Final OS Findings Reported For TURANDOT Bevacizumab-Based Chemotherapy Regimens

The primary endpoint of the TURANDOT trial finds no significant difference in stratified overall survival between patients given bevacizumab plus capecitabine and those given bevacizumab with paclitaxel

medwireNews: The final overall survival (OS) analysis of TURANDOT supports the use of bevacizumab plus capecitabine as a first-line therapy for select patients with HER2-negative locally recurrent or metastatic breast cancer.

The phase III open-label trial indicates that bevacizumab plus capecitabine offers “good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel”, the investigators report in The Lancet Oncology.

Median OS for the per-protocol population was 26.1 months for the 265 patients given the capecitabine regimen (bevacizumab 15 mg/kg on day 1 of a 3-week cycle plus capecitabine 1000 mg/m2 twice daily on days 1–14) versus 30.2 months for the 266 patients given the paclitaxel regimen (bevacizumab 10 mg/kg on days 1 and 15 of a 4-week cycle plus paclitaxel 90 mg/m2 on days 1, 8 and 15).

This gave a nonsignificant hazard ratio (HR) of 1.02 – meeting the primary objective criteria for noninferiority of bevacizumab plus capecitabine – when patients were stratified by oestrogen and progesterone receptor status, country and menopausal status.

However, Christoph Zielinski, from Medical University Vienna in Austria, and co-authors note that the unstratified COX analysis gave a significant HR of 1.13 for OS in favour of bevacizumab plus paclitaxel.

Intention-to-treat analyses were “consistent” with these per-protocol findings, they write, but admit that “[c]rossover to the opposite chemotherapy regimen in almost half of the patients could have contributed to the absence of overall survival benefit detected in TURANDOT”.

The author of an accompanying editorial agrees on this possible explanation and notes that bevacizumab has been associated with normalisation of tumour vasculature and possible improved uptake of chemotherapy, while discontinuation has been reported to be followed by “rapid re-establishment of neoangiogenesis”.

“Would bevacizumab continued during second-line therapy and beyond have resulted in a potential overall survival benefit to bevacizumab plus paclitaxel in TURANDOT?”, writes Adam Brufsky, from the University of Pittsburgh in Pennsylvania, USA.

“We cannot answer this, although several clinical trials are currently in progress to address this question.”

Progression-free survival (PFS) results at the final TURANDOT analyses indicated a significant benefit with the paclitaxel regimen, with a stratified HR of 1.32.

Exploratory Cox analysis of 526 female patients, taking into consideration prognostic factors associated with poorer OS, such as ECOG performance status, and interactions detected between treatment regimen and both body surface area and menopausal status, indicated there was no overall significant OS difference between the bevacizumab combinations.

But for postmenopausal women with a body surface area below 1.8 m2, the capecitabine regimen offered a significant OS benefit (HR=0.74), whereas for premenopausal women with a body surface area of 1.8 m2 or larger, the paclitaxel regimen was superior (HR=2.63)

“Our exploratory analyses provide no definitive answers on the importance of body surface area and menopausal status in relation to first-line bevacizumab-containing therapy for HER2-negative metastatic breast cancer, but these observations generate interesting hypotheses”, the study authors comment.

Recommending further research into these associations, they conclude that when choosing between the two regimens, “physicians might consider body surface area and menopausal status (taking into account the limitations of these exploratory analyses), together with better established risk factors, the individual's treatment priorities (the relative importance of progression-free survival, the likelihood of achieving an overall response, and overall survival), and the effect on patients' quality of life because of the differing safety profiles and administration routes and schedules.”

References

Zielinski C, Láng I, Inbar M, et al. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol 2016; Advance online publication 5 August. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30154-1

Brufsky A. Is there room for bevacizumab in metastatic breast cancer? Lancet Oncol 2016; Advance online publication 5 August. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30295-9

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