UMIN-CTR Clinical Trial
| Unique ID issued by UMIN | UMIN000061339 |
|---|---|
| Receipt number | R000070186 |
| Scientific Title | Pathological complete response and major pathological response as surrogate endpoints in RCTs of neoadjuvant systemic therapies for NSCLC |
| Date of disclosure of the study information | 2026/04/25 |
| Last modified on | 2026/04/21 17:08:01 |
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Basic information
Public title
Pathological complete response and major pathological response as surrogate endpoints in RCTs of neoadjuvant systemic therapies for NSCLC
Acronym
Pathological complete response and major pathological response as surrogate endpoints in RCTs of neoadjuvant systemic therapies for NSCLC
Scientific Title
Pathological complete response and major pathological response as surrogate endpoints in RCTs of neoadjuvant systemic therapies for NSCLC
Scientific Title:Acronym
Pathological complete response and major pathological response as surrogate endpoints in RCTs of neoadjuvant systemic therapies for NSCLC
Region
| Japan |
Condition
Condition
NSCLC
Classification by specialty
| Pneumology |
Classification by malignancy
Malignancy
Genomic information
NO
Objectives
Narrative objectives1
In 2024, Hines et al. reported that lack of correlation between pathological response and OS. Nonetheless, this null finding may be attributable to a statistical phenomenon known as the correlation of restricted range caused by label assignment. Because ICIs have shown substantial efficacy in nearly all RCTs, improving both pathological response and survival simultaneously, the data points tend to cluster within a narrow range, thereby underestimating the true surrogacy. We should not assess surrogacy directly from the raw data whose labels were assigned based on medical custom. In this systematic review, we evaluated study-level correlation coefficient and surrogate threshold effect (STE) for NSCLC neoadjuvant systemic therapies between pathological response and survival, using exhaustive label assignment method.
Basic objectives2
Others
Basic objectives -Others
In 2024, Hines et al. reported that lack of correlation between pathological response and OS. Nonetheless, this null finding may be attributable to a statistical phenomenon known as the correlation of restricted range caused by label assignment. Because ICIs have shown substantial efficacy in nearly all RCTs, improving both pathological response and survival simultaneously, the data points tend to cluster within a narrow range, thereby underestimating the true surrogacy. We should not assess surrogacy directly from the raw data whose labels were assigned based on medical custom. In this systematic review, we evaluated study-level correlation coefficient and surrogate threshold effect (STE) for NSCLC neoadjuvant systemic therapies between pathological response and survival, using exhaustive label assignment method.
Trial characteristics_1
Trial characteristics_2
Developmental phase
Assessment
Primary outcomes
Two surrogate endpoints are defined as the odds ratio (OR) of pathological complete response (pCR) and major pathological response (mPR). Two true endpoints are the HR of overall survival (OS) and event-free survival (EFS). Surrogacy is evaluated for four pairs: (i) pCR and EFS, (ii) pCR and OS, (iii) mPR and EFS, and (iv) mPR and OS.
Various survival endpoints used in surgical trials--including RFS, PFS, and DFS--are collectively handled as EFS in this analysis to ensure consistency across neoadjuvant systemic therapy trials.
Key secondary outcomes
Base
Study type
Others,meta-analysis etc
Study design
Basic design
Randomization
Randomization unit
Blinding
Control
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment
Intervention
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
Eligibility
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 neoadjuvant systemic therapy for NSCLC are eligible for inclusion. Conference abstracts are accepted.
Patients
Patients with operable NSCLC are evaluated, irrespective of pathological subtype or driver mutation, provided they are considered candidates for neoadjuvant systemic therapy by the original study authors.
Treatment
This study focuses on neoadjuvant systemic therapy, including chemotherapy, molecular targeted therapy, immune checkpoint inhibitors (ICI), and chemoimmunotherapy. 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.
Key exclusion criteria
Non English articles.
Target sample size
Research contact person
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
0457872700
horitano@yokohama-cu.ac.jp
Public contact
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
horitano@yokohama-cu.ac.jp
Sponsor or person
Institute
Yokohama City University Hospital
Institute
Department
Personal name
Funding Source
Organization
Yokohama City University Hospital
Organization
Division
Category of Funding Organization
Other
Nationality of Funding Organization
Other related organizations
Co-sponsor
Name of secondary funder(s)
IRB Contact (For public release)
Organization
Yokohama City University Hospital
Address
3-9, Fukuura, Kanazawa, Yokohama, Japan
Tel
045-787-2800
horitano@yokohama-cu.ac.jp
Secondary IDs
Secondary IDs
NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW
Institutions
Institutions
Other administrative information
Date of disclosure of the study information
| 2026 | Year | 04 | Month | 25 | Day |
Related information
URL releasing protocol
Publication of results
Unpublished
Result
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
Progress
Recruitment status
Preinitiation
Date of protocol fixation
| 2026 | Year | 04 | Month | 01 | Day |
Date of IRB
Anticipated trial start date
| 2026 | Year | 04 | Month | 01 | Day |
Last follow-up date
| 2028 | Year | 12 | Month | 31 | Day |
Date of closure to data entry
Date trial data considered complete
Date analysis concluded
Other
Other related information
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 iterations.
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.
Management information
Registered date
| 2026 | Year | 04 | Month | 21 | Day |
Last modified on
| 2026 | Year | 04 | Month | 21 | Day |
Link to view the page
Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000070186
