P1424

The plasma ctDNA monitoring during epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)
treatment in patients with EGFR mutant non-small cell lung cancer (JP-CLEAR trial)
Kazuhiro Usui1, Takuma Yokoyama2,Akira Kisohara3, Yoshiaki Mori4, Yuuichiro Takeda5, Hiroo Ishida6, Nobuko Kusano7, Kazuma Kishi8, Utae Katsushima9, Tomohito Kuwako10, Hiromi Aono11, Yusuke Shikama12,Koichi Minato13, Hidekazu Matsushima14, Kohei Uemura15, Yasuo Ohashi16, Hideo Kunitoh17.
1 NTT Medical Center, 2Kyorin University Hospital, 3Kasukabe Medical Center, 4Iwate Prefectural Central Hospital, 5National Center for Global Health and Medicine, 6Showa University School of Medicine, 7Fujisawa City Hospital, 8Toranomon Hospital, 9Kansai Electric Power Hospital,10National Hospital Organization Shibukawa Medical Center, 11Mitsui Memorial Hospital, 12Showa University Fujigaoka Hospital, 13Gunma Prefectural Cancer Center, 14Japanese Red Cross Saitama Hospital, 15The University of Tokyo, 16Chuo University, 17Japanese Red Cross Medical Center

Clinical Trial Number: UMIN 000023248
This clinical trial is funded and supported by AstraZeneca

Circulating ctDNA monitoring Although the resistance mechanisms vary, the most common
one is T790M second mutation, which accounts forapproximately 60%.
 Osimertinib, a 3rd generation EGFR‐TKI targeting EGFR T790M
mutation, is reported to be highly active against T790M
positive NSCLC.
 To detect T790M mutation following acquired resistance,re‐biopsy of the tumor is necessary. However, frequentre‐biopsies with invasive procedures (bronchoscopy or needle
biopsy) are infeasible in the usual care of NSCLC patients.
There is also a possibility of false‐negative due to intra‐tumor
heterogeneiety.
 Circulating tumor DNA (ctDNA) detected in the plasma sample
is recognized as a noninvasive biomarker for quantifying themolecular analysis of NSCLC.
 Cobas EGFR Mutation Test® using plasma specimens as acompanion diagnostic test for the detection of EGFR mutations
has been approved to identify such patients with NSCLC.
 T790M monitoring in patients receiving oimertinib by plasma
ctDNA could give valuable clinical information.

Study Objectives
Primary endpoints
 The plasma DNA T790M positivity rates by Cobas EGFR Mutation
Test® in the T790M positive tumors patients.
 The plasma DNA T790M positivity rates by Cobas EGFR Mutation
Test® at each clinical point.

Secondary endpoints
 The plasma DNA EGFR Exon 19 deletion or Exon 21 L858R
mutation positivity rates by Cobas EGFR Mutation Test® in clinicalcourses.
 Time from plasma T790M positivity to tissue T790M positivity inthe tissue T790M‐positive cases.
 Response Rate and PFS with osimertinib.
 Response Rate and PFS with re‐challenge of other EGFR‐TKIs.

 All patients: Baseline and every 1~3 month, until end oftreatment with EGFR-TKI or second biopsy of the lesion of PD
revealed no T790M mutation.
 All patients: At the time of radiological PD to EGFR-TKI.
 Those who continued to receive 1st treatment of EGFR-TKI
beyond radiological PD: At the time of systemic PD, and/orsymptomatic PD.
 Those who received second biopsy for PD: At the time of thesecond biopsy.
 Those who received osimertinib: Immediately before
osimertinib administration.
 Those who received another EGFR-TKI than osimertinib as rechallenge:Immediately before re-challenge administration.

Consort diagram
Enrolled
N=122Ineligible
N=1Eligible
N=121Stop
N=64

In 15(78.9%) of 19 patients with T790M detection in plasma,
T790M was detected in plasma before and/or at disease progression(PD).

EGFR mutation status of rebiopsied samples

Treatment after failure of the first EGFR-TKI

A. Frequency of rebiopsy
Re-biopsy

Results
122 patients were enrolled between Sep 2016 and Mar 2017 from15 centers in Japan. Of them, 121 patients were eligible andassessable. At data cut‐off for this analysis, Aug 30, 2018, CRF of 6
and 12 months after enrollment were collected from 121 and 109
patients, respectively.
Median follow up time was 364 days(SD 93.8).
Total 1291 plasma samples were analyzed.

