Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial

Abstract

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.

Fig. 1. CONSORT diagram.

FEC 5-fluorouracil, epirubicin, and cyclophosphamide. HER2 human epidermal growth factor receptor 2, tpCR total pathologic complete response.

Fig. 2. Kaplan–Meier plots of the long-term efficacy endpoints EFS and DFS.

a EFS in the ITT population and b DFS in all patients who underwent surgery. 95% CIs and p values (two-sided) for differences in event rates were from z-tests using the standard errors for the Kaplan–Meier estimates. CI confidence interval, DFS disease-free survival, EFS event-free survival, HR hazard ratio, ITT intention-to-treat.

Fig. 3. Kaplan–Meier plot of DFS according to tpCR in the ITT population with both treatment arms combined.

CI confidence interval, DFS disease-free survival, ITT intention-to-treat, tpCR total pathologic complete response.

Fig. 4. Subgroup analysis of DFS in the tpCR population.

CI confidence interval, DFS disease-free survival, tpCR total pathologic complete response.

Fig. 5. Subgroup analysis of DFS in the population with residual invasive disease.

CI confidence interval, DFS disease-free survival.

Fig. 6. Biomarker subgroup analysis of tpCR rates in the ITT population.

Boxes represent sample sizes and odds ratios; whiskers represent 95% CI; the vertical dotted line represents the odds ratio for all patients. CI confidence interval, HER2 human epidermal growth factor receptor 2, IHC immunohistochemistry, ITT intention-to-treat; mRNA, messenger RNA, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, PTEN phosphatase and tensin homolog, tpCR total pathologic complete response.