time to RECIST‐PD (Progression‐free survival): 297 days
Disease flare after discontinuation: 6 (2.4%)
AliveDead
Due to NSCLCTreatment‐related death (interstitial lung disease)
Due to other causes
Lost to follow‐up
Not reported
Median overall survival
Survivalrate– Advanced or post‐operational recurrent non‐small‐cell lung cancer– Diagnosed as having tumor harboring EGFR mutation• Definition of EGFR gene mutation positive (mutation of sensitivegene)– (A) Deletion of Exon19 (irrespective of the subtype)– (B) Exon 21 L858R– (C) Other rare mutations (Exon 18 G791X, etc.)• EGFR gene mutation excluded from this study:– (A) Exon 20 insertion mutation– (B) T790M– Treatment with EGFR‐TKI (Gefitinib or Erlotinib) was started fromJanuary 1, 2009 until December 31, 2011 as the initial anti‐cancer
therapy– Prior treatment with cytotoxic chemotherapy– Concomitant malignancy

発表者・研究責任者の利益相反開⽰事項
研究費の財源■受託 □寄付 □科学研究費 □その他(所属/⾝分
⾦額（年間）)

三井記念病院
呼吸器内科 科⻑

財源の供給元発表者⽒名：
⾦ 永学

該当該当有りの場合：企業名等なし

公益財団法⼈パブリックヘルスリサーチセンター所属/
⾝分
⾦額（年間）

京都⼤学⼤学院医学研究科
呼吸器内科 助教
該当該当有りの場合：企業名等なし―■

法⼈の代表―■

企業等の顧問職100万円以上■

企業等の顧問職100万円以上■

株式・エクイティ

100万円以上の利益、全株式の5％以上■

株式・エクイティ

100万円以上の利益、全株式の5％以上

■

講演料など

50万円以上□ ⽇本イーライリリー

講演料など50万円以上□ 中外製薬

原稿料など50万円以上■原稿料など50万円以上■

寄付⾦200万円以上■

法⼈の代表

1.0000Overall survival
0.75000.50000.2500Acknowledgement
This study was conducted by Comprehensive Support Project For Oncology Research(CSPOR) ofPublic Health Research Foundation. The study fund was provided to CSPOR with Support from an
investigator Sponsored Study Programme of AstraZeneca.
We would like to thank patients, their families, and following institutions;
Iwate Prefectural Central Hospital, Ibaraki Prefectural Central Hospital, Gunma PrefecturalCancer Center, Nishigunma National Hospital, Saitama Cancer Center, The Cancer InstituteHospital Of JFCR, Japanese Red Cross Medical Center,T oranomon Hospital, National Center for
Global Health and Medicine, Kitasato University Hospital, Kanagawa Cardiovascular andRespiratory Center, Fujisawa City Hospital, Shinshu University Hospital, Nagoya University
Graduate School Of Medicine, Hiroshima Prefectural Hospital, Kurume University School ofMedicine, Nagasaki University Hospital, Tosei General Hospital, Hamamatsu University Schoolof Medicine, Graduate School of Medicine and Faculty of Medicine Kyoto University, NTT
Medical Center Tokyo, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome
Hospital, National Cancer Center Hospital East, University of Tokyo Hospital, Mitsui MemorialHospital

試験責任者⽒名：
國頭 英夫

97161
148
2324
2800days

Overall survival

Study subjects• Exclusion
criteria

%
1.8
64.1
20.8
3.2
7.7
2.5

Living status– Worsening after start of the post‐therapy is excluded.
– Clinical deterioration not related to the exacerbation ofNSCLC, such as infection and thrombophlebitis, is alsoexcluded.

• Inclusion
criteria

Total
115
7738
1638200万円以上■

寄付⾦

委受託研究(治験等) 総額200万円以上■

委受託研究(治験等) 総額200万円以上□ 中外製薬専⾨的助⾔・証⾔(裁判)100万円以上■

専⾨的助⾔・証⾔(裁判)100万円以上■

その他

5万円以上の贈答他■

その他

5万円以上の贈答他■

00180360

540

720

900

1080

1260

1440

1620

Overall survival from initiation of the EGFR‐TKI therapy (days)

Overall survival according to the reason of TKI discontinuation
Reason for Discontinuation
RECIST‐PD
Clinical PD*

No. of patients110

Median survival (days)
794

85636

(*including those on TKI, with RECIST‐PD)
1.0000Survivalrate

Stopped due to RECIST‐PD
Stopped due to Clinical PD

0.75000.50000.250000180360

540

720

900

1080

1260

1440

1620

Overall survival after initiation of EGFR‐TKI therapy (days), according to the reason of discontinuation

First post‐TKI systemic therapy
No systemic therapy given
Deterioration of PS
Death
Patient refusal
Lost to follow‐up/ others
Not reported

8433
12101118

Systemic therapy given
Cisplatin‐based combination
Carboplatin‐based combination
Single‐agent cytotoxic agent
Another EGFR‐TKI
Others/ unknown

157
44382745
3Conclusions• Pattern of care for the patients who got radiological PD after first‐line EGFR‐TKI
therapy was surveyed.
• “Disease flare” rate after discontinuation of EGFR‐TKI appears to be lower thanpreviously reported.
• Some patients received prolonged (>90days) administration of EGFR‐TKI beyond
radiological PD, without clinical deterioration.
• Identification of the patient subgroup who benefit from extended use od EGFR‐TKI“beyond PD” warrants further investigation.