UMIN-CTR Clinical Trial

Public title

Real world evidence of long-term safety and efficacy in patients treated with durvalumab after concurrent chemoradiation for unresectable stage III NSCLC
;AYAME study

Acronym

Real world evidence of long-term safety and efficacy in patients treated with durvalumab after concurrent chemoradiation for unresectable stage III NSCLC
;AYAME study

Scientific Title

Real world evidence of long-term safety and efficacy in patients treated with durvalumab after concurrent chemoradiation for unresectable stage III NSCLC
;AYAME study

Scientific Title:Acronym

Real world evidence of long-term safety and efficacy in patients treated with durvalumab after concurrent chemoradiation for unresectable stage III NSCLC
;AYAME study

Region

Japan

Condition

Unresectable stage III NSCLC

Classification by specialty

Pneumology

Chest surgery

Classification by malignancy

Malignancy

Genomic information

NO

Narrative objectives1

Primary objectives
To assess ILDs and AESIs that occurred within three years from the start of durvalumab treatment in patients who are diagnosed stage III unresectable NSCLC treated durvalumab following chemoradiation therapy
To assess PFS from start of durvalumab treatment in patients who are diagnosed stage III unresectable NSCLC and treated durvalumab following chemoradiation therapy.

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

1.ILDs and AESIs will be summarized at least following categories
ILDs within three years from the start of durvalmab treatment
ILDs and AESIs during treatment period of durvalmab
ILDs and AESIs after durvalmab treatment
2.PFS and PFS rates at 12 months,18 months and 24 months from the start of durvalmab treatment

Key secondary outcomes

1.OS and OS rates at 24 months and 36 months from the start of durvalmab treatment
2.Summary of ILDs and AESIs in each durvalumab treatment status in patient subset populations
3.PFS and OS in patient subset populations
4.OR,TTDM
5.Reasons of treatment discontinuation of durvalumab (discontinuation by reasons of AE or PD or others)
6.Detailed subsequent treatments regimens until 3 years after start of durvalumab treatment

Study type

Observational

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

Purpose of intervention

Type of intervention

Interventions/Control_1

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

Patients who receive durvalumab for unresectable stage III NSCLC at first time following chemoradiation therapy.
Include patients with recurrent after resection of the primary site and judged to have unresectable stage III NSCLC (N2-3).

Patients who provided written informed consent.

Key exclusion criteria

Patients who would join PMS for durvalumab.
Patients who would join any interventional clinical studies using unapproved drugs or off-label use of drugs from the time of initial diagnosis to the end of the treatment of durvalmab.
Age < 20

Target sample size

500

Name of lead principal investigator

1st name	Hirosi
Middle name
Last name	Kitagawa

Organization

AstraZeneca K.K.

Division name

Head of Oncology Medical

Zip code

530-0011

Address

3-1, Ofuka-cho, Kita-ku, Osaka-city,Osaka 530-0011,Japan

TEL

06-7711-3044

Email

Hiroshi.kitagawa@astrazeneca.com

Name of contact person

1st name	Hajime
Middle name
Last name	Kanazaki

Organization

A2healthcare Corporation

Division name

Clinical Development Department4

Zip code

112-0002

Address

1-4-1,Koishikawa,Bunkyo-Ku,Tokyo 112-0002 JAPAN

TEL

03-3830-1075

Homepage URL

Email

AYAME_Core@a2healthcare.com

Institute

AstraZeneca K.K.

