BackgroundEGFRኚ␗㝧ᛶ⫵䛜䜣䛻ᑐ䛩䜛ึᅇ
EGFR-TKI἞⒪⪏ᛶ໬ᚋ䛾⤒㐣䛻㛵䛩䜛ほᐹ◊✲䠖CSPOR LC-2ຍ⸨᫭ྐ㻌 ᚋ⸨᜶㻌 ⴥΎ㝯㻌 ⣽ぢᖾ⏕㻌Ჴ஭༓᫓㻌 ኱ᶫ㟹㞝㻌 ᅧ㢌ⱥኵ㻌• Although NSCLC with activating EGFR mutation is generally sensitive
to EGFR-TKI, such as gefitinib or erlotinib, acquired resistance iseventually seen.
• In the prospective trials of first-line EGFR-TKI, the progression-freesurvival generally ranges from 9-14 months. On the other hand, theoverall survival approximately 3 years, thus the prognosis of thosepatients is favorable after radiological “PD”.
• The clinical course after radiological (RECIST-based) “progressive
disease (PD) judgment" is highly variable, and some patients arereported to do well with continuation of TKI beyond PD, with orwithout local therapy. Those reports are anecdotal, and based only
on selected patients.
• There is a concern for “disease flare” after discontinuation of EGFRTKI.

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

Study endpoints• Primary– Time from RECIST-based radiological PD to clinical PD, in patients
who continuously received an EGFR-TKI beyond “RECIST-PD”.
• 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 judging it 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– Survival time after clinical PD to EGFR-TKI– Reason for discontinuation of EGFR-TKI therapy.
– Overall survival.

Study subjects• Inclusion – Advanced or post-operational recurrent non-small-cell lung cancer
criteria – 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

Definition of specific terms• Clinical PD(diseaseprogression)– Symptomatic progression– Decline 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 of EGFR-TKI.
– Exacerbation after the start of the post-therapy isexcluded.
– Clinical deterioration not related to theexacerbation of NSCLC, such as infection andthrombophlebitis, is also excluded.

• Exclusion – Prior treatment with cytotoxic chemotherapy
criteria – Concomitant malignancy

Results
Patient accrual status as of Sep.9/2014• Participating Institutions, which registered at least 1patient: 31• Registered patients: 580• Initial CRF received: 577

Results
Patient characteristics
No. of patients(n = 580)%

TKI agent
Gefitinib/Erlotinib

531/4991.6/8.4

Registration for clinical studies
Yes/No31/5495.3/94.7

GenderMale/Female

178/40230.7/69.3

Agemedian(min-max)

69(27-93)

ECOG PS
0/1/2/3-4/unknown

191/246/84/56/3

32.9/42.4/14.5/9.7/0.5

EGFR mutation
Ex19Del/Ex21 L858R/Other

282/274/24

48.6/47.2/4.2

Smoking history
Never/Current/Past/unknown

384/42/152/2

66.2/7.2/26.2/0.4

Characteristics

Results

Results

Treatment outline

Response Ratio

Advance stage NSCLC with EGFR mutation (N=577)
EGFR TKI

TKI stopped orcontinued at R-PD
concurrently
occurring with C-PD
Group A
(N=169, 29%)%

11/386/113/33/34

2/67/20/6/6

still on TKI without R-PD
Group E (N=47, 8%)

RECIST PD with
Clinical PD
D

No. of patients(n = 577)
CR/PR/SD/PD/NE

RECIST PD withoutt
Clinical PD
TKI stoppedtat RPD without C-PD
Group B
(N=184, 32%)

R-PD

TKI stopped dueto other reasons,such as toxicity

TKI contin
continued
beyond R-PD

Group D(N=79, 14%)Group C
(N=98, 17%)

R-PD: RECIST based PD, C-PD: Clinical PD

34.8% (98/282) of the patients without clinical deterioration at R-PD were
continued on TKI

Results

Results

Time from RECIST-based radiological PD to clinical PD
Progression free survival
GroupGroup C

More than 6 months
More than 1 year

No. of patients98

40 patients
15 patientsMedian time from
R-PD to C-PD (range)
150 (37-799) days

40.8%
15.3%

Median survival (days)

