Neoadjuvant, Adjuvant Pertuzumab/Trastuzumab Regimen Continues to Have Clinical Benefit in Early or Locally Advanced HER2+ Breast Cancer

Neoadjuvant and adjuvant pertuzumab (Perjeta) plus trastuzumab (Herceptin) with docetaxel continued to show improvements in event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) vs trastuzumab/docetaxel and placebo in Asian patients with HER2-positive early or locally advanced breast cancer, according to long-term efficacy and safety data from the phase 3 PEONY trial (NCT02586025).

The findings, which were presented during the 2022 San Antonio Breast Cancer Symposium, revealed that the 5-year EFS rate in the pertuzumab/trastuzumab/docetaxel arm (n= 175) was 84.8% vs 73.7% in the placebo arm (n= 82; HR, 0.53; 95% CI; 0.32-0.89; P = .027). Three-year EFS rates were 88.9% and 79.7% in the pertuzumab and placebo arms, respectively (P = .043).

The 5-year disease free survival (DFS) rates were 86.0% and 75.0% in in the pertuzumab and placebo arms (HR, 0.52; 95% CI; 0.30-0.88; P = 0.028). The 3-year DFS rates were 90.1% and 81.1%, respectively. 

Additionally, the 5-year OS rates were 93.9% in the combination arm and 90.0% for the trastuzumab/placebo arm (HR, 0.53; 95% CI, 0.23-1.19; P = .053). The OS rate at 3 years was 97.0% for the combination arm and 91.0% for the placebo arm.

“In this 5-year follow up of the PEONY trial, long-term efficacy end points EFS and DFS showed a clinically meaningful improvement with neoadjuvant and adjuvant pertuzumab plus trastuzumab and docetaxel, with favorable OS results [although the number of events were low in both arms],” lead study author Zhimin Shao, MD, said in a poster presentation on the data.

Previous data from the phase 2 NEOSPHERE trial (NCT00545688), which compared pertuzumab/trastuzumab and docetaxel with trastuzumab/docetaxel, resulted in an increased pathologic complete response.2 The multicenter, double-blind, placebo-controlled, phase 3 PEONY trial evaluated the same regimen in an Asian population. Earlier findings from PEONY showed that the triplet regimen improved pathologic complete response vs trastuzumab/docetaxel alone.³

To be eligible for enrollment, patients had to be at least 18 years old with centrally confirmed HER2-positive disease, with tumors were greater than 2 cm. Additional criteria were known hormone receptor status and an ECOG performance status of 0 or 1, with a baseline left ventricular ejection of at least 55%.

Patients were randomized 2:1 to either receive the combination 840 mg loading dose of pertuzumab and a 420 mg dose every 3 weeks, 8 mg/kg loading of trastuzumab and a 6 mg/kg dose every 3 weeks, and 75 mg/m² of docetaxel once every 3 weeks, or placebo every 4 weeks plus the same trastuzumab and docetaxel dosing, all for 4 cycles until surgery. This was followed by an 840-mg loading dose of pertuzumab and a 420-mg dose every 3 weeks with an 8-mg/kg loading dose of trastuzumab and a 6-mg/kg dose every 3 weeks for 13 cycles. The placebo arm post surgery was comprised of the same trastuzumab dose and placebo given once every 3 weeks. All drugs were administered intravenously.

“HER2-targeted therapy was administered until disease progression, disease recurrence, or unacceptable toxicity for up to 1 year,” Shao added.

The primary end point was pCR; EFS, DFS, and OS were secondary end points.

Regarding safety, the combination of pertuzumab plus trastuzumab with docetaxel led to more frequent diarrhea and upper respiratory tract infections. However, there was similar incidences of grade 3 or higher adverse effects (AEs) in both arms, with the most common being neutropenia, leukopenia, and febrile neutropenia. Serious AEs included febrile neutropenia, myelosuppression, and pneumonia.

Both significant left ventricular ejection and death were low on both arms, though no primary cardiac events occurred during the study periods.

“The PEONY trial adds to the totality of data reinforcing the long-term clinical benefit of adjuvant and neoadjuvant pertuzumab plus trastuzumab with docetaxel in patients with HER2-positive early breast cancer,” Shao concluded.

References

1. Shao Z, Pang D, Yang H, et al. Final analysis of the phase III PEONY trial: long-term efficacy and safety of neoadjuvant–adjuvant pertuzumab or placebo, plus trastuzumab and docetaxel, in patients with HER2-positive early or locally advanced breast cancer. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract PD18-03.
2. Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1)25-32. Doi:10.1016/S1470-2045(11)70336-9
3. Shao Z, Pang D, Yang H, et al. Efficacy, safety, and tolerability of pertuzumab, trastuzumab, and docetaxel for patients with early or locally advanced ERBB2-positive breast cancer in Asia: the PEONY phase 3 randomized clinical trial. JAMA Oncol. 2020;6(3):e193692. doi:10.1001/jamaoncol.2019.3692