Institute

Department

Personal name

Organization

AstraZeneca K.K.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

The Japan Lung Cancer Society

Name of secondary funder(s)

Organization

Not applicable

Address

Not applicable

Tel

03-3830-1075

Email

NA

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

北海道がんセンター　独立行政法人国立病院機構(以降独法) (北海道)、旭川医科大学病院 (北海道)、岩手医科大学附属病院（岩手県）、仙台厚生病院 財団（宮城県）、宮城県立がんセンター（宮城県）、新潟県立がんセンター新潟病院（新潟県）、群馬県立がんセンター（群馬県）、埼玉県立がんセンター（埼玉県）、埼玉医科大学国際医療センター（埼玉県）、千葉大学医学部附属病院（千葉県）、獨協医科大学病院（栃木県）、自治医科大学附属病院（栃木県）、茨城県立中央病院（茨城県）、順天堂大学医学部附属順天堂医院（東京都）、がん研有明病院 財団（東京都）、日本医科大学付属病院（東京都）、国立がん研究センター中央病院（東京都）、東京医科大学病院（東京都）、神奈川県立がんセンター（神奈川県）、神奈川県循環器呼吸器病センター（神奈川県）、横浜市立市民病院（神奈川県）、北里大学病院（神奈川県）、静岡がんセンター 県立（静岡県）、名古屋大学医学部附属病院（愛知県）、藤田医科大学病院（愛知県）、松阪市民病院（三重県）、名古屋医療センター 独法（愛知県）、愛知県がんセンター中央病院（愛知県）、金沢大学附属病院（石川県）、京都府立医科大学附属病院（京都府）、京都大学医学部附属病院（京都府）、兵庫県立がんセンター（兵庫県）、神戸市立医療Ｃ中央市民病院（兵庫県）、関西医科大学附属病院（大阪府）、大阪市立総合医療センター（大阪府）、大阪市立大学医学部附属病院（大阪府）、大阪国際がんセンター（大阪府）、和歌山県立医科大学附属病院（和歌山県）、近畿大学医学部附属病院（大阪府）、近畿中央呼吸器センター　独法（大阪府）、広島大学病院（広島県）、岩国医療センター 独法（山口県）、岡山大学病院（岡山県）、島根大学医学部附属病院（島根県）、四国がんセンター 独法（愛媛県）、徳島大学病院（徳島県）、九州大学病院（福岡県）、九州がんセンター 独法（福岡県）、長崎大学病院（長崎県）、久留米大学病院（福岡県）、
琉球大学医学部附属病院（沖縄県）

Date of disclosure of the study information

2019

Year

06

Month

17

Day

URL releasing protocol

Publication of results

Published

URL related to results and publications

Number of participants that the trial has enrolled

511

Results

The result of this study showed the long-term safety and effectiveness of durvalumab, in patients with unresectable stage III NSCLC who received concurrent chemoradiation in the real-world setting in Japan. No new safety concerns were suggested including post-durvalumab treatment period, and the effectiveness results showed similar trends to the PACIFIC study, a phase III clinical trial of durvalumab.

Results date posted

2025

Year

01

Month

17

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

In the safety analysis population (n=511), the median(min-max) age was 69.0 (31-88) years, and 362 (70.8%) patients were older than 65 years. The number of male patients were 393 (76.9%), and females were 118(23.1%). The most common smoking status was `Ex-smoker` in 380 (74.4%) patients, followed by `Smoker` in 71 (13.9%) and `Non-smoker` in 60 (11.7%).The median smoking index (min-max) was 45.5 (1-162) pack-years. For the ECOG PS before the start of durvalumab treatment, most patients' PS was 0 or 1; PS=0 in 262 (51.3%) patients, followed by PS = 1 in 239 (46.8%), PS = 2 in 7 (1.4%), PS = 3 in 1 (0.2%), and missing in 2 (0.4%).

Participant flow

A total of 529 patients were enrolled from 52 sites, of whom 512 (96.8%) started durvalumab treatment and 17 (3.2%) discontinued the study before starting durvalumab treatment. The reasons for discontinuation were `Eligibility criteria not met` in 7 patients, `Withdrawal of consent by a patient` in 2 patients, and `Others` in 8 patients. Of the enrolled patients, the safety analysis population comprised all patients who received durvalumab, and the effectiveness analysis population was defined as all patients who met the eligibility criteria and received durvalumab. One patient (0.2%) who violated the enrollment process was excluded by decision of the ethics committee, resulting in 511 patients (96.6%) in the safety analysis population. Excluding 16 (3.0%) patients due to violation of eligibility criteria found after the start of durvalumab treatment, 495 (93.6%) patients were included in the effectiveness analysis population.

