1290-P

Observational study of treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in activating EGFR mutationpositive (EGFRm+) advanced or recurrent non-small-cell lung cancer (NSCLC) after radiological progression to first-line therapy with EGFR-TKI

ComprehensiveSupport
Project

Yuki Yamane1, Hiroshi Sakai1, Futoshi Kurimoto1, Junko Sudo1, Hayami Tsuzuki1, Satoshi Takahashi1,Yukio Hosomi2, Chiharu Tanai3 , Kiyotaka Yoh4, Yasushi Goto5, Yasuo Ohashi6, Hideo Kunitoh7

UMIN#000010538

1 Saitama Cancer Center, Saitama/JAPAN, 2 Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo/JAPAN, 3 NTT Medical Center, Tokyo/JAPAN, 4 National Cancer Center Hospital East, Chiba/JAPAN, 5 The University of Tokyo Hospital,
Tokyo/JAPAN, 6 Chuo University, Tokyo/JAPAN, 7 Japanese Red Cross Medical Center, Tokyo/JAPANBackgroundResults• Primary – Time from RECIST-based radiological PD toclinical PD, in patients who continuously
received an EGFR-TKI beyond “RECIST-PD”.
• Secondary – Proportion of patients who continued toreceive EGFR-TKI beyond “RECIST- PD”,
with or without concomitant therapy.
– Proportion of patients in which “diseaseflare” developed after
discontinuation of treatment with EGFRTKI.
– Organ at the time of judging it as RECISTbased PD– Overall duration of treatment with EGFRTKI– Survival time after discontinuation ofEGFR-TKI.
– Survival time after RECIST-based PD toEGFR-TKI– Survival time after clinical PD to EGFR-TKI– Reason for discontinuation of EGFR-TKI
therapy.
– Overall survival.

• Inclusion – Advanced or post-operational recurrent noncriteria
small-cell lung cancer– Diagnosed as having tumor harboring EGFRmutation• Definition of EGFR gene mutation positive(mutation of sensitive gene)–(A) Deletion of Exon19 (irrespective of thesubtype)–(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-cancertherapy• Exclusion – Prior treatment with cytotoxic chemotherapy
criteria – Concomitant malignancy

Definition of specific terms• Clinical PD(disease progression)• Disease flare– Symptomatic progression– Decline of PS due to progression– Threat to major organ(s)– Unequivocal multi-organ progression– 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 is excluded.
– Clinical deterioration not related to the exacerbation of NSCLC, such as infection andthrombophlebitis, is also excluded.

Time from RECIST-based radiological PD to clinical PD

Characteristics
TKI agent
Gefitinib/Erlotinib
Registration for clinical studies
Yes/NoGenderMale/Female
Agemedian(min-max)
ECOG PS
0/1/2/3-4/unknown
EGFR mutation
Ex19Del/Ex21 L858R/Other
Smoking history
Never/Current/Past/unknown

No. of patients(n = 580)%

531/4991.6/8.4

31/5495.3/94.7

178/40230.7/69.3

GroupGroup C

191/246/84/56/3

32.9/42.4/14.5/9.7/0.5

282/274/24

48.6/47.2/4.2

384/42/152/266.2/7.2/26.2/0.4

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

TKI stopped orcontinued at R-PD
concurrently
occurring with C-PD
Group A
(N=169, 29%)RECIST PD withoutClinical PD
TKI stopped at RPD without C-PD
Group B
(N=184, 32%)

TKI continued
beyond R-PD
Group C
(N=98, 17%)

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

40.8%
15.3%

TKI stopped due
to other reasons,such as toxicity
Group D
(N=79, 14%)All
Group CGroup D

0.750095%CI (days)
268-322428-554

0GroupGroup AGroup B
Group CGroup DNo. of patients
78893435%
46.2%
48.4%
34.7%
44.3%

0180

360

540

GroupGroup AGroup B
Group C720900• Pattern of care for the patients who got radiological PD after first-line EGFR-TKI therapy was surveyed.
• About one-third of the patients without clinical deterioration at R-PD were continued on TKI.
Median time to clinical deterioration (Clinical PD) or discontinuation of TKI was 150 days.
40% of them continued to receive TKI and were clinically stable for 6 months or more after radiological PD.
• Among clinically stable patients with R-PD, survival of those with continued TKI was no worse than that with its discontinuation.
• Re-administration of EGFR-TKI were carried out in 45% of the cases.

