GeparSepto Trial Demonstrates Improved Survival in High-Risk Early Breast Cancer With Nab-Paclitaxel

Andreas Schneeweiss, MD

In findings from the phase III GeparSepto trial presented during the 2017 San Antonio Breast Cancer Symposium, long-term disease-free survival (DFS) rates were improved with neoadjuvant nab-paclitaxel (Abraxane) compared with standard paclitaxel in patients with high-risk early breast cancer. With a median follow-up of 49 months, patients randomized to nab-paclitaxel in the GeparSepto trial had significantly higher DFS rate compared with those who received paclitaxel, with a hazard ratio of 0.69 (95% CI, 0.54-0.89; P= .0044).

The 3-year DFS rate was 87.1% with nab-paclitaxel, compared with 80.7% in patients randomized to paclitaxel, for an absolute difference of 6.4%. The absolute improvement in 4-year DFS was 7.3%; the rate with nab-paclitaxel was 83.5% versus 76.2% with conventional paclitaxel.¹

The GeparSepto study was conducted at 69 cancer centers by the German Breast Group from July 2012 through December 2013. Investigators previously reported that the substitution of nab-paclitaxel for solvent-based paclitaxel significantly increased the rate of pathologic complete response (pCR) overall by 9%, from 29% to 38% (P<.001).²The largest absolute improvement in pCR with nab-paclitaxel (P<.001), occurred in patients with triple-negative breast cancer (TNBC).

Andreas Schneeweiss, MD, who presented the updated findings at SABCS, said that nab-paclitaxel is so effective that 16 patients would have to be treated with the drug instead of solvent-based paclitaxel in order to prevent 1 DFS event within the first 3 years. &ldquo;This number...is important because so far, 61% of the DFS events that have occurred in GeparSepto are distant relapses,&rdquo; he said.

During the trial, 1200 patients with high-risk nonmetastatic early breast cancer were randomized to either 12 weekly cycles of solvent-based paclitaxel at 80 mg/m², or 12 weekly cycles of nab-paclitaxel at 150 mg/m², each followed by 4 cycles of epirubicin/cyclophosphamide. After enrollment of 464 patients at a preplanned safety interim analysis, the dosage of nab-paclitaxel was reduced to 125 mg/m²with the goal of scaling back the rate of neuropathy associated with the initial randomized dosage. &ldquo;After this dose reduction, grade 3/4 neuropathy rate dropped from 15% to 8%,&rdquo; said Schneeweiss.

In addition to chemotherapy, all patients with HER2-positive disease received dual antibody treatment with trastuzumab (Herceptin) at a loading dose of 8 mg/kg followed by 6 mg/kg, and pertuzumab (Perjeta), given as an 840-mg loading dose followed by 420 mg. Following surgery, all patients received standard adjuvant local and systemic treatment according to German breast cancer guidelines.

The main eligibility criteria were unilateral or bilateral primary breast cancer with a clinical stage of T2 to T4, including inflammatory breast cancer or a clinical stage T1c plus 1 additional high-risk factor, which included axillary node involvement, estrogen receptor (ER)- and progesterone receptor (PR)-negative disease, a baseline level of Ki-67 greater than 20%, or HER2 overexpression.

Patient and tumor characteristics were well balanced between the 2 treatment arms. Median age at baseline was 49 years. The median tumor size was 30 mm, 45.7% had axillary node involvement, 69.1% had a Ki67 level greater 20%, and 54.5% had a grade 3 breast cancer. &ldquo;It means we clearly enrolled high-risk patients,&rdquo; said Schneeweiss. Some 22.9% of the overall cohort had TNBC and 44.3% had HR-positive/HER2-negative disease.

When DFS was stratified by breast cancer subtype, the improvement with nab-paclitaxel was about 10% at 3 years and at 4 years in patients with TNBC, for an HR of 0.66 that did not quite achieve significance (P= .0694), most likely due to the low number of events, he said. The effect was nearly the same in patients with HR-positive/HER2-negative disease, who had improvements in their 3-year and 4-year DFS of about 8%, for a HR of 0.71 (P= .660).

The improvement in DFS with nab-paclitaxel was homogenous by subgroup, including biological subtype, HER2 status, ER/PR status, and low versus high Ki-67. The interaction test for Ki-67 was significant, &ldquo;which suggests that nab-paclitaxel generates a long-term benefit in tumors with lower proliferation,&rdquo; Schneeweiss said.

The overall survival data are not mature, with no difference between groups after a total of 133 deaths.

&ldquo;GeparSepto confirms the surrogate value of pCR for survival. Patients who achieved a pCR regardless of whether they received nab-pac or solvent-based pac had an improved and favorable disease-free and overall survival,&rdquo; Schneeweiss said.

Patients who did not achieve a pCR had a significantly better DFS when they had received nab-paclitaxel compared with paclitaxel. &ldquo;This interesting finding, if it is real, argues for effect of nab-pac on DFS beyond its effect on the improvement of pCR,&rdquo; Schneeweiss noted.

References

1. Schneeweiss A, Jackisch C, Schmatloch S, et al. Survival analysis of the prospectively randomized phase III GeparSepto trial comparing neoadjuvant chemotherapy with weekly nab-paclitaxel with solvent-based paclitaxel followed by anthracycline/cyclophosphamide for patients with early breast cancer—GBG69. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS3-05. abstracts2view.com/sabcs/view.php?nu=SABCS17L_943&terms=
2. Untch M, Jackisch C, Schneeweiss A, et al; German Breast Group (GBG); Arbeitsgemeinschaft Gyn&auml;kologische Onkologie—Breast (AGO-B) Investigators.Lancet Oncol.2016;17(3):345-356. doi: 10.1016/S1470-2045(15)00542-2.