Adverse events

See results for the primary endpoints.

Outcome measures

Primary endpoints
In the safety analysis population (N=511), ILD was reported in 387 (75.7%) patients during the whole period (1), 383 (75.0%) during the whole period (2), and 380 (74.4%) during durvalumab treatment period. After the end of durvalumab treatment, ILD was reported in 43 (9.0%) patients during the whole period (1) and 13 (2.7%) during the whole period (2) in the safety analysis population excluding patients who discontinued the study within the end date of durvalumab treatment + 90 days (N=480). During the whole period (2), the median time to first onset of ILD following the first dose of durvalumab was 44.0 days. In the patients who developed ILD, 111 (29.0%) patients interrupted durvalumab treatment and 99 (89.2%) patients re-started treatment. Of those patients, 4 (4.0%) patients re-developed ILD. In the multivariate logistic regression analysis of the onset of ILD, the variables which did not include 1.0 for the 95% CI of the adjusted odds ratio were V5 and ILD before the start of durvalumab treatment for any grade ILD, ILD before the start of durvalumab treatment, V20, and V5 for grade 2 or higher ILD, histology and autoimmune disease for grade 3 or higher ILD.
The reported any grade of AESI during durvalumab treatment period were dysfunction thyroid in 64 (12.5%) patients, hepatic function disorder in 37 (7.2%), colitis/severe diarrhea in 10 (2.0%), renal disorder in 6 (1.2%), dysfunction adrenal and infusion reaction in 4 (0.8%), and others in 6 (1.2%). No events of type 1 diabetes mellitus were observed. The reported grade 3 AESI were hepatic function disorder in 11 (2.2%) patients, colitis/severe diarrhea in 6 (1.2%), dysfunction thyroid in 2 (0.4%), renal disorder and infusion reaction in 1 (0.2%), and others in 5 (1.0%), respectively. Two events of grade 5 AESI were observed; hepatic function disorder and colitis/severe diarrhea in 1 (0.2%) patient, respectively. After the end of durvalumab treatment, the reported AESIs with grade 3 or higher were hepatic function disorder in 8 (1.7%) patients, colitis/severe diarrhea in 3 (0.6%), and dysfunction thyroid, renal disorder, infusion reaction, and others in 1 (0.2%), respectively. No AESI considered related to durvalumab by the investigator was observed after the end of durvalumab treatment.
In the effectiveness analysis population, the median PFS was 23.2 months (95% CI: 18.2 - 27.2), and the PFS rate at 12 months, 18 months and 24 months was 62.5% (95% CI: 58.0 - 66.6), 54.6% (95% CI: 50.0 - 58.9), and 49.4% (95% CI: 44.8 - 53.8), respectively.
Secondary endpoints
The median OS was not estimated. The OS rate at 24 months and 36 months was 75.5% (95% CI: 71.3 - 79.1) and 65.6% (95% CI: 61.0 -69.8), respectively.
ILD, AESI, PFS, and OS for each patient subset population were analyzed. In the patient subset populations categorized by patient background factor from the start of chemoradiation therapy to the end of chemoradiation therapy, the incidence of any grade of ILD, grade 2 or higher ILD, and grade 3 or higher ILD trended to be numerically higher in MLD >= 13 than MLD < 13Gy, in V20 >= 25% than V20 < 25%, in V20 >= 30% than V20 < 30%, and in MLD >= median than V5 < median. The 95% CI of those variables did not include 1.0 in univariate analysis.
In the patient subset populations categorized by patient background factor from the end of chemoradiation therapy to the start of durvalumab treatment, the incidence of any grade of ILD trended to be numerically lower in ILD before the start of durvalumab treatment (grade 1) than absent. The incidence of any grade of ILD and grade 2 or higher ILD trended to be numerically higher in period from the end of chemoradiation therapy to the start of durvalumab treatment >= 14 than < 14 days. The incidence of grade 3 or higher ILD trended to be numerically higher in autoimmune disease present than absent. The 95% CI of those variables did not include 1.0 in univariate analysis.
