P2.09-23. A Multicentre, Real-World Observational Study of First-Line
Osimertinib and Post Progression Patterns in EGFR Positive NSCLC(Reiwa Study)

K. Watanabe1, Y. Hosomi1, K. Naoki2, T. Kato3, Y. Tsukita4, H.
Matsumoto5, K. Yoh6, Y. Fujisaka7, S. Takahashi8, S. Takata9, K.
Usui10, K. Kishi11, G. Naka12, S. Tamano13, K. Uemura14, H.
Kunitoh15
1Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo/JP ,2Kitasato

University School of Medicine, Sagamihara/JP ,3Kanagawa Cancer Center, Yokohama/JP ,4Tohoku
University Graduate School of Medicine, Sendai/JP ,5Hyogo Prefectural Amagasaki General MedicalCenter, Amagasaki/JP ,6National Cancer Center Hospital East, Kashiwa/JP ,7Osaka Medical andPharmaceutical University Hospital, Takatsuki/JP ,8Tokyo Medical University, Tokyo/JP ,9Kyorin
University School of Medicine, Mitaka/JP ,10NTT Medical Center Tokyo, Tokyo/JP ,11Toho University
Omori Medical Center, Tokyo/JP ,12National Center for Global Health and Medicine,Tokyo/JP ,13Graduate School of Interdisciplinary Information Studies, The University of Tokyo,
Tokyo/JP ,14The Interfaculty Initiative in Information Studies, The University of Tokyo,
Tokyo/JP ,15Japan Red Cross Medical Center, Tokyo/JPDeclaration of interests
This study was sponsored by the Public Health Research Foundation.
This study is financially supported by AstraZeneca.
AstraZeneca is not be directly involved in the data management, source data verification, or
the statistical analysis.

Background⚫ Osimertinib is a third-generation, irreversible epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitor (TKI) that selectively inhibits both EGFR-TKIsensitizing and EGFR-T790M (resistant) mutations.
⚫ In a phase III trial (FLAURA), osimertinib showed efficacy superior to that of firstgeneration gefitinib and erlotinib, with a similar safety profile and lower rates ofserious adverse events.
⚫ Osimertinib is widely used as the first-line treatment for EGFR mutation-positive nonsmall cell lung cancer (NSCLC) , but its efficacy and safety of osimertinib in real-world
clinical practice remain to be fully elucidated in Japanese population.
⚫ In addition, most cases ultimately acquire resistance to osimertinib, and no effective
treatment has been currently established for cases having progressive disease (PD)with osimertinib.

Methods【Design】
A multicenter, prospective real-world cohort study【Patients】
 EGFR mutation-positive Advanced or recurrent NSCLC patients
 Started EGFR-TKI treatment from
September 2018 to August 2020 were enrolled Those receiving first-line osimertinib monotherapy
were followed-up for efficacy, safety, progression
patterns, post-progression treatments andoutcomes until August 2022.

EGFR mutation-positive NSCLC
From Sep 2018 to Aug 2020

Obtained consent
Ineligible (n=1)(n=660)

Osimertinib(n=583)

A survey wasconducted once
every six months

Other EGFR-TKI(n=76)

Data cut-off
Aug 31th, 2022

Methods【 Primary endpoint 】
 Progression free survival* with Osimertinib* Time from the start of osimertinib to RECIST PD or death from anycause.
 Percentage of patients with progression patterns when RECIST PD wasencountered with osimertinib treatment.

Patient characteristics (n=583)
Median (range) or number (%)
Age, median (range), years

Gender, male / female
ECOG PS*, 0 / 1 / 2 / 3 / 4 / missing
Smoking status, never / former / current
Histology, adeno / squamous / NOS / LCNEC

72 (30-95)

224 (38.4) / 359 (61.6)
216 (37.1) / 281 (48.2) /60 (10.3) / 20 (3.4) / 2 (0.3) / 4 (0.7%)325 (55.8) / 224 (38.4) / 34 (5.8)
571 (97.9) / 9 (1.5) / 2 (0.3) / 1 (0.1)

Mutation type*, Ex19del / L858R / others

285 (48.9) / 266 (45.6) / 33 (5.7)

Stage, locally advanced / metastatic / recurrence

19 (3.3) / 395 (67.8) / 169 (29.0)

Brain metastases, yes / no169 (29.0) / 414 (71.0)

NOS: not otherwise specified, LCNEC: large cell neuroendocrine carcinoma.
* One patient had both Ex19del and L858R mutations.

