Correlation between progression-free survival and overall survival in metastatic breast cancer patients receiving anthracyclines, taxanes, or targeted therapies: a trial-level meta-analysis

Abstract

Over the past decade, several new drugs have received regulatory approval for metastatic breast cancer (MBC). However, some of these approvals were based on improvement in progression-free survival (PFS), without a concomitant increase in overall survival (OS). This has led some to question the utility of using PFS as a measure for drug approval. To address the uncertainty of using PFS as a surrogate for OS in MBC, a systematic literature review followed by a trial-level correlative analysis was conducted in patients receiving anthracyclines, taxanes, or targeted therapies. Electronic databases were searched to identify randomized trials published between January 1990 and August 2015. Data extraction included hazard ratios for PFS (HRPFS) and OS (HROS) between comparative arms as well as trial-level parameters. Weighted multivariate regression analysis was then used to test the strength of the association between HRPFS and HROS. 72 trials providing 84 comparative arms met the inclusion criteria. HRPFS was a significant predictor of HROS (model coefficient = 0.18, p = 0.04). However, only 31 % (i.e., model R2) of the variability between the PFS–OS association was accounted for. When trials were limited to ≥2nd-line setting, the strength of the association improved (model coefficient = 0.40, p < 0.001) and the model R2 increased to 55 %. However, the HRPFS–HROS association was no longer significant when only 1st-line trials were considered (p = 0.90). HRPFS is a predictor for HROS in MBC randomized trials. However, the effect was driven by trials in the ≥2nd-line setting. Therefore, PFS can be a suitable surrogate for OS in trials evaluating new treatments in the 2nd setting and beyond. The use of PFS alone as a primary trial endpoint in the 1st-line setting is not recommended.

Real‐life activity of eribulin mesylate among metastatic breast cancer patients in the multicenter national observational ESME program

“…Overall, our results are highly consistent with the results of the two pivotal randomized studies of EM in MBC, reporting a significant and meaningful impact on OS and marginal impact on PFS, and no significant difference in the early therapeutic lines. These results are surprising, as it is generally assumed that PFS could be used as a surrogate endpoint for OS, but that a significant increase in PFS is required to increase OS. Nevertheless, our results, that is, a modest effect on PFS and a greater impact on OS, are extremely consistent with all previously reported comparative data of EM use in MBC .…”

Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors

“…An FDA‐sponsored meta‐analysis of more than 12,000 patients receiving therapy in randomized clinical trials for lung cancer performed between 2003 and 2014 found no clear association between PFS and OS . Associations between PFS and OS in recent trials of patients with advanced breast cancer or ovarian cancer have also been inconsistent .…”

“…Since then, several novel therapies have been approved for use in patients with advanced NET based on their ability to slow tumor progression. The mammalian target of rapamycin (mTOR) inhibitor everolimus and the tyrosine kinase inhibitor sunitinib both improve PFS in pancreatic NET; everolimus was also recently confirmed to improve PFS in nonpancreatic NET . Although these randomized studies clearly demonstrated improvements in PFS, they did not show clear improvements in OS, although the number of deaths in these studies was relatively low at the time of data analysis .…”

Phosphatidylinositol 3-kinase (PI3Kα)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells

“…Modern cancer therapies for breast cancer include chemoterapeutic, anti-hormonal and molecular agents [ 6 – 9 ]. Different classes of chemoterapic agents are currently approved for treatment of metastatic BC: antracylines, anti-mitotic agents (including taxanes, vinorelbine, eribulin), alkylating agents (such as cisplatin and carboplatin) and anti-metabolites (5-fluorouracile, capecitabine, and gemcitabine) [ 7 – 9 ].…”