0.50000.2500

1080

1260

1440

0180

360

Overall survival since the start of TKI (days)

All

1.0000

540

720

900

1440

Group A :n=110

Group AGroup B
Group C

0.50000.2500Group B :n=140Group C :n=790.7500

0n=5301260

Responder(CR,PR) :n=329

1.00000.75001080

Median survival from RECIST PD(days; range)
196 (1-1921+)
372 (5-1600+)
390 (63-1901+)

No. of patients
169184980.5000

0.2500

0180

360

540

720

900

1080

1260

1440

0180Survival since RECIST PD (days)

360

540

720

900

1080

1260

1440

Initial* EGFR-TKI treatment period of each groupMedianre-administration period (days; range)
104 (1-524)
74 (1-1344)
43 (6-1013)
154 (1-1039)

GroupGroup A
Group B
Group CGroup DNo. of patients
169
184
98
79

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

Conclusions

Group C :n=79
Group D :n=350.750000Re-administration of EGFR-TKI in later line

Group B :n=140Group BPost-TKI systemic therapy
No systemic therapy given
Deterioration of PS
Death
Patient refusal
Not determined
Lost to follow-up/ others
Not reported
Systemic therapy given

Group A :n=110

Group A

0.2500No. of Patients
149
93
36
20
77
32
45351

Responder(CR,PR):n=364

1.00000.5000Median survival (days)
299
483

RECIST PD free survival
Clinical PD free survival

No. of patients
169
184
98
79

1.0000The cases that were discontinued without PD, were censored cases

Advance stage NSCLC with EGFR mutation (N=577)

R-PD

40 patients
15 patients

Progression free survival

Treatment outline

RECIST PD withClinical PD

No. of patients
98

More than 6 months
More than 1 year

69(27-93)

EGFR TKIMedian time from
R-PD to C-PD (range)
150 (37-799) days

GroupGroup A
Group B
Group CGroup DSurvival rate

Patient characteristics%
2/67/20/6/6

Median survival from the start of EGFR-TKI(days; range)
509 (5-1987+)
704 (32-1935+)
813 (140-1989+)
440 (20-1710)

Survival rate

Study subjects

CR/PR/SD/PD/NE

No. of patients(n = 577)
11/386/113/33/34

All1.0000

Median days (Range)
249 (3-1550)
298 (7-1536)
555 (119-1661)
56 (2-1038)* start of therapy up to end of therapyGroup AGroup B

0.7500Group CGroup D

0.50000.250000180360

540

720

900

1080

1260

Rate of EGFR-TKI administration

Study endpoints• Participating Institutions, which registered at least 1 patient: 31• Registered patients: 580• Initial CRF received: 577

Survival rate

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

Survival of each group

Survival rate

Study design and purpose

Response Ratio

Patient accrual status as of Sep.9/2014

Rate of EGFR-TKI administration• Although NSCLC with activating EGFR mutation is generally sensitive to EGFR-TKI, such as gefitinib or erlotinib, acquired
resistance is eventually seen.
• In the prospective trials of first-line EGFR-TKI, the progression-free survival generally ranges from 9-14 months. On theother hand, the overall survival 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" is highly variable, and somepatients are reported to do well with continuation of TKI beyond PD, with or without local therapy. Those reports areanecdotal, and based only on selected patients.
• There is a concern for “disease flare” after discontinuation of EGFR-TKI.

1440

1.0000

Responder(CR,PR) :n=364
Group A :n=110
Group B :n=140Group C :n=79
Group D :n=350.7500

0.50000.250000180360

540

720

90010801260

Initial EGFR-TKI treatment period (days)
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;
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 National Hospital, 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 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, Kanazawa University Hospital, 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 Memorial Hospital

1440