Hot TopicEvolving options for the treatment of metastatic breast cancer: Progression-free survival as an endpoint
Introduction
Overall survival (OS) remains the gold standard measure of clinical efficacy when evaluating experimental chemotherapy regimens for cancer.1 The advantage of OS is that it is of direct clinical relevance to the patient. Furthermore, OS is an objective endpoint, whereas other endpoints such as response rate and progression free survival may be influenced by methods of evaluation and the drug schedules used, and may be biased by the knowledge of therapy.2
This review discusses the use of OS as a primary endpoint, particularly in the metastatic setting, and considers PFS as an alternative endpoint. PFS, TTP and OS data from recent, large, randomized trials of novel single agent or combination regimens for the treatment of patients with MBC are compared.
Section snippets
Obstacles to the interpretation of OS
A number of challenges exist in achieving an accurate assessment of survival in the randomized clinical trial setting. As the median survival for metastatic breast cancer is relatively long, patients who do not respond to one therapy are often well enough to go onto another regimen. Thus, at the time of disease progression, study participants with advanced breast cancer are able to switch to another active non-experimental treatment after coming off study. These subsequent treatments, which are
Surrogate endpoints for survival: PFS and TTP
Given these challenges, investigators in oncology have begun to evaluate alternative clinical trial endpoints that better reflect the small gains that contribute positively to the quality of life of patients with previously treated MBC. PFS and TTP have become common primary endpoints in clinical trials, and the US Food and Drug Administration (FDA) has accepted both as surrogate endpoints for accelerated approval in cancer trials. PFS is defined as the time from randomization until objective
Chemotherapy trials showing TTP and OS benefit
A small number of randomized phase III clinical trials were able to demonstrate significant improvements in both TTP and OS in MBC (Table 1A).[8], [9], [10], [11], [12], [13] These have included trials of taxanes as single agents or in combination with anthracyclines, gemcitabine, or capecitabine.
A head-to-head comparison of q3 weekly single agent docetaxel (100 mg/m2) vs. paclitaxel (175 mg/m2) in patients with MBC whose disease had progressed after anthracycline therapy (N = 449) showed that
Survival outcomes in MBC – progression free vs. overall
A recent analysis of phase III treatment trials in patients with advanced breast cancer (75 trials; 159 trial arms; N = 28,973) indicated that OS increased in trials of first-line hormone-based therapy and decreased with subsequent lines of any type of treatment. For trials of first-line chemotherapy (with or without targeted agents) and hormone therapy (with or without chemotherapy), the median OS was 20.7 and 31.1 months, respectively. With trials of second-line chemotherapy and hormone therapy,
Conclusions
Although OS remains the gold standard for assessing efficacy, there is a need for more practical outcome measures. PFS and TTP are commonly used primary endpoints in MBC, but are not yet validated surrogates for overall survival in this setting. In heavily pretreated MBC in particular, significant PFS improvements may indicate a clinically meaningful benefit for patients with otherwise limited salvage therapy options available. Powering studies to detect significant OS increases may not be
Conflict of interest
The author receives research funding from Genentech/Roche and is on the Speakers Bureau for BMS.
Acknowledgements
The author takes full responsibility for the content of this publication and confirms that it reflects her viewpoint and medical expertise. The author also wishes to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editing support. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the author receive financial compensation for authoring the manuscript.
References (48)
- et al.
Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature
Ann Oncol
(2010) - et al.
Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial
Lancet Oncol
(2007) - et al.
HER2/neu expression correlates with vascular endothelial growth factor-C and lymphangiogenesis in lymph node-positive breast cancer
Ann Oncol
(2010) - et al.
Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis
Lancet Oncol
(2006) - Food and Drug Administration. Guidance for Industry. Clinical Trial Endpoints for the Approval of Cancer Drugs and...
- et al.
Overall survival is not a realistic end point for clinical trials of new drugs in advanced solid tumors: a critical assessment based on recently reported phase III trials in colorectal and breast cancer
J Clin Oncol
(2003) - et al.
Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193)
J Clin Oncol
(2003) - et al.
Final efficacy and safety results of a randomized phase II study of the PARP inhibitor iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple negative breast cancer (TNBC)
Ann Oncol
(2010) - et al.
Issues in using progression-free survival when evaluating oncology products
J Clin Oncol
(2009) - et al.
The role of the US food and drug administration review process: clinical trial endpoints in oncology
The Oncologist
(2010)
Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer
J Clin Oncol
Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre
J Clin Oncol
Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial
J Clin Oncol
Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-Line therapy for women with advanced breast cancer: long-term analysis of the previously published trial
Onkologie
Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results
J Clin Oncol
Gemcitabine plus Paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment
J Clin Oncol
For the Early Breast Cancer Trialists’ Collaborative Group University of Oxford. The worldwide overview: new results for systemic adjuvant therapies
Breast Cancer Res Treat
Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial
J Clin Oncol
Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer
J Clin Oncol
Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study
J Clin Oncol
Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment
J Clin Oncol
Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes
Breast Cancer Res Treat
Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane
J Clin Oncol
A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane
J Clin Oncol
Cited by (17)
Issues surrounding clinical trial endpoints in solid malignancies with a focus on metastatic non-small cell lung cancer
2012, Lung CancerCitation Excerpt :Meta-analyses have addressed whether PFS constitutes an appropriate surrogate for OS [16–19]. In advanced colorectal cancer, PFS has been shown to be an acceptable surrogate for OS, as supported by several meta-analyses [15,20–22]. Conversely, on the basis of a meta-analysis of 66 randomized studies conducted across various metastatic tumor types, it was concluded that PFS reflects the effect of a drug on tumor growth during the time period of administration and is not a surrogate for OS [23].
Overall survival with ribociclib plus fulvestrant in advanced breast cancer
2020, New England Journal of MedicineOverall survival with ribociclib plus endocrine therapy in breast cancer
2019, New England Journal of Medicine