Time to Second Objective Disease Progression (PFS2): An Emerging Clinical Trial Endpoint with Regulatory and Reimbursement Implications

Abstract Introduction: Overall survival (OS) continues to be the preferred endpoint for measuring sustained clinical benefits in oncology trials. In some cases, measuring OS can be problematical due to trial design, multiple lines of treatment (Tx), long survival times, and other factors. In this context, there is growing interest in the time to second objective disease progression (PFS2) for Txs with good toxicity profiles. The European Medicines Agency (EMA) recommends the use of PFS2 to help understand the relevance of meaningful improvements in PFS when OS cannot be measured (e.g. maintenance Tx, increased number of “induction” cycles) (EMA, 2012). PFS2 is defined as “time from randomisation to objective tumour progression on next-line treatment or death from any cause. In some cases, time on next-line therapy may be used as proxy for PFS.” PFS2 is likely to become an important endpoint for regulatory and reimbursement evaluations in Europe and elsewhere as a result of the recent EMA guidance. Therefore there is a need to optimally understand the role PFS2 is likely to play in clinical trial results and their application. Methods: We undertook a search on clinicaltrials.gov for cancer trials that include PFS2 as an endpoint (search terms: cancer AND PFS; cancer AND PFS2). Through mapping of drugs vs. other endpoints, stage of development, likely or current indications, and other factors, we considered whether PFS2 would have a role in a potentially new or changed indication and therefore in regulatory and health technology assessment (HTA) submissions. Based on this, we have identified critical areas where understanding and use of PFS2 data may pose challenges in the submission processes, from the perspectives of the clinical trial sponsor and regulatory agency. Results: As of July 2014, a total of 7,957 cancer trials list PFS as an endpoint; 14 of these include PFS2. In all cases, PFS2 is listed as a secondary endpoint. PFS is the primary endpoint in 13/14, with time to failure as the primary endpoint in 1 trial. OS is not a primary endpoint in any trial that lists PFS2, but is a secondary endpoint in 13 of the 14 trials. It is being studied in the context of either maintenance (10/14 trials) or sequential Tx (3/14) and has the potential for inclusion in regulatory and HTA submissions in all cases. The types of oncology trials in which PFS2 is being assessed included multiple myeloma (n = 3), prostate cancer (n = 2), breast cancer (n = 2), head and neck cancer (n = 1), colorectal cancer (n = 4), non-small cell lung cancer (n = 1), and pancreatic cancer (n = 1). There are 6 phase 2 and 8 phase 3 trials that are listed as either not yet recruiting (n = 4), ongoing (n = 4), or recruiting (n = 6). We identified a number of issues for key groups that may arise from the inclusion of PFS2 in clinical trials. For healthcare professionals there is a need to understand the clinical relevance of a new endpoint that may provide additional and complementary information on Tx of progressive disease from both medical and patient (pt) perspectives. For trial sponsors, clear and clinically relevant communication of PFS2 results is needed and data must be included in medical and economic models. Agencies evaluating regulatory or HTA submissions must understand the benefits shown by an improved PFS2, whether or not there is an improvement in OS, and methodologies for evaluating the medical and economic value of PFS2 are required. Restricting our search to clinicaltrials.gov was associated with some limitations. For example, some trials in which PFS2 has been measured could have been missed due to ongoing updates to publically available information. Also, in some cases, post-hoc analyses may have evaluated PFS2 without a change to website details. Trials in which PFS2 has been measured and data published were not part of the search strategy. Conclusions: PFS2 is emerging as a secondary endpoint in a growing number of clinical oncology trials assessing the benefits of maintenance or sequential Tx. Although data are currently limited, the results of trials currently listed on clinicaltrials.gov will help to determine how PFS2 provides additional and complementary information about Tx of progressive disease from both medical and pt perspectives. Disclosures Mbanya: PHMR Associates: Consultancy. Chadda:PHMR Associates: Consultancy.