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TANIA trial: efficacy and safety of continued or reintroduced Bevacizumab after first-line Bevacizumab for HER2-negative locally recurrent / metastatic breast cancer


Combining Bevacizumab ( Avastin ) with first- or second-line chemotherapy in randomised phase III trials showed significantly improved progression-free survival in HER2-negative locally recurrent / metastatic breast cancer.
Sustained VEGF blockade may be important for long-term disease control.

The open-label randomised phase III TANIA study evaluated further Bevacizumab in Bevacizumab-pretreated locally recurrent / metastatic breast cancer.

The study results were presented at ESMO Congress.

Patients with HER2-negative locally recurrent / metastatic breast cancer who had progressed during / after greater than or equal to 12 weeks of first-line Bevacizumab plus chemotherapy were randomised 1:1 to second-line single-agent chemotherapy either alone or with Bevacizumab ( 15 mg/kg q3w or 10 mg/kg q2w ).

Stratification factors were: hormone receptor status; time to first-line progression ( less than 6 vs greater than or equal to 6 months ); chemotherapy choice ( taxane vs non-taxane vs Vinorelbine ); and LDH concentration ( less than or equal to 1.5 vs more than 1.5 × upper normal limit ).

Second-line therapy was continued until disease progression, unacceptable toxicity or consent withdrawal. At disease progression, patients in the chemotherapy arm received thirrd-line chemotherapy without Bevacizumab ( no crossover ); patients initially randomised to chemotherapy plus Bevacizumab received third-line chemotherapy plus Bevacizumab.

Chemotherapy options were based on investigator’s choice, but doublets were not allowed: Paclitaxel, Nab-paclitaxel, Docetaxel, Capecitabine, Gemcitabine, Pegylated liposomal Doxorubicin, non-pegylated liposomal Doxorubicin, Doxorubicin, Epirubicin, Vinorelbine, Cyclophosphamide, Ixabepilone and in 3rd line only Eribulin.

The primary endpoint was progression-free survival from randomisation to second disease progression / death. Additional endpoints included second-line progression-free survival in prespecified subgroups, second- and third-line progression-free survival calculated from randomisation to third disease progression / death, second-line objective response rate, overall survival, safety, quality of life ( QoL ) and biomarkers.

Sample size was calculated based on assuming prolonging median progression-free survival from 7 to 9.3 months and a hazard raio of 0.75.
PFS events were required in 384 of 488 patients for 80% power at 2-sided alpha=0.05.

At ESMO 2014, the investigators presented the mature pre-specified second-line PFS analysis. Endpoints relating to third-line therapy will be presented at the final analysis.

During the period 2011-2013, 494 patients were enrolled ( 247 in chemotherapy arm and 247 in chemotherapy plus Bevacizumab arm ).
Baseline characteristics were similar in chemotherapy vs chemotherapy plus Bevacizumab groups: median age 54 vs 56 years; triple negative disease 23.1% vs 19.8%; disease-free interval less than or equal to 12 months 9.7% vs 7.3%.

The most frequently chosen second-line chemotherapy was Capecitabine, 59.7% in chemotherapy group and 60.4% in the chemotherapy plus Bevacizumab group.

Median follow-up was similar in both groups. At data cut-off on 20 December 2013, median second-line progression-free survival was 4.2 months in chemotherapy vs 6.3 months in chemotherapy plus Bevacizumab groups ( stratified HR = 0.75, p = 0.0068 ).
Subgroup analysis for progression-free survival by stratification factor was also more favourable for the Bevacizumab / chemotherapy grooup.

The best objective response ratewas not statistically different in two groups ( 16.8% vs 20.9% ). However, the stable disease was recorded in 33.5% patients in the chemotherapy arm and 48.9% in the Bevacizumab/chemotherapy arm.

Median duration of response was 10.6 vs 8.3 months for chemotherapy and Bevacizumab / chemotherapy paients.

The rate of side effects was slighlty higher in the chemotherapy / Bevacizumab arm: hypertension ( 7.1% vs 13.5% ); proteinuria ( 0.4% vs 6.9% ); venous thromboembolic event ( 2.1% vs 3.3% ); febrile neutropaenia ( 1.7% vs 3.3% ); congestive heart failure ( 0.4% vs 2.0% ); bleeding ( 1.7% vs 0.4% ); arterial thromboembolic event ( 1.3% vs 0% ); wound-healing complication ( 0% vs 0.8% ); gastrointestinal perforation ( 0% vs 0.4% ); and fistula / abscess ( 0% in both groups ).

The authors concluded that the primary objective of the study was met, showing statistically significantly improved progression-free survival with Bevacizumab after disease progression on first-line Bevacizumab-containing therapy.
Second-line safety results were as expected from previous Bevacizumab trials in locally recurrent/metastatic breast cancer. ( Xagena )

Source: ESMO Congress, 2014

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