Hope S. Rugo, MD
Treatment with nab-paclitaxel (Abraxane) showed promising improvements in overall survival (OS) and progression-free survival (PFS) compared with standard paclitaxel for patients with metastatic triple-negative breast cancer (TNBC), according to post-hoc findings from the CALGB 40502/NCCTG N063H trial presented at the 2017 San Antonio Breast Cancer Symposium (SABCS).
For those with TNBC in the phase III trial (n = 201), the median OS with nab-paclitaxel was 21.0 months compared with 15.3 months with standard paclitaxel, representing a 26% reduction in the risk of death. Given the limitations of the post-hoc assessment, these findings were not powered for statistical significance, explained lead investigator Hope S. Rugo, MD. The hazard ratio for the comparison was 0.74 (95% CI, 0.51-1.07).
In patients with hormone receptor (HR)-positive disease (n = 546), standard paclitaxel remained superior to nab-paclitaxel. The median OS with paclitaxel was 33.2 months compared with 26.6 months with nab-paclitaxel (HR, 1.25; 95% CI, 0.99-1.58). Similar findings were seen for PFS in each of the subtypes.
"In this post-hoc subset analysis, there was significant interaction with receptor status between nab-paclitaxel and paclitaxel for PFS and OS. In triple-negative breast cancer, there is a suggestion of improved PFS and OS with nab-paclitaxel compared with paclitaxel," Rugo, from the University of California, San Francisco, said during her presentation of the results. "Further investigation is required to explain and validate the subtype specificity seen in this exploration."
The phase III trial randomized 799 patients between 2008 and 2011 to receive paclitaxel (n = 283), nab-paclitaxel (n = 271), or ixabepilone (n = 245). Most patients also received concurrent bevacizumab (98%), as it was approved for breast cancer when the study was initiated. Nab-paclitaxel was given at a higher-than-approved dose of 150 mg/m2
weekly. Paclitaxel was administered at 90 mg/m2
and ixabepilone was administered at 16 mg/m2
Baseline characteristics were well-balanced across arms. Overall, 44% of patients had received adjuvant treatment with a taxane before entering the trial with a disease-free interval of >2 years for 56% of patients. Most patients in the study had visceral metastases (78%) and 25% had triple-negative breast cancer. At the time of the analysis for SABCS, the median follow-up was 5.5 years.
Across the full study, the median PFS with paclitaxel was 10.8 months compared with 9.2 months with nab-paclitaxel (HR, 1.13; 95% CI, 0.94-1.34; P
= .16). The median OS was 27.1 months with paclitaxel and 24.2 months with nab-paclitaxel (HR, 1.10; 95% CI, 0.91-1.33; P
= .33). The ixabepilone arm, which was closed early due to futility, was inferior across all efficacy measures.
For those with TNBC, the median PFS was 6.4 months with paclitaxel and 7.4 months with nab-paclitaxel (HR, 0.79; 95% CI, 0.55-1.12). In the HR-positive group, the median PFS was 12.2 months with paclitaxel and 9.6 months with nab-paclitaxel (HR, 1.29; 95% CI, 1.04-1.59). Response rates were similar by subtype. For those with TNBC, the objective response rate (ORR) was 38%, 32%, and 33% for paclitaxel, nab-paclitaxel, and ixabepilone, respectively. In the HR-positive group, the ORRs were 40%, 46%, and 25% across the 3 groups.
Similar findings were seen in multivariate models for OS and PFS for the superiority of nab-paclitaxel in TNBC. In this analysis, there was a significant interaction demonstrated between paclitaxel and nab-paclitaxel with hormone receptor status for OS (P
= .0073) and PFS (P
= .0018). For PFS the hazard ratio for HR-negative disease was 0.71, favoring nab-paclitaxel (95% CI, 0.51-1.00; P
= .052). For OS, the hazard ratio in the HR-negative arm was 0.73 in favor of nab-paclitaxel versus paclitaxel (95% CI, 0.51-0.85; P
Overall, grade ≥3 adverse events (AEs) were experienced by 84% of those in the nab-paclitaxel arm versus 60% in the paclitaxel group. Grade ≥3 hematologic AEs were experienced by 55% of patients in the nab-paclitaxel arm compared with 22% for the paclitaxel group. Additionally, grade ≥3 sensory neuropathy occurred in 27% of those treated with nab-paclitaxel and grade ≥3 motor neuropathy occurred in 10% compared with 18% and 3% for paclitaxel, respectively.
The dose was modified for 68% of patients in the nab-paclitaxel arm compared with 42% in the paclitaxel group. In most instances, the dose was reduced to 125 mg/m2
. Additionally, 26% of patients discontinued treatment with nab-paclitaxel due to AEs.
"Adverse events, discontinuations, and dose reductions were more frequent with weekly nab-paclitaxel dosed as 150 mg/m2
. This dose should not be further used in patients with breast cancer," said Rugo. "GeparSepto also suggested improved efficacy in TNBC with less toxicity and similar pCR rates with 125 mg/m2
Nap-paclitaxel is approved across several indications. For those with breast cancer, the agent is indicated after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. The recommended dose for this indication is 260 mg/m2
every 3 weeks; however, in other disease settings, nab-paclitaxel is approved at 125 mg/m2
on days 1, 8, and 15 of each 28-day cycle.
Rugo HS, Barry WT, Moreno-Aspitia A, et al. Long-term follow-up of CALGB 40502/NCCTG N063H (Alliance): A randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-Paclitaxel (NP) or ixabepilone (Ix) +/- bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer (MBC). Presented at: the 2017 San Antonio Breast Cancer Symposium; Dec. 5-9, 2017. Abstract GS3-06.