Follow-up period, median 28.5 months (range, 0.1-48.0)

Overall response rate and disease control rate

response%CR

3.4

PR

64.8

SD

18.7

PD

8.1

NE

5.0

Overall response rate

68.3% (95％CI, 54.3-72.0)

Disease control rate

87.0% (95%CI, 84.0-89.6)

Progression free survival
All20.0 months (95%CI, 17.6-21.7)

Ex19del23.5 months (95%CI, 21.3-28.0)

L858R

16.9 months (95%CI, 15.1-19.4)
HR:0.68 (95%CI, 0.56-0.84), p=0.0002

deldelOverall survivalAll

41.0 months (95%CI, 37.1-44.1)

Ex19del44.2 months (95%CI, 41.3-NA)

L858R

36.1 months (95%CI, 30.3-41.1)
HR:0.63 (95%CI, 0.48-0.81), p=0.0004

deldelCourse of treatment
Reason for
discontinuationn (%)

AE leading todiscontinuationn (%)

PD by RECIST

170 (29.2)

All events117 (20.1)

Clinical exacerbation

90 (15.4)

Pneumonitis

61 (10.5)

Adverse events117 (20.1)

Hematotoxicity

8 (1.4)

Patients’ refusal

12 (2.1)

Rash*7 (1.2)

Judgment by attending physician

13 (2.2)

Paronychia

6 (1.0)

Others45 (7.7)

AST/ALT increased

6 (1.0)(Ongoing treatment)

136 (23.3)

Anorexia

6 (1.0)

Prolonged QT interval

3 (0.5)

Diarrhea

2 (0.3)Other

18 (3.1)* Included rash acneiform, rash maculopapular, erythema multiforme and urticaria

Exacerbation pattern on RECIST PDn (%)

Asymptomatic andSymptomatic andno clinical exacerbation no clinical exacerbation

Clinicalexacerbation*

Total

Central nervous system(CNS) metastasis only

16(4.7%)4(1.2%)

17(4.9%)37(10.8%)

Oligo-progression**109(31.7%)30(8.7%)17(4.9%)156(45.4%)

Multiple organs

70(20.4%)

39(11.3%)

42(12.2%)

151(43.9%)

Total

195(56.7%)73(21.2%)

76(22.1%)

344(100%)* Clinical exacerbation is defined as decline in PS and/or an exacerbation threatening major organs(carcinomatous lymphangiosis, bone marrow metastasis, carcinomatous meningitis, liver metastasis with liver damage, etc.)** Single organ other than CNS (up to 3 per organ)Percentage of patients who continued on osimertinibat the time of RECIST PD%（n/n）

Asymptomatic andSymptomatic andno clinical exacerbation no clinical exacerbation

Clinical
exacerbation*Total

Central nervous system(CNS) metastasis only

87.5
(14/16)

75.0
(3/4)

47.1
(8/17)

67.6(25/37)

Oligo-progression**49.5(54/109)

56.7(17/30)35.3(6/17)

49.4(77/156)

Multiple organs

55.7(39/70)35.9(14/39)19.0(8/42)

40.4(61/151)

Total

54.9
(107/195)46.6(34/73)

28.9(22/76)

47.4(163/344)* Clinical exacerbation is defined as decline in PS and/or an exacerbation threatening major organs(carcinomatous lymphangiosis, bone marrow metastasis, carcinomatous meningitis, liver metastasis with liver damage, etc.)** Single organ other than CNS (up to 3 per organ)Survival after RECIST-PD with osimertinib
A1 CNS-only progression

