Inefficiencies and Patient Burdens in the Development of the Targeted Cancer Drug Sorafenib: A Systematic Review

Abstract

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.

Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma

“…Notably, among the 10 common types of human cancers examined using archival specimens, the phenomenon of tumor nests surrounded by endothelial cells of sinusoidal vasculature has been found in HCC, renal cell carcinoma, and follicular thyroid carcinoma . Furthermore, sorafenib was approved by the U.S. Food and Drug Administration for advanced renal cell carcinoma in 2005, for advanced HCC in 2007, and for metastatic differentiated thyroid cancer in 2013 . Thus, it is plausible that a VETC‐like pattern may also be used to predict sorafenib efficacy in other types of cancer, such as renal cell carcinoma and follicular thyroid carcinoma.…”

Trials that say “maybe”: the disconnect between exploratory and confirmatory testing after drug approval

“…Of all monotherapy trials launched within five years of their US approval (n=132),78 we found 41 (31%) that met their primary efficacy endpoint with acceptable toxicity. Five of these trials were the basis of four recommendations for off-label use in clinical practice guidelines by the National Comprehensive Cancer Network (NCCN), an organisation whose guidelines in the US are used to set reimbursement policies.…”

“…But, for this system to work, early phase exploratory testing must be tightly coupled with late phase, confirmatory trials. Studies of clinical development78 indicate that drug companies and public funding agencies often generate prolonged clinical agnosticism, which can be sufficient to influence physicians and healthcare system decisions. Who could blame companies for not seeking to capitalise on this opportunity?…”

How well are Phase 2 cancer trial publications supported by preclinical efficacy evidence?

“…We accessed a convenience sample of eligible trial publications included in the Studies of Translation, Research, Ethics and Medicine (STREAM) laboratory database (this database contains all primary publications for Phase 2 trials, published from 2004 to 2016, for 12 anticancer drugs receiving first Food and Drug Administration [FDA] approval 2005–2007, of which six were classified as novel and included in our study; Table ). Search strategies for Embase and MEDLINE databases, as well as general search terms for drugs, are described elsewhere (also see Supporting Information Texts S1 and S2). Trial publications were included based on the following criteria: ( i ) primary report, ( ii ) final report, ( iii ) interventional trials, ( iv ) human subjects, ( v ) Phase 2, ( vi ) monotherapy clinical trial, ( vii ) began enrolment before FDA approval of the drug in the same indication as the trial and ( viii ) the primary endpoint was efficacy.…”