Immune-checkpoint Inhibitors and Surrogate Endpoints in Cancer Trials
Conditions: Cancer Treated With Immune-checkpoint Inhibitors
Sponsor: Institut Bergonié

     
 
 
 
 
IMMUNE-CHECKPOINT INHIBITORS AND SURROGATE 
ENDPOINTS IN CANCER TRIALS  
 
SURROGATE-ICI 
 
05/01/2017 
NCT03963518 
 
 
 
 
 
 
 
 
 
 
 
 

Synopsis_[Acronyme]_v0.X_DD/MM/YYYY 
 
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SYNOPSIS 
 
Title 
of 
the 
study  
 
Immune-checkpoint Inhibitors and Surrogate Endpoints in Cancer Trials (SURROGATE-
ICI) 
Abbreviation  
of the trial 
SURROGATE-ICI 
Number 
of 
patients 
631 
Medical 
conditions 
Cancer patients treated with  
Rationale of the  
study 
Advanced cancer treatment has been recently revolutionized by the development 
of the immune-checkpoint inhibitors (ICI). These immunomodulatory monoclonal 
antibodies are designed to either elicit a novel anti-tumoral immune response or 
revitalize an existing one to fight against cancer. Patients with cancer are living 
longer due to these improved therapies. Powering a study for overall survival (OS), 
the gold standard primary endpoint in randomized controlled trial (RCT) of 
anticancer drugs is becoming increasingly challenging. Therefore, it is of 
importance to identify and validate novel surrogate endpoints (SE) for OS in ICI-
treated patients for expediting patients’ access to innovative and potentially life 
extending medicines.  
 
Objectives 
1/ We will first systematically review published studies reporting on an 
association between alternative endpoints and OS in ICI-treated patients.  
 
2/ Then, based on the learnings from this systematic literature review and from 
the specificity of the mechanism of action of ICIs, we will evaluatd the surrogacy 
properties of an emerging intermediate endpoint in solid tumors, namely time to 
next treatment (TNT), in ICI-treated patients with advanced melanoma and 
renal cell carcinoma (aRCC), through recent innovative statistical models for the 
validation of SE.  
Study design  
Statistical analyses based on the re-utilization of already published data 
Inclusion 
criteria 
For objective 2 : advanced melanoma patients treated with immune 
checkpoint inhibitors 
Treatment 
For objective 2 : nivolumab monotherapy ; nivolumab plus ipilimumab 
Endpoints 
OS :  time from the date of randomization to the date of death (any cause). 
TNT-D :  the time between the date of randomisation and the date of 
subsequent systemic treatment initiation, or the date of death (any cause), 
whichever occurred first.  
Statistical 
methods 
OS and TNT-D distributions will be generated using the Kaplan-Meier estimator. 
Median follow-up will be estimated by the reverse KaplaneMeier method.  
To describe these efficacy outcomes, hazard ratios (HRs) will be estimated using 
a Cox proportional-hazards model stratified according to the factors used in the 
randomisation process.  
For the surrogate endpoint (SE) analysis, HRs will be estimated with a joint 
frailty-copula model. 
Robust assessment and validation of an SE require evaluation at both the 
individual and trial levels (meta-analytic approach). 
For two time-to-event endpoints, several metaanalytic surrogacy validation 
approaches are available, including 1-step and 2-step validation approaches. We 
Will consider the SE 1-step validation statistical method based on a joint frailty-
copula model (Gumbel copula) as it has been demonstrated to reduce 
substantially numerical problems encountered with the 2-step method. 

     
Institut Bergonié 
Synopsis [Acronyme] 
 
In this approach, Kendall’s s is used to estimate the strength of association 
between the candidate SE and the final endpoint at the individual level. The 
Kendall’s s will be estimated as a function of the copula parameter, where values 
above an informal threshold of 0.6 are regarded as sufficient for the validity of 
the SE at the individual level, while it is uncommon to observe a value higher 
than 0.7.