Background: Non-epithelial gonadal tumours largely comprise sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Specific somatic mutations in DICER1, a microRNA maturation pathway gene, have been identified in these tumours. We conducted a study that aimed to confirm, refine and extend the previous observations.

Failure in cancer drug development exacts heavy burdens on patients and research systems. To investigate inefficiencies and burdens in targeted drug development in cancer, we conducted a systematic review of all prelicensure trials for the anticancer drug, sorafenib (Bayer/Onyx Pharmaceuticals). We searched Embase and MEDLINE databases on October 14, 2014, for prelicensure clinical trials testing sorafenib against cancers. We measured risk by serious adverse event rates, benefit by objective response rates and survival, and trial success by prespecified primary endpoint attainment with acceptable toxicity. The first two clinically useful applications of sorafenib were discovered in the first 2 efficacy trials, after five drug-related deaths (4.6% of 108 total) and 93 total patient-years of involvement (2.4% of 3,928 total). Thereafter, sorafenib was tested in 26 indications and 67 drug combinations, leading to one additional licensure. Drug developers tested 5 indications in over 5 trials each, comprising 56 drug-related deaths (51.8% of 108 total) and 1,155 patient-years (29.4% of 3,928 total) of burden in unsuccessful attempts to discover utility against these malignancies. Overall, 32 Phase II trials (26% of Phase II activity) were duplicative, lacked appropriate follow-up, or were uninformative because of accrual failure, constituting 1,773 patients (15.6% of 11,355 total) participating in prelicensure sorafenib trials. The clinical utility of sorafenib was established early in development, with low burden on patients and resources. However, these early successes were followed by rapid and exhaustive testing against various malignancies and combination regimens, leading to excess patient burden. Our evaluation of sorafenib development suggests many opportunities for reducing costs and unnecessary patient burden in cancer drug development.

The validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response to sorafenib monotherapy in any cancer published until April 20, 2012. We estimated effect sizes from experiments assessing changes in tumor volume and conducted subgroup analyses based on prespecified experimental design elements associated with internal, construct, and external validity. The meta-analysis included 97 experiments involving 1,761 animals. We excluded 94 experiments due to inadequate reporting of data. Design elements aimed at reducing internal validity threats were implemented only sporadically, with 66% reporting animal attrition and none reporting blinded outcome assessment or concealed allocation. Anticancer activity against various malignancies was typically tested in only a small number of model systems. Effect sizes were significantly smaller when sorafenib was tested against either a different active agent or combination arm. Trim and fill suggested a 37% overestimation of effect sizes across all malignancies due to publication bias. We detected a moderate dose-response in one clinically approved indication, hepatocellular carcinoma, but not in another approved malignancy, renal cell carcinoma, or when data were pooled across all malignancies tested. In support of other reports, we found that few preclinical cancer studies addressed important internal, construct, and external validity threats, limiting their clinical generalizability. Our findings reinforce the need to improve guidelines for the design and reporting of preclinical cancer studies.

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<p>Frequencies of captured time points per experiment. A) The last common time point (LCT) between control and treatment arms and B) the closest time point to day 14 after treatment initiation in the control arm. Filled bars in B) indicate standardized ({plus minus}3 days from day 14) common time points for dose-response analysis.</p>

<p>Coding details for internal validity categories in Table 2. Adapted from our previous meta-analysis of the drug, sunitinib (5).</p>

<p>PRISMA flow diagram.</p>