95%CI (days)RECIST PD free survival

299268-322

Clinical PD free survival

483

428-554

The cases that were discontinued without PD, were censored cases

Results

Results

Post-TKI systemic therapy
Re-administration of EGFR-TKI in later line㻌㻌 㻌 㻌 㻌 㻌 㻌 㻌 㻌 㻌 n=530
No. of Patients
No systemic therapy given

149

Deterioration of PS

93

Death36

Patient refusal

20

Not determined

77

Lost to follow-up/ others

32

Not reported

45

Systemic therapy given

351

Group

No. of patients%

Medianre-administration period (days; range)

Group A78

46.2%

104 (1-524)

Group B89

48.4%

74 (1-1344)

Group C3434.7%43 (6-1013)

Group D3544.3%154 (1-1039)

Results

Results
Survival of each group

Survival of each groupAll

Median survival from the start of EGFR-TKI(days; range)

Group A169

509 (5-1987+)

Group B184

704 (32-1935+)Group C98

813 (140-1989+)

Group D79

440 (20-1710)*URXS$*URXS%*URXS&*URXS'

*URXS$ :n=110*URXS% :n=140

*URXS& :n=79*URXS' :n=35Survival rate

No. of patients

Survival rate

Group

Responder(CR,PR):n=364



Overall survival since the start of TKI (days)



Results

Results
Survival of each group

Survival of each groupAll

Median survival from RECIST PD(days; range)

Group A169

196 (1-1921+)

Group B184

372 (5-1600+)

Group C98

390 (63-1901+)*URXS$*URXS%*URXS&



*URXS$ :n=110*URXS% :n=140*URXS& :n=79



Survival rate

No. of patients

Survival rate

GroupResponder(CR,PR) :n=329











Survival since RECIST PD (days)

Results

Results
Initial* EGFR-TKI treatment period of each group* start of therapy up to end of therapy

Initial* EGFR-TKI treatment period of each groupAll

No. of patientsMedian days (Range)

Group A169

249 (3-1550)

Group B184

298 (7-1536)

Group C98555 (119-1661)

Group D7956 (2-1038)*URXS$*URXS%*URXS&*URXS'Rate of EGFR-TKI administration

GroupResponder(CR,PR) :n=364





Rate of EGFR-TKI administration*URXS$ :n=110*URXS% :n=140*URXS& :n=79*URXS' :n=35








Initial EGFR-TKI treatment period (days)









AcknowledgementConclusions• Pattern of care for the patients who got radiological PD after firstline EGFR-TKI therapy was surveyed.
• About one-third of the patients without clinical deterioration at RPD were continued on TKI.
Median time to clinical deterioration (Clinical PD) or discontinuationof TKI was 150 days.
40% of them continued to receive TKI and were clinically stable for6 months or more after radiological PD.
• Among clinically stable patients with R-PD, survival of those withcontinued TKI was no worse than that with its discontinuation.
• Re-administration of EGFR-TKI were carried out in 45% of the cases.

•This study was conducted by Comprehensive Support Project For Oncology
Research(CSPOR) of Public Health Research Foundation. The study fund wasprovided to CSPOR with Support from an investigator Sponsored Study Programmeof AstraZeneca.
• We would like to thank patients, their families, and following institutions;– Hokkaido University Hospital, KKR Sapporo Medical Center, Iwate Prefectural
Central Hospital, Tohoku University Hospital, Ibaraki Prefectural Central Hospital,Tochigi Cancer Center, Gunma Prefectural Cancer Center, Nishigunma NationalHospital, Saitama Cancer Center, The Cancer Institute Hospital Of JFCR, Japanese
Red Cross Medical Center, Toranomon Hospital, Teikyo University School of Medicine,Tokyo Teishin Hospital, 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 of Medicine, Nagasaki University Hospital, Tosei General Hospital,Hamamatsu University School of Medicine, Kanazawa University Hospital, Graduate
School of Medicine and Faculty of Medicine Kyoto University, NTT Medical CenterTokyo, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome
Hospital, National Cancer Center Hospital East, University of Tokyo Hospital, Mitsui
Memorial Hospital