Abstract
The approval of a new drug for cancer treatment by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is based on positive, well-designed randomized phase III clinical trials (RCTs). However, not all of them are analyzed to support the recommendations. For this reason, there are different scales to quantify and evaluate the quality of RCTs and the magnitude of the clinical benefits of new drugs for treating solid tumors. In this review, we discuss the value of the progression-free survival (PFS) as an endpoint in RCTs and the concordance between it and the overall survival (OS) as a measure of the quality of clinical trial designs. We summarize and analyze the different scales to evaluate the clinical benefits of new drugs such as the The American Society of Clinical Oncology value framework (ASCO-VF-NHB16) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the concordance between them, focusing on metastatic colorectal cancer (mCRC). We propose several definitions that would help to evaluate the quality of RCT, the magnitude of clinical benefit and the appropriate approval of new drugs in oncology.
Highlights
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RCTs—randomized clinical trials; CYT—cytotoxic therapy; TA—targeted agents; IT—immunotherapy; HT—hormone therapy; ND—not described; NE—not evaluated; European Medicines Agency (EMA)—European Medical Agency; Food and Drug Administration (FDA)—Food and Drug Agency. * % of drugs approved by EMA or FDA that fulfills ESMO-MCBS or American Society of Clinical Oncology (ASCO)-value framework (VF) criteria. ** % ESMO-MCBS analyzed in palliative trials. *** % analyzed with adapted ESMO-MCBS
We propose several definitions that would help to evaluate the quality of RCT and the magnitude of clinical benefit
Summary
Despite the clear definition of events for PFS (Progression Free Survival) (i.e., first of progression or death), the definition to objectively censor patients for PFS is more obscure. Targeted agents can alter intrinsic biological characteristics such as consensus molecular subtypes (CMS) at the time of progressive disease [14] and modify clinical (ECOG PS) or tumor biology status (LDH (Lactate dehydrogenase), PAL (alkaline phosphatase)) that potentially can affect PPS This is of special importance because these characteristics are usually not recorded in RCTs and potentially can influence PFS and OS. The superior limit of the ratio should ideally be less than 0.9 to guarantee that a benefit in PFS can be translated to a minimum benefit for OS To assess these controversial results, we focused on the slope regression line between PFS and OS and rHR = HRPFS/HROS in 11 studies in first-line therapy comparing doublets with or without bevacizumab [4] and doublets with or without anti-EGFR agents [6] (see Table 2).
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