Phase III Trial Shows Adjuvant Pertuzumab Reduces Recurrence in HER2-Positive Breast Cancer

Gunter von Minckwitz, MD

Gunter von Minckwitz, MD

Adding pertuzumab (Perjeta) to trastuzumab (Herceptin) and chemotherapy reduced the risk of recurrence of invasive disease or death (invasive disease-free survival; iDFS) in patients with HER2-positive early breast cancer in the phase III APHINITY study, according to Genentech, the manufacturer of the monoclonal antibody.

There were no new safety signals reported for the pertuzumab regimen. The complete results of the study will be presented this year at an upcoming medical meeting. Genentech collaborated on the trial with the Breast International Group (BIG), Breast European Adjuvant Study Team (BrEAST) and Frontier Science Foundation (FS).

“APHINITY provides yet another example of the importance of industry-academic collaborations and their value in advancing cancer care for people affected by this challenging disease,” Gunter von Minckwitz, MD, study coordinator from BIG, managing director of the German Breast Group, and an associate professor and senior physician at University Women’s Hospital in Frankfurt, said in a statement.

APHINITY is the confirmatory trial for the September 2013 accelerated approval of pertuzumab for use in combination with trastuzumab and docetaxel as a neoadjuvant treatment for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer.

“These results from the positive APHINITY study represent an important addition to the body of data for Perjeta in the treatment of people with HER2-positive early breast cancer,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, said in a statement. “We look forward to discussing these adjuvant results with global regulatory authorities.”

The phase III double-blind, placebo-controlled APHINITY trial randomized 4805 patients with operable HER2+ early breast cancer in a 1:1 ratio to adjuvant treatment with trastuzumab plus chemotherapy (anthracycline or non-anthracycline-containing regimen) with or without pertuzumab. The study accrued both lymph-node—positive and –negative patients.

The pertuzumab arm received 6 to 8 cycles of chemotherapy with pertuzumab and trastuzumab, followed by pertuzumab and trastuzumab alone every 3 weeks for a total of 1 year of therapy. The control arm received the same treatment schedule, with placebo replacing pertuzumab.

At the end of adjuvant chemotherapy, patients could start receiving radiotherapy and/or endocrine therapy. The primary endpoint was iDFS, with secondary endpoints including cardiac and overall safety, overall survival, disease-free survival (DFS), and health-related quality of life.

The neoadjuvant approval of pertuzumab was primarily based on the phase II NeoSphere trial. In a 5-year analysis of the trial presented at the 2015 ASCO Annual meeting the pathologic complete response (pCR) rate was 39.3% for the pertuzumab regimen compared with 21.5% with trastuzumab and chemotherapy alone (P = .0063). Additionally, the risk of disease progression or recurrence was reduced by 31% and 40%, respectively, with the addition of pertuzumab to trastuzumab and chemotherapy compared with trastuzumab and chemotherapy alone.

The phase II trial evenly randomized 417 patients with newly diagnosed HER2-positive early-stage breast cancer to one of four treatment arms: trastuzumab plus docetaxel (n = 107, group A), pertuzumab and trastuzumab plus docetaxel (n = 107, group B), pertuzumab plus trastuzumab (n = 107, group C), or pertuzumab plus docetaxel (n = 96, group D).

In arms with pertuzumab, the agent was administered at a loading dose of 840 mg followed by 420 mg every 3 weeks. Trastuzumab was delivered at an 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks, and docetaxel was administered at docetaxel 75 mg/m², escalating, if tolerated, to 100 mg/m² every 3 weeks. Treatment was delivered for 4 cycles.

Patients that received pertuzumab and trastuzumab plus docetaxel experienced a significant improvement in pCR of 39.3%. The pCR rate was 21.5%, 11.2%, and 17.7%, for groups A, C, and D, respectively.

The 5-year progression-free survival (PFS) rate was 86% with the pertuzumab, trastuzumab, and docetaxel regimen (95% CI, 77-91) compared with 81% (95% CI, 71-87), 73% (95% CI, 64-81), and 73% (95% CI, 63-81), for groups A, C, and D, respectively. The hazard ratio for PFS for arm A versus B was 0.69 (95% CI, 0.34-1.00).

The 5-year DFS findings were 81%, 84%, 80%, and 75%, in the A, B, C, and D arms, respectively. The DFS hazard ratio for arm A versus B was 0.60 (95% CI, 0.28-1.27).

The most common severe grade ≥3 adverse events (AEs) for pertuzumab, trastuzumab, and docetaxel were neutropenia (44.9%), febrile neutropenia (8.4%), leukopenia (4.7%) and diarrhea (5.6%). Left ventricular dysfunction (LVD) was higher in the pertuzumab containing arms. Across all arms, all-grade LVD and congestive heart failure rates were 1.9%, 8.4%, 3.7%, and 7.4% in arms A, B, C, and D, respectively.

The FDA initially approved pertuzumab in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Gianni L, Pienkowski T, Im Y-H, et al. Five-year analysis of the phase II NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D) and/or trastuzumab (T) and/or pertuzumab (P). J Clin Oncol. 2015;33 (suppl; abstr 505). The Lancet Oncology. 2017;18(2):241-250. doi:10.1016/s1470-2045(16)30632-5.