8071

Observational study of treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKI) in activating EGFR mutation‐positive (EGFRm+) advanced or recurrent non‐small‐cell lung cancer (NSCLC) after radiological progression to first‐line therapy with EGFR‐TKI
Yukio Hosomi1, Chiharu Tanai2, Kiyotaka Yoh 3, Yasushi Goto 4, Yasuo Ohashi 5, Hideo Kunitoh 6

Comprehensive Support
Project

1 Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo/JAPAN, 2NTT Medical Center, Tokyo/JAPAN, ,Japanese Red Cross Medical Center, Tokyo/JAPAN

3 National Cancer Center Hospital East, Chiba/JAPAN, 4 The University of Tokyo Hospital, Tokyo/JAPAN, 5 The University of Tokyo, Tokyo/JAPAN, 6

Background%

530/4991.5/8.5

Registration for clinical studies
Yes/No31/548

5.4/94.6

GenderMale/Female

178/40130.7/69.3

69(27‐93)

ECOG PS
0/1/2/3‐4/unknown

190/246/85/55/3

32.8/42.5/14.7/9.5/0.5
48.9/47.5/3.6– Time from RECIST‐based radiological PD to clinical PD, in patients who continuously
received an EGFR‐TKI beyond “RECIST‐PD”.

EGFR mutation
Ex19Del/Ex21 L858R/Other

283/275/21• 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.
(We present the data in bold)

Smoking history
Never/Current/Past/unknown

383/152/42/2– 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.

Study subjects• Inclusion
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• Exclusioncriteria– Prior treatment with cytotoxic chemotherapy– Concomitant malignancy

384‐523

Group B

154

24.4 (19.7‐28.8)

Group C84

28.6 (24.6‐40.1)

Group D64

15.9 (8.4‐24.3)

16.7 (14.4‐19.6)

120

Deterioration of PS

71

Death

28

Patient refusal

21

Not determined

23

Lost to follow‐up/ others9

Not reported
Systemic therapy given

14294

Disease flare after discontinuation
Median time from the stopping initial TKI therapy to the start of 2nd line therapy (days)

66.1/26.3/7.3/0.3::

Overall survival since the start of TKI (days)

6 (1.3%)11.5 (0‐645)

Treatment outline

Group

No. of patients%

Medianre‐administration period (days; range)

Group A51

34.5%

77 (2‐348)

Group B53

34.4%

Group C

2125.0%Group D

1929.7%77.5 (8‐385)
N.S.

Survival since RECIST PD (days)

Initial* EGFR‐TKI treatment period of each groupRe‐administration of EGFR‐TKI in later line

77.5 (6‐1013)
77 (7‐1039)* start of therapy up to end of therapyGroupGroup A

Median days (95%CI)
247 (205‐268)

Group B

264 (224‐307)

Group C557 (496‐644)

Group D55(44‐82)

Initial EGFR‐TKI treatment period (days)

Clinical course of each grouppatients• Disease flare461

No systemic therapy given

Definition of specific terms––––

Clinical PD free survival

No. of Patients

Symptomatic progression
Decline of PS due to progression
Threat to major organ(s)Unequivocal multi‐organ progression• Clinical PD(disease progression)

148

Post‐TKI systemic therapy

Agemedian(min‐max)• PrimaryNo. of patients

Group AThe cases that were discontinued without PD, were censored cases

No. of patients(n = 579)

Characteristics
TKI agent
Gefitinib/Erlotinib

Median survival from the start of EGFR‐TKI(months; 95%CI)

Group

RECIST PD free survival

95%CI (days)
244‐295

Survival rate

Patient characteristics

Survival of each groupMedian survival (days)
264

patients

Study endpoints

Progression free survival• Participating Institutions, which registered at least 1 patient : 31
• Registered patients : 579• Initial CRF received : 511

Survival rate

• Multicenter cooperative, prospective cohort study.
• To survey actual treatment pattern after PD judgment according to RECIST criteria as well as the clinicalcourse 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).

Patient accrual status as of Mar.31/2014

Rate of EGFR‐TKI administration

Study design and purpose

Results

patients• Although NSCLC with activating EGFR mutation is generally sensitive to EGFR‐TKI, such as gefitinib orerlotinib, acquired resistance is eventually seen.
• In the prospective trials of first‐line EGFR‐TKI, the progression‐free survival generally ranges from 9‐14months. On the other hand, the overall survival approximately 3 years, thus the prognosis of those patientsis favorable after radiological “PD”.
• The clinical course after radiological (RECIST‐based) “progressive disease (PD) judgment" is highly 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 selected patients.
• There is a concern for “disease flare” after discontinuation of EGFR‐TKI.

35% (84/238) of the patients without clinical deterioration at R‐PD
were continued on TKI
Group ATime from RECIST‐based radiological PD to clinical PDGroupNo. of patients

Group C84

162 (37‐1479) days

More than 6 months
More than 1 year
Acknowledgement

33 patients
16 patients(days)

Group B(days)

Group C(days)

Conclusions

Median time fromR‐PD to C‐PD (range)

39.3%
19.0%

• Pattern of care for the patients who got radiological PD after first‐line EGFR‐TKI therapy was surveyed.
• About 35% 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 162 days. About
40% of them received TKI therapy and were clinically stable for 6 months or more after radiological PD.
• “Disease flare” rate after discontinuation of EGFR‐TKI appears to be lower than previously reported.
• The prognosis of the patients who received initial EGFR‐TKI treatment until clinical progression (Group C) were numerically better in this population.
• Re‐administration of EGFR‐TKI were carried out in one third of case.

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,T oranomon 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