UMIN-ICDS Clinical Trial

Public title

HR of PFS as surrogate endpoints for HR of OS in RCTs of systemic immuno-therapies for advanced, locally advanced, and relapsed NSCLC

Acronym

HR of PFS as surrogate endpoints for HR of OS in RCTs of systemic immuno-therapies for advanced, locally advanced, and relapsed NSCLC

Scientific Title

HR of PFS as surrogate endpoints for HR of OS in RCTs of systemic immuno-therapies for advanced, locally advanced, and relapsed NSCLC

Scientific Title:Acronym

HR of PFS as surrogate endpoints for HR of OS in RCTs of systemic immuno-therapies for advanced, locally advanced, and relapsed NSCLC

Region

Japan

Condition

advanced, locally advanced, and relapsed NSCLC

Classification by specialty

Pneumology

Classification by malignancy

Malignancy

Genomic information

NO

Narrative objectives1

Although OS is universally recognized as the gold-standard endpoint in oncology clinical trials due to its direct clinical benefit to patients and objective, bias-free measurement, evaluating it has become ironically complex. Thanks to therapeutic breakthroughs by ICIs, the survival of patients with inoperable NSCLC spans several years. Consequently, executing randomized controlled trials (RCTs) with mature OS as the primary endpoint requires protracted follow-up periods, making them increasingly impractical. To overcome this logistical barrier, intermediate metrics such as progression-free survival (PFS) have gained widespread adoption as a primary endpoint. Most of published systematic review did not show very good relationship between HRs of PFS and OS, partially due to pseudo-progression. Another issue is underestimating the surrogacy due to statistical phenomenon, insufficient correlation by restricted range. Recent ICI trials showed highly favorable HRs of PFS and OS because of excellent therapeutic effect by ICI and because of medical tradition assigning standard treatment to the reference arm and novel treatment to the experiment arm. In this study, we conducted a trial-level systematic review to assess the formal validity of HR of PFS as a surrogate endpoint for HR of OS in RCTs with ICI for advanced, locally advanced, and relapsed NSCLC.

Basic objectives2

Others

Basic objectives -Others

Most of published systematic review did not show very good relationship between HRs of PFS and OS, partially due to pseudo-progression. Another issue is underestimating the surrogacy due to statistical phenomenon, insufficient correlation by restricted range. Recent ICI trials showed highly favorable HRs of PFS and OS because of excellent therapeutic effect by ICI and because of medical tradition assigning standard treatment to the reference arm and novel treatment to the experiment arm. In this study, we conducted a trial-level systematic review to assess the formal validity of HR of PFS as a surrogate endpoint for HR of OS in RCTs with ICI for advanced, locally advanced, and relapsed NSCLC.

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

The surrogacy of HR of PFS for HR of OS.
To eliminate potential bias arising from arbitrary label-/arm-assignment, an exhaustive label-assignment method is developed. For N RCTs, all 2^N possible label-assignment patterns are evaluated. STE, correlation coefficient, and P-values are determined as the median values across all 2^N sign-permutations.
Surrogacy is evaluated using the weighted Peason's correlation coefficient (r). According to the generic inverse variance method, the weight assigned to each study is determined by the inverse variance of the natural log HR of survival, where the variance is the squared standard error. The correlation is interpreted as follows: no correlation (|r| < 0.2), weak (0.2 < |r| < 0.4), moderate (0.4 < |r| < 0.6), strong (0.6 < |r| < 0.8), very strong (0.8 < |r| < 0.9), or excellent (0.9 < |r|).
Statistical significance is determined by a Z-statistic by dividing the random-effects meta-regression slope coefficient by its standard error, which inherently incorporates both within-trial sampling variances and between-trial heterogeneity (tau^2). The corresponding P-value is derived from this Z-statistic.
A bivariate random-effects meta-analytic model is utilized to jointly model treatment effects on both endpoints and to estimate their variance-covariance structure. From this joint framework, the trial-level surrogate regression line and its 95% prediction interval (PI) are derived. The Surrogate threshold effect (STE) is defined as the threshold where this 95% PI crosses the line of no effect (HR = 1.0). This structural model-based approach is prioritized over ordinary univariate mixed-effects meta-regression to ensure a more robust estimation of the surrogacy relationship.

Key secondary outcomes

Study type

Others,meta-analysis etc

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

Not applicable

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

Study selection
Articles written in English that present a randomised controlled trial (RCT) evaluating systemic immune-therapy for advanced, locally advanced, and relapsed NSCLC are eligible for inclusion. Conference abstracts are not accepted.

Patients
Patients with operable NSCLC are evaluated, irrespective of pathological subtype or driver mutation, provided they are considered candidates for systemic immune-therapy by the original study authors.

Treatment
This study focuses on ICI-based systemic immuno-therapy such as ICI monotherapy, dual ICI therapy, and chemoimmunotherapy.
Absence or presence of previous systemic therapy is not considered. However, subgroup analysis focusing on first-line treatment and on second- or later-line treatment are expected.

Key exclusion criteria

Conference abstracts are not accepted.

Systematic therapy without ICI is not allowed. Multimodal treatment combined with radiotherapy is excluded. Studies utilising regimens containing obsolete cytotoxic agents, such as mitomycin C and vindesine, are also excluded as they do not represent current standard-of-care.

Target sample size

Name of lead principal investigator

1st name	Nobuyuki
Middle name
Last name	Horita

Organization

Yokohama City University Hospital

Division name

Chemotherapy Center

Zip code

236-0004

Address

3-9, Fukuura, Kanazawa, Yokohama, Japan

TEL

045-787-2800

Email

horitano@yokohama-cu.ac.jp

Name of contact person

1st name	Nobuyuki
Middle name
Last name	Horita

Organization

Yokohama City University Hospital

Division name

Chemotherapy Center

Zip code

236-0004

Address

3-9, Fukuura, Kanazawa, Yokohama, Japan

TEL

045-787-2800

Homepage URL

Email

horitano@yokohama-cu.ac.jp

Institute

Yokohama City University Hospital

Institute

Department

Personal name

Organization

Yokohama City University Hospital

Organization

Division

Category of Funding Organization

Other

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Yokohama City University Hospital

Address

3-9, Fukuura, Kanazawa, Yokohama, Japan

Tel

045-787-2800

Email

horitano@yokohama-cu.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2026

Year

05

Month

30

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

Results

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Preinitiation

Date of protocol fixation

2026

Year

05

Month

29

Day

Date of IRB

Anticipated trial start date

2026

Year

05

Month

29

Day

Last follow-up date

2027

Year

12

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

S. Yamamoto and N. Horita extract data regarding study characteristics, hazard ratios (HR) for survival data with 95% confidence intervals (CI), and risk-of-bias items. Extracted data are cross-verified. For studies reporting multiple populations, the primary endpoint population or the population with the larger sample size is selected. Priority is given to the protocol-specific primary endpoint; however, updated data are used for overall survival (OS) if the primary article's data are immature.

Registered date

2026

Year

05

Month

30

Day

Last modified on

2026

Year

05

Month

30

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000070662