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Adding Pertuzumab to Trastuzumab Shows Benefits in Early HER2-Positive Breast Cancer

By Anita Shaffer
PUBLISHED THURSDAY, JANUARY 1, 1970
Gunter von Minckwitz, MD, PhD

Gunter von Minckwitz, MD, PhD

The addition of pertuzumab (Perjeta) to standard postoperative trastuzumab (Herceptin) therapy for patients with HER2-positive early breast cancer slightly improved the rate of recurrence overall but had a greater benefit for individuals with higher-risk disease, particularly as more time elapsed, according to early results from the phase III APHINITY trial.

The findings suggest that the dual HER2 targeting strategy in early-stage adjuvant settings should be stratified by risk level, experts said while discussing the results at the 2017 ASCO Annual Meeting.

The APHINITY findings demonstrated that patients who received adjuvant pertuzumab along with trastuzumab plus chemotherapy had an invasive disease-free survival (IDFS) rate of 94.1% after 3 years’ follow-up versus 93.2% for those who received trastuzumab plus chemotherapy and placebo (HR, 0.82; 95% CI, 0.67-1.00). In all, 4805 patients participated in the study.

The benefit was more pronounced among higher-risk subgroups, with the curve widening over time. After a follow-up of 4 years, the IDFS rate for patients with node-positive disease was 89.9% with pertuzumab versus 86.7% with standard therapy (HR, 0.77; 95% CI, 0.62-0.96; P = .019). For participants with hormone receptor (HR)–negative disease, the IDFS rate with pertuzumab was 91.0% after 4 years compared with 88.7% in the control group (HR, 0.76; 95% CI, 0.56-1.04; P = .085)

“These are very early results, but given that the absolute benefit from adding pertuzumab was modest, we should consider using it primarily in women with the highest risk—those with node-positive and hormone receptor-negative breast cancer,” said lead study author Gunter von Minckwitz, MD, PhD, said in a statement.

Von Minckwitz, who is president of the German Breast Group in Neu-Isenburg, Germany, said the study met its primary endpoint by exceeding a preset threshold for reducing the risk of an IDFS event. He said the pertuzumab-containing regimen reduced the risk of developing invasive breast cancer by 19%. After a median follow-up of 45.4 months, 7.1% (n = 171) in the pertuzumab group had developed invasive breast cancer, compared with 8.7% (n = 210) in the standard therapy group (HR, 0.81; 95% CI, 0.66-1.00; = .045).

The number of patients needed to treat to achieve benefit was 112 for the study overall, 63 in the HR-negative subgroup, and 56 in the node-positive subgroup.

The APHINITY trial results represent “a step forward in the treatment of HER2-positive breast cancer,” said ASCO expert Harold J. Burstein, MD, PhD, FASCO, during a presscast on June 5, where the findings were discussed. “The relatively narrow benefits in numerical terms that you are seeing reflect the overall good prognosis.”

Burstein, an associate professor at the Dana-Farber Cancer Institute, said the prognosis for HER2-positive breast cancer had evolved “from worst to first” in the 12 years since adjuvant trastuzumab was first shown to improve disease-free survival for patients with HER2-positive breast cancer. “Because of that success, when you look at data from studies like the APHINITY trial, the boats have been raised very high.”

In translating the potential for the dual HER2 regimen into clinical practice in early breast cancer, Burstein said the strategy seems most beneficial in the subgroups where it showed more activity but not for patients with stage I disease where the risk of recurrence is less than 5%.

“In the management of HER2-positive breast cancer, we really are seeing 2 diverging strands,” Burstein said. “For low-risk, particularly stage I tumors, there’s a lot of talk about de-escalating regimens, finding biologically driven regimens, and sparing patients longer durations of treatment or extra medicines and, on the other extreme for higher-risk cases, demonstrating that additional anti-HER2 therapy will help lower the risk of recurrence.”

Rationale for APHINITY Trial

Pertuzumab and trastuzumab are monoclonal antibodies that target HER2 activity by different mechanisms of action. Pertuzumab targets the HER2 dimerization domain, blocking its interaction with other HER family members including EGFR, HER3, and HER4, while trastuzumab inhibits proliferation of HER2-overexpressing tumor cells.

The FDA has approved pertuzumab in combination with trastuzumab and docetaxel as neoadjuvant therapy for patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (>2 cm or node positive). The combination also is approved for HER2-positive metastatic disease.

The APHINITY trial sought to determine whether the addition of pertuzumab would improve outcomes in the adjuvant setting. The study recruited patients with T1-3 HER2-positive early breast cancer who had undergone mastectomy or lumpectomy. Overall, 63% of the participants had node-positive disease, and 36% had HR-negative disease.
Participants were randomized to receive adjuvant chemotherapy for 18 weeks and 1 year of either pertuzumab plus trastuzumab (n = 2400) or trastuzumab plus placebo (n = 2405). A choice between several standard anthracycline-taxane sequences or a nonanthracylcine (TCH) regimen was permitted. Additionally, patients could receive radiotherapy and/or endocrine therapy after the end of adjuvant chemotherapy.

Von Minckwitz said the addition of pertuzumab did not significantly increase cardiotoxicity, which can be a worrisome adverse event with anti-HER2 therapy. The primary cardiac endpoint was heart failure, defined as New York Heart Association class III/IV failure plus a drop in left ventricular ejection fraction (≥10% from baseline and to <50%). Heart failure was reported in 17 patients (0.7%) in the pertuzumab-containing arm versus 8 participants in the standard therapy group (0.3%). Approximately half of the patients in each group recovered, and there were 2 cardiac deaths in each arm.

Diarrhea of grade ≥3 severity