Dose-Dense iddEPC Demonstrates Significant Benefits in HR+/HER2- Breast Cancer

Andreas Schneeweiss, MD

Neoadjuvant chemotherapy (NACT) with intense dose-dense epirubicin (Ellence), paclitaxel (Taxol), and cyclophosphamide (Cytoxan) (iddEPC) demonstrated significant benefit in the treatment of patients with HR+/HER2- breast cancer, according to data from a secondary endpoint review that were presented at the 2020 ESMO Virtual Congress.

As well as comparing iddEPC to weekly paclitaxel and liposomal doxorubicin (PM) in patients with high-risk early breast cancer, the GeparOcto trial (NCT02125344) examined the addition of carboplatin in patients with triple negative breast cancer (TNBC).

In an earlier readout, the primary endpoint of pathological complete response was found to be comparable in all groups, including TNBC and high-risk early breast cancer subgroups (pCR; ypT0/is ypN0).

In the review presented at ESMO, researchers reported on the secondary endpoints of invasive disease-free survival (iDFS) and overall survival (OS).

To achieve these findings, a total of 961 patients were first stratified by breast cancer subtype:

• HR+/HER2- versus HER2-/HR- versus HER2+/HR+/-
• Ki67 at baseline (less than or equal to 20% versus greater than 20%), and
• lymphocyte-predominant breast cancer (LPBC)

Patients were then separated into two groups and received either nine cycles of intensified dose dense epirubicin (150 mg/m2) followed by paclitaxel (225 mg/m2) followed by cyclophosphamide (2000 mg/m2), every two weeks, or weekly paclitaxel (80 mg/m2) plus liposomal doxorubicin (20 mg/m2) for 18 weeks.

Patients with TNBC also received carboplatin (AUC 1.5) weekly.

In both treatment arms, patients with HER2+ breast cancer additionally received trastuzumab (Herceptin) (6 [loading dose 8]mg/kg every two weeks) and pertuzumab (420 [840]mg every three weeks) concurrently with each paclitaxel and carboplatin cycle.

Adjuvant locoregional and endocrine therapy were administered according to German national guidelines.

Between December 2014 and June 2016, a total of 945 patients started receiving treatment (iddEPC, n=470; PM(Cb), n=475).

Investigators planned to evaluate both secondary endpoints as time-to-event endpoints, with iDFS to be performed at 169 events to detect a hazard ratio (HR) of 0.65 with 80% power. However, due to the COVID-19 pandemic, follow-up analysis was performed at 162 events, to detect the HR of 0.65, with only 2% less power than initially planned, according to lead author Andreas Schneeweiss, MD.

After a median follow-up of 47 months, 162 iDFS events were reported, the majority of which were distant relapses (47 in the iddEPC versus 51 in the PM(Cb) arm) and invasive locoregional relapses (18 versus 24).

Additionally, 79 deaths were reported (41 in the iddEPC arm and 38 in the PM(Cb) arm).

Overall, investigators found no difference in iDFS (HR PM(Cb) to iddEPC, 1.16; 95% CI, 0.85-1.59; P=.3357) or OS (HR, 0.90; 95% CI, 0.58-1.40; P =.6371) between both arms. Four-year iDFS was 81.9% following iddEPC versus 79.7% in PM(Cb), while OS after 4 years was 90.6% and 90.3% respectively.

In the subgroup of HR+/HER2- breast cancer, iDFS was significantly longer for iddEPC (4-year iDFS 62.5% with PM vs.77.9% with iddEPC; HR, 2.11; 95% CI, 1.08-4.10; P =0.0284), which indicated a benefit in OS (4-year OS 80.1% vs. 94.7%; HR, 3.26; 95% CI, 1.06-10.00; P =.0388).

There was no significant difference in survival in HER2+ or TNBC.

In an exploratory analysis, researchers found that in patients with a higher likelihood of relapse following neoadjuvant chemotherapy based on their CPS-EG score, those with HR+/HER2- breast cancer were 3.5 times more likely to experience an iDFS event following weekly PM(Cb) compared to those who received iddEPC.

Despite the lack of evidence of improved survival following NACT with iddEPC or PM(Cb) in any group, patients with HR+/HER2- breast cancer had a better iDFS with treatment with iddEPC, which Schneeweiss said supports the idea that neoadjuvant chemotherapy could have an additional effect in patients with luminal-like, HER2-negative breast cancer. These benefits could be possibly due to the inclusion of cytotoxic agent cyclophosphamide.

“Cyclophosphamide might play an important role in adjuvant treatment of patients with high risk, HR+/HER2- breast cancer, maybe due to an immunogenic long-term effect, not indicated by pCR and CPS-EG score,” said Schneeweiss.

Reference

Schneeweiss A, Möbus V, Tesch H, et al. Survival analysis of the randomized phase III GeparOcto trial comparing neoadjuvant chemotherapy (NACT) of iddEPC versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer, TNBC) (PM(Cb)) for patients (pts) with high-risk early breast cancer (BC). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 160O.