9.0 months (95%CI, 3.7-19.4)

A2 oligo-progressions

21.4 months (95%CI, 16.4-29.7)

A3 multiple organ-progressions

11.3 months (95%CI, 8.3-13.5)

Survival after RECIST-PD with osimertinib
B1 Asymptomatic and no clinical exacerbation

21.1 months (95%CI, 16.5-28.7)

B2 Symptomatic and no clinical exacerbation

12.5 months (95%CI, 7.8-17.2)

B3 Clinical exacerbation

3.4 months (95%CI, 1.5-5.4)

Survival after RECIST-PD in a clinically stable population
at the time of osimertinib RECIST-PD
osimertinib beyond PD

13.3 months (95%CI, 10.9-16.4)

discontinued osimertinib

24.1 months (95%CI, 17.7-34.0)

HR:2.01 (95%CI, 1.38-2.91), p=0.0002

The clinically stable population is as follows.

osimertinib beyond PDdiscontinued osimeritinib

osimertinib beyond PD
discontinued osimeritinib

Adverse events
AE ≧ Grade 3n (%)

Pneumonitisn (%)

All events

136 (23.3)

Any grade75 (12.9)

Pneumonitis

18 (3.1)

Grade 121 (3.6)

Rash*

18 (3.1)

Grade 236 (6.2)

AST/ALT increased

15 (2.6)

Grade 3

12 (2.1)

Anemia13 (2.2)

Grade 46 (1.0)Anorexia

12 (2.1)

Grade 50 (0)Neutropenia

11 (1.9)

Paronychia

9 (1.5)

Diarrhea

6 (1.0)Thrombocytopenia

5 (0.9)

Leukopenia

5 (0.9)Prolonged QT interval

4 (0.7)* Included rash acneiform, rash maculopapular,
erythema multiforme and urticaria

Comparison with other trials

Trial

Area

DesignN

PFS (m)OS (m)ORR (%)AE ≧ Grade 3 (%)

FLAURA

GlobalPhase III trial

279

18.9

38.6

80

42

OSI-FACTJapan

Retrospective
cohort study

538

20.5

NR

79.8

NE

Reiwa (this study)

Japan

Prospective
cohort study

583

20.0

41.0

68.3

23.3

NR: not reported
NE: not evaluated (?)

Conclusions⚫ First-line osimertinib showed good effectiveness in clinical practice,compatible with pivotal study results.
⚫ Both PFS and OS were significantly better in patients with exon 19 deletion

than those with exon21 L858R point mutation.
(median PFS: 23.5 month vs. 16.9 months; median OS: 44.2 month vs. 36.1 months.)⚫ The progression patterns were CNS-only in 10.8%, oligo-progression in

45.4%, and multiple organ-progressions in 43.9%.
⚫ 56.7% of the patients were asymptomatic at the time of RECIST PD.
⚫ 47.7% of the patients continued to receive osimertinib beyond RECIST PD.

⚫ Survival after RECIST PD in the clinically stable population was worse in theosimertinib continuation group than in the osimertinib discontinuation group.

References
1.
2.
3.
4.

Watanabe K, et al. BMJ Open. 2022 Jan 4;12(1):e046451.
Soria JC, et al. N Engl J Med. 2018 Jan 11;378(2):113-125.
Ramalingam SS, et al, N Engl J Med. 2020 Jan 2;382(1):41-50.
Sakata Y, et al, Eur J Cancer. 2021 Dec;159:144-153.

Funding:
This study was sponsored by the Public Health Research Foundation under the funding
support from AstraZeneca.
Correspondence to:Kageaki Watanabe, MD,
Department of Thoracic Oncology and RespiratoryMedicine, Tokyo Metropolitan Cancer andInfectious Diseases Center Komagome Hospital,Bunkyo, Tokyo 113-8677, Japan
E-mail: kageaki_watanabe@tmhp.jp