11‐011

Preliminary results of: Observational study of treatment of epidermal growth factor receptor
activating mutation positive (EGFRm+) advanced or recurrent non‐small‐cell lung cancer (NSCLC), afterradiological progression to the first‐line therapy with EGFR tyrosine kinase inhibitors (EGFR‐TKI).
Hideo Kunitoh1, Chiharu Tanai2, Yukio Hosomi3, Kiyotaka Yoh4, Yasushi Goto5, Yasuo Ohashi6ComprehensiveSupport
Project

1Mitsui Memorial Hospital, Tokyo/JAPAN, 2NTT Medical Center, Tokyo/JAPAN, 3Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo/JAPAN,4National Cancer Center Hospital East, Chiba/JAPAN, 5Tokyo University Hospital, Tokyo/JAPAN,6University of Tokyo, Tokyo/JAPANBackgroundResults• Although NSCLC with activating EGFR mutation is generally sensitive to EGFR‐TKI, such as
gefitinib or erlotinib, it eventually gets acquired resistance.
• In the prospective trials of first‐line EGFR‐TKI, the progression‐free survival generally
ranges in 9‐14 months. On the other hand, the overall survival are approximately 3 years,
thus the prognosis of those patients is favorable after radiological “PD”.
• The clinical course after radiological (RECIST‐based) “progressive disease (PD) judgment" ishighly variable, and some patients are reported to do well with continuation of TKI beyond
PD, with or without local therapy. Those reports are anecdotal, and based only on selectedpatients.
• 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 afterPD judgment according to RECIST criteria
as well as the clinical course afterdiscontinuation of the treatment inpatients with EGFRm+ advanced orrecurrent NSCLC who receive first‐line
therapy with EGFR‐tyrosine kinase
inhibitor (EGFR‐TKI).

Treatment outline
Advance stage NSCLCwith EGFR mutation

Stop
EGFR TKI
by doctor
discretion

9 ‐ 14m?
EGFR TKI
Beyond PDClinicalPD

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

• Primary

Living status• Participating Institutions, which registered at least 1 patient: 25(planned participation: 34)• Registered patients: 450 (planned registry: 500 ‐ 800)
• Initial CRF received: 284

Alive97Dead161• Secondary – Proportion of patients who continued to receive EGFR‐TKI beyond “RECIST‐PD”, with or without concomitant therapy.
– 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 was judged.
– 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.

417/33

Registration for clinical studies
Yes/No24/426– Worsening after start of the post‐therapy is excluded.
– Clinical deterioration not related to the exacerbation of NSCLC, such as
infection and thrombophlebitis, is also excluded.

Study subjects• Inclusion
criteria• Exclusion
criteria– 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 sensitive gene)– (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 from January 1, 2009 until
December 31, 2011 as the initial anti‐cancer therapy– Prior treatment with cytotoxic chemotherapy– Concomitant malignancy

392.7/7.3

Patients with termination of EGFR‐TKI
EGFR‐TKI continued beyond RECIST‐PD (without Clinical PD)
Time from RECIST‐PD to Clinical PD

139/311Age
20‐49/50‐69/70‐

157/257/36

34.9/57.1/8.0

0.7500150/190/67/42/1

33.3/42.2/14.9/9.3/0.2

0.5000

EGFR mutation
Ex19Del/Ex21 L858R/Other

223/210/17

49.6/46.7/3.8

0.2500

Smoking history
Never/Current/Past/unknown

298/34/116/2

66.2/7.6/25.8/0.4

30.9/69.1

31‐90days

891‐days

14

Overall survival

1150180360

540

720

900

1080

1260

1440

1620

Overall survival according to the reason of TKI discontinuation

Clinical PD w/ or w/o AE

77

AE or patient’s pref.

38

Reason for Discontinuation
RECIST‐PD
Clinical PD*

Others16(*including those on TKI, with RECIST‐PD)

Treatment on‐going38

No. of patients110

Median survival(days)
794

85636

Survival
rate

1.0000Stopped due to RECIST‐PD
Stopped due to Clinical PD

Efficacy of EGFR‐TKI
0.7500No. of patients(n = 284)

%

CR

51.8

PR

18264.1

SD5920.8PD

93.2

NE227.7Not reported

72.5

Best response

Median time to RECIST‐PD (Progression‐free survival): 297 days
Disease flare after discontinuation: 6 (2.4%)(N=38)
28

With RECIST‐PD and Clinical PD

1

With RECIST‐PD, no Clinical PD

949‐573 days

First post‐TKI systemic therapy

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

RECIST‐PD w/ or w/o Clinical PD

10Time from RECIST‐PD to Clinical PD

Reasons for discontinuation
Total

32
7‐403 days

1‐30days

Without RECIST‐PD

0Reason(N=246)

2Patients with continued administration of EGFR‐TKISurvival 1.0000
rate41
96 days800days

Overall survival

5.3/94.7

GenderMale/Female

ECOG PS
0/1/2/3‐4/unknown

Median time from RECIST‐PD to Clinical PD24

Median overall survival

Definition of specific terms– Symptomatic progression(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 necessitatedhospitalization and made it impossible to go on to the next
treatment, within 1month after discontinuation of EGFR‐TKI.

• Clinical PD

2

Due to other causes
Not reported%Total No. of patients who received EGFR‐TKI “beyond PD”

148

Treatment‐related death (interstitial lung disease)
Lost to follow‐up

No. of patients(n = 450)

TKI agent
Gefitinib/Erlotinib

EGFR‐TKI beyond RECIST‐PD

Due to NSCLC

Patient characteristics
Characteristics

EGFR TKI
PD
by RECIST

Patient accrual status as of Sep.30/2013

No systemic therapy given

84

Deterioration of PS

33

Death

12

Patient refusal

10

Lost to follow‐up/ others

11

Not reported

18

Systemic therapy given

157

Cisplatin‐based combination

44

Carboplatin‐based combination

38

Single‐agent cytotoxic agent

27

Another EGFR‐TKI

45

Others/ unknown

3Conclusions

0.50000.2500

00180

360

540

720

900

1080

1260

1440

1620

• 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
than previously 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.

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

Acknowledgement
This study was conducted by Comprehensive Support Project For Oncology Research(CSPOR) of Public 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 Prefectural Cancer Center, Nishigunma National Hospital, Saitama Cancer Center, The Cancer Institute Hospital Of JFCR, Japanese Red Cross Medical Center,T oranomon Hospital, National Center for Global Health and Medicine,Kitasato University Hospital, Kanagawa Cardiovascular and Respiratory Center, Fujisawa City Hospital, Shinshu University Hospital, Nagoya University Graduate School Of Medicine, Hiroshima Prefectural Hospital, Kurume University School of Medicine, Nagasaki University Hospital, Tosei General Hospital,Hamamatsu University School of 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