For the AESI incidence by presence or absence of autoimmune disease, hepatic function disorder and colitis/severe diarrhea were reported in 1 (4.5%) patient, respectively, and both maximum grades were grade 3 in the patients with autoimmune disease.
As for PFS, in the patient subset populations categorized by patient background factor from the start of chemoradiation therapy to the end of chemoradiation therapy, PFS rate trended to be numerically higher in postoperative recurrence than disease stage IIIA, B, C, in V20 < 25% than V20 >= 25%, and in PD-L1 expression rate >= 50% than <50%. The 95% CI of these covariates did not include 1.0 in univariate analysis, except for disease stage. PFS between the epidermal growth factor receptor (EGFR) gene mutation positive and negative was similar.
As for OS, in the patient subset populations categorized by patient background factor from the start of chemoradiation therapy to the end of chemoradiation therapy, OS rate trended to be numerically higher in V20 < 25% than V20 >= 25%, in PD-L1 expression rate >=50% than < 50%, and in EGFR gene mutation positive than negative. The 95% CI of those covariates did not include 1.0 in univariate analysis.
The OR was observed in 173 patients, and the response rate was 45.3% (95% CI: 40.2 - 50.4).
The median TTDM was not estimated. The number of patients who were reported death or distant metastasis was 172 (34.7%). Of those patients, 44 (25.6%) patients were dead and 128 (74.4%) had distant metastasis.
In the safety analysis population, 301 (58.9%) patients discontinued treatment. The reasons of discontinuation were PD in 112 (37.2%) patients, AE in 157 (52.2%), patient's voluntary discontinuation in 21 (7.0%), and others in 11 (3.7%).
A total of 205 (40.1%) patients received subsequent treatment. The most common first subsequent regimen was Chemo/other in 121 (59.0%) patients, followed by EGFR-tyrosine kinase inhibitor (TKI) in 23 (11.2%) and IO in 20 (9.8%). The second subsequent treatment was given to 111 (21.7%) patients, and the third subsequent treatment was given to 57 (11.2%) patients during the study period. Chemo/other was dominant in both lines. During the period from the start of first subsequent treatment until the start of second subsequent treatment, study discontinuation, death, or the final survival confirmation date whichever is the earliest, the common ILD onset group by first subsequent treatment regimen was IO in 6 (30.0%) patients, followed by IO+Chemo/other in 4 (12.5%), and Other TKI in 1 (11.1%). Grade 5 ILD occurred in both Chemo/other and IO+Chemo/other groups, and the number of patients was 2 (1.7%) and 1 (3.1%), respectively. In a total of 23 patients who received EGFR-TKI as the first subsequent treatment, only 1 (4.3%) patient developed ILD (grade 1).

Plan to share IPD

IPD sharing Plan description

Recruitment status

Main results already published

Date of protocol fixation

2019

Year

04

Month

26

Day

Date of IRB

2019

Year

06

Month

27

Day

Anticipated trial start date

2019

Year

07

Month

25

Day

Last follow-up date

2024

Year

03

Month

07

Day

Date of closure to data entry

2024

Year

03

Month

07

Day

Date trial data considered complete

2024

Year

03

Month

27

Day

Date analysis concluded

2024

Year

08

Month

31

Day

Other related information

Patient's information
Cancer information
Chemoradiation therapy information before durvalumab treatment
Durvalumab treatment information
Subsequent treatment information
Safety events
ILDs including radiation pneumonitis .all grade
AESIs
Efficacy

Registered date

2019

Year

06

Month

17

Day

Last modified on

2025

Year

01

Month

24

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000042121