Abstract
Introduction. The push for personalized medicine in oncology has generated an influx of therapies targeting similar pathways, despite only 5% of clinically tested agents receiving FDA approval (Mattina 2017). Acute myeloid leukemia (AML) is a malignancy where identification of prognostically significant mutations suggests growing potential for therapeutic inhibition. FMS-like tyrosine kinase 3 (FLT3) mutations are deemed one of few "actionable" mutations and include 30% of de novo AML cases (25% ITD, 5% TKD) (Garcia 2017; Fathi 2016). In 2017 there will be approximately 21000 new AML cases, roughly 6000 of these patients will be FLT3+ (ACS 2017). In line with prior research in melanoma elucidating the growing number of trials aimed at personalized medicine, we sought to identify the total number of therapeutic trials studying FLT3 inhibitors (Tang 2018). We analyzed the total number of FLT3+ patients required for recruitment to these trials to ensure successful completion compared to incidence of this molecular abnormality within the AML patient population.
Methods.A systematic review of therapeutic clinical trials focusing on adult FLT3+ AML from 2000-2017 was conducted using the PRISMA 2009 guidelines (Figure 1). We identified 78 therapeutic trials of FLT3 targeted therapies by cross-referencing ClinicalTrials.gov (66) and PubMed publications (12). Assuming constant accrual rate over the duration of each trial and constant rate of FLT3 mutations at 30% since 2000, statistical analysis was performed using the study start dates and primary completion dates of all trials from ClinicalTrials.gov. Incidence data was collected from the CDC, SEER database, and literature review (De Kouchkovsky 2016; ASCO 2018). Projections of discrepancies between anticipated clinical trial enrollment were provided using consistently cited rates of adult participation of 1%, 3% and 5% versus participant enrollment needed to satisfy current projected trends (Rinde 2018; Unger 2016).
Results. Twenty-four therapeutic FLT3 inhibitors being investigated were identified in 78 distinct clinical trials. Pharmaceutical versus cooperative group support was 2.23:1, with 29 different pharmaceutical sponsors and 13 cooperative group/non-profit/academic sponsors(Table 1). Thirty-eight (48.7%) trials/publications accrued in the US only, 21 (26.9%) at international sites only, 15 (19.2%) accrued in both the US and internationally, and 4 (5.1%) had no location listed at time of search. Only one study (NCT03258931) proposed a head-to-head comparison of midostaurin versus crenolanib.
The number of patients needed to satisfy enrollment began to surpass the upper bound of estimated participation in 2010, dropping slightly from 2013-2014 and noticeably surpassing projected participation rates from 2015-2016 (Figures 2 & 3). In 2017, approximately 21380 patients were diagnosed with AML, roughly 6414 were FLT3 positive. Assuming 5% participation rate, 320.7 FLT3 positive patients would be expected to enroll in clinical trials. However, the total number of patients needed to satisfy enrollment in 2017 was 1235; after excluding international and completed trials, the total number needed is 844.49 patients. Based on statistical analyses, we estimate that 13.2% of all US patients with FLT3 pos AML would have to enroll to satisfy eligibility in 2017; roughly 3 times the upper level of historical clinical trial participation rates in the US.
Conclusions. The current clinical trial process investigating targeted therapies in AML requires an unusually high and unsustainable enrollment, given the discrepancy between the incidence of AML patients with targetable mutations and the number of pharmaceutical agents being studied for these small patient populations. This discrepancy becomes even more startling when considering barriers to enrollment, including insurance market restrictions, geographical, socioeconomic, and demographic factors. Most of these trials do not compare available agents to identify the drug that may provide the most patient benefit. Whether this method of finding new therapies eventually leading to FDA approval continues to be sustainable or whether such duplicative trials dilute the valuable resource of AML patients with rare, targetable mutations, thus impeding development of the most effective therapeutic agents, must considered by the research and regulatory community.
Borate:Novartis: Consultancy; Agios: Consultancy.
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