Longitudinal assessment of ROPRO as an early indicator of overall survival in oncology clinical trials: a retrospective analysis

Background The gold standard to evaluate treatment efficacy in oncology clinical trials is Overall Survival (OS). Its utility, however, is limited by the need for long trial duration and large sample sizes. Thus methods such as Progression-Free Survival (PFS) are applied to obtain early OS estimates across clinical trial phases, particularly to decide on further development of new molecular entities. Especially for cancer-immunotherapy, these established methods may be less suitable. Therefore, alternative approaches to obtain early OS estimates are required. In this work, we present a first evaluation of a new method, ΔRisk. ΔRisk uses the ROPRO, a state-of-the-art pan-cancer OS prognostic score, or DeepROPRO to predict OS benefit by measuring the patient’s improvement since baseline. Patients and methods We modeled the ΔRisk using Joint Models and tested whether a significant ΔRisk decrease correlated with OS improvement. We studied this hypothesis by comparing classical OS analysis against ΔRisk in a retrospective analysis of 12 real-world data emulated clinical trials, and 3 additional recent phase III immunotherapy clinical trials. Results Our new ΔRisk method correlated with the final OS readout in 14 out of 15 clinical trials. The ΔRisk, however, identified the treatment benefit up to seven months earlier than the OS log-rank test. Additionally, in two immunotherapy trials where PFS would have failed as an early OS estimate, the ΔRisk correctly predicted the treatment benefit. Conclusions We introduced a new method, ΔRisk, and demonstrated its correlation with OS. In retrospective analysis, ΔRisk is able to identify OS benefit earlier than standard methodology, and we show examples of lung cancer trials, where it maintains its predictive relevance whereas PFS does not correlate with OS. ΔRisk may prove useful for early decision support resulting in reduced need of resources. We also show the potential of ΔRisk as a candidate to define surrogate endpoints. To this purpose, more methodological work and further investigation of treatment-specific performance will be done in the future. ### Competing Interest Statement ABM, AK, HL and TK are employed by F. Hoffmann-La Roche. DR is employed by Bayer AG. ABM, AK and TK report to hold shares of F. Hoffmann-La Roche. TB is a contractor paid by F.Hoffmann-La Roche. All remaining authors declare no conflicts of interest. ### Funding Statement This study was funded by F. Hoffmann-la Roche LTD. No grant number is applicable. ### 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: Institutional Review Board approval of the Flatiron Health study protocol for data collection from the real world cohort was obtained prior to study conduct, and included a waiver of informed consent. For the Roche datasets, an independent data monitoring committee reviewed safety. Protocol approval was obtained from independent ethics committees for each site. Additional information on the datasets used in this analysis is available alongside the original published studies: IMpower150 (), IMvigor211 (https://doi.org/10.1016/S0140-6736(17)33297-X) and OAK (https://doi.org/10.1016/S0140-6736(16)32517-X). All of the used datasets had been previously anonymized. Additional details on Flatiron's institutional review board approval are outlined below: IRB name - WCG IRB Protocol number and title - RWE-001: The Flatiron Health Real World Evidence Parent Protocol Registration number - IRB00000533 Protocol approval ID / tracking number - 420180044 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data presented is owned by either Flatiron Health Inc or F. Hoffmann-la Roche LTD. Access to Flatiron Health may be made available upon request, and are subject to a license agreement with Flatiron Health. Requests to access these datasets should be directed to DataAccess{at}flatiron.com.