P1-14-01: Randomized Phase II Trial of Weekly vs. q 2-Weekly vs. q 3-Weekly Nanoparticle Albumin-Bound Paclitaxel with Bevacizumab as First-Line Therapy for Metastatic Breast Cancer.

Abstract Background: Nanoparticle albumin-bound paclitaxel (nab-P) 260 mg/m2 is superior to paclitaxel 175 mg/m2 (P) every 3 weeks (Gradishar et al. JCO 2005) in metastatic breast cancer (MBC), and weekly uninterrupted P is more effective than q3wk P in MBC (Seidman et al. JCO 2008). Bevacizumab (bev) nearly doubles response rate and time to progression (TTP) when added to P as 1st line therapy for MBC (Miller et al. NEJM 2007). Methods: This open-label, phase II study randomized patients (pts) to nab-P at 260 mg/m2 q3wk (arm A) vs. 260 mg/m2 q 2wk with filgrastim (arm B) vs. 130 mg/m2 weekly uninterrupted (arm C), all with bev (15 mg/kg q 3 weeks arm A, 10 mg/kg q 2 weeks arms B and C). Patients were required to have measurable, HER2 negative MBC and no prior chemotherapy for MBC. The primary endpoints were response rate and toxicity. Results: Of 212 pts randomized, 208 (75 arm A, 54 arm B, 79 arm C) were treated, with balanced demographics and baseline characteristics. The median age was 57 (range 29–85), 82% were postmenopausal and 89% had visceral disease (64% lung, 50% liver). ECOG PS 0:60%, 1:35%, 2:5%. 62% had prior neo-adjuvant or adjuvant chemotherapy for early stage disease: anthracycline: 54%, taxane: 38%. No significant differences in confirmed complete and partial response rates were noted (A: 40%, B: 44%, C: 46%). Median TTP was longer in Arm C (9.0 months) versus both arms B (6.3 months) and A (8.0 months), overall p=0.065. There were no differences in overall survival (Arm A: 21.3 months, Arm B: 19 months, Arm C: 25.3 months). As per protocol-specified stopping rule, arm B was closed early due to an unacceptable safety profile with significantly more grade ≥ 2 fatigue (B:57%, A: 39%, C:39%, p=0.048) and bone pain (B:19%, A:10%, C:4%, p=0.024). Sensory neuropathy was common; grades 2/3/4: Arm A: 29%/32%/1%, Arm B: 15%/50%/2%, Arm C: 27%/43%/1%). Sensory neuropathy was commonly readily reversible with dose delay and reduction. Febrile neutropenia occurred in <2% of pts in all arms. Arm C patients experienced significantly less arthralgia compared with arms A and B, but dose delays were frequent (86% of pts) on this planned uninterrupted weekly schedule. Bevacizumab-related events were consistent with prior phase III trials of taxane/bev; there were no new safety signals. Conclusions: Significant and similar antitumor activity was observed in all arms. Weekly nab-P with bev (arm C) resulted in longer TTP. Weekly nab-P with bev (arm C) appears to have the highest therapeutic index, however sensory neuropathy is limiting, suggesting that a 3 week on/1 week off schedule could be preferable and should be studied comparatively. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-14-01.