Global Transportability of Clinical Trial Outcomes to Real-World Lung Cancer Populations: A case Study using Lung-MAP S1400I

Abstract

Importance The relevance of randomized clinical trials (RCTs) outcomes to real-world settings – especially across countries – is sometimes limited by their restrictive eligibility criteria and variations in standards of care compared to routine clinical practice.

Objective To assess the transportability of findings from the RCT Lung-MAP S1400I to real-world populations in the United States (US), Germany and France.

Design This empirical validation study used patient-level data from the RCT Lung-MAP S1400I to build a transportability model to adjust for differences in patient characteristics from real-world target patient populations. Two sets of adjustments were performed – one limited to the set of measured clinical variables, and the second additionally including external information drawn from published literature and substantive knowledge on patient subgroups excluded from the trial. The latter enabled transportability to a significantly more diverse and representative real-world patient population by relaxing the stringent exclusion criteria used in Lung-MAP S1400I. For benchmarking, we compared how well the transportability analysis approximated observed overall survival in the respective real-world cohorts.

Setting Observational study.

Participants Eligible individuals diagnosed with advanced or metastatic NSCLC and previously treated with systemic therapy.

Intervention/exposure Nivolumab monotherapy.

Main outcome measures Overall survival.

Results Sample size for the nivolumab arm in Lung-MAP S1400I was 127 and ranged from 133 to 1051 for the various real-world cohorts included. Patients with ECOG scores of 2+, index cancer stage <IV, presence of ALK/EGFR mutations, presence of comorbidities and prior exposure to immunotherapy/targeted therapies were excluded from Lung-MAP S1400I, were but were eligible to receive nivolumab monotherapy in real-world care. Adjusting for measured clinical differences improved alignment of patient outcomes in the RCT and the real-world cohorts. However, only when variables related to excluded patient groups were also addressed did the results fully satisfy control conditions, yielding the closest approximation to real-world survival in the US, Germany, and France (mean discrepancy: 0.27 months over ∼30 months).

Conclusions Overall survival in a more diverse real-world patient population could be extrapolated using data from the Lung-MAP S1400I trial when complemented with external information about excluded patient groups.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Protocols

https://www.medrxiv.org/content/10.1101/2024.05.25.24307916v2

Funding Statement

Manuel Gomes acknowledges fundings from a NIHR Advanced Fellowship. This study did not receive any other funding.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This work was performed using data from the NCTN Data Archive of the National Cancer Institute's (NCI's) National Clinical Trials Network (NCTN). Data were originally collected from clinical trial NCT number NCT02785952.

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Data Availability

This work was performed using data from the NCTN Data Archive of the National Cancer Institute's (NCI's) National Clinical Trials Network (NCTN). Data were originally collected from clinical trial NCT number NCT02785952. Data can be requested online via Project Data Sphere.

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