Post-treatment
No
13Yes
50
Withdrawal 1

Continue
N=57

Sample size justification
In the prior CSPOR‐LC02 study (Observational study of treatment ofEGFR mutation positive advanced or recurrent
NSCLC:UMIN000010538), radiological PD was documented inapproximately 80% of the patients. In the 80% of the patients whoacquired resistance to gefitinib, about 60% patients are presumed
to have T790M. From the above results, this study uses descriptivestatistics, and it was set to 120 cases in consideration of feasibilityof research.

Timing of T790M detection in plasma ctDNAPD

 Treatment with 1st or 2nd generation epidermal growth factor
receptor-tyrosine kinase inhibitors(EGFR‐TKIs) is effective fornon-small cell lung cancer(NSCLC) patients harboring EGFR
mutation. However, acquired resistance is inevitable after amedian period of 9 to 14 months.

Plasma sampling schedule

2nd line
treatment

Background: Approximately 60% of EGFR mutant non-small celllung cancer (NSCLC) patients treated with first/second generation
EGFR-TKIs will acquire resistance by the T790M mutation. Sinceosimertinib, a third generation EGFR-TKI, is active for NSCLC withT790M, re-biopsy to examine the T790M status at the diseaseprogression is necessary to administer osimertinib adequately.
T790M monitoring in patients receiving EGFR-TKIs by plasma
ctDNA could give valuable clinical information.
Methods: Patients with advanced or post-operative recurrent
NSCLC with the sensitive EGFR mutations who receive the first
EGFR-TKI treatment are eligible. Plasma samples at the baseline
and the several timings of the disease are analyzed for EGFR
mutation status using Cobas EGFR Mutation Test®.
Results: Between September 2016 and March 2017, 122 patientsat 15 institutions in Japan were enrolled. Total 1291 plasma
samples from 121 patients were analyzed for EGFR mutation
status at Aug 2018. At the baseline, the sensitive EGFR mutation(Ex19 del 14, L858R 15) was detected in 29 (23.9%) of 121 patientsand the resistant EGFR mutation T790M was detected in 3 (2.5%)
patients. During the follow up period, 66 (54.5%) patients
experienced disease progression and 64 (52.9%) stopped the first
EGFR-TKI treatment. Twenty-two (18.2%) patients showed T790M
in plasma ctDNA. Median time from the first EGFR-TKI treatment
to the detection of T790M in plasma ctDNA was 441 days.
Although 33 patients received re-biopsy to examine the EGFR
mutation status at the disease progression, T790M was detected
in only nine (22.0%) of the 41 re-biopsied materials. Seven (77.8%)of the nine patients who showed T790M in the re-biopsiedmaterials received osimertinib, whereas 15 (68.2%) of the 22
patients with T790M detection in plasma received osimertinib, 3(13.6%) continued the first EGFR-TKI, and 2 (9.0%) received
platinum-based chemotherapy.
Conclusions: Although ctDNA monitoring during the EGFR-TKI
treatment is useful, further investigation is necessary to elucidate
the efficacy of osimertinib treatment based on the T790M
detection in plasma ctDNA.

Introduction

1st lineEGFR-TKI

Abstract

No-PD

55

PD

31

Yes35

No66

C. EGFR status of rebiopsied sample

B. Samples rebiopsiedTreatment after T790M detection
A. Re-biopsied (N=9)

B. Plasma (N=22)

Patient characteristics

Patients and methods
Key inclusion criteria
Histologically confirmed advanced or postoperative recurrent NSCLC
harboring activating EGFR mutation.
[Definitions of activating EGFR mutation]A) Exon 19 deletion (regardless of subtype)B) Exon 21 L858R
C) Other rare mutations (e.g. Exon 18 G719X)• De novo T790M not excluded.

Key exclusion criteria
Prior therapy with an EGFR-TKI(other than the current therapy, ifbeing treated with one)

EGFR mutation status of plasma ctDNA
100%
80%
60%

917462

notdetectedConclusions
Although ctDNA monitoring during the EGFR-TKI treatment is useful,further investigation is necessary to elucidate the efficacy ofosimertinib treatment based on the T790M detection in plasma ctDNA.

T790M
40%
20%

1322
sensitive

326

33

37

Baseline

6month12month0%

Acknowledgments
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 aninvestigator Sponsored Study Program of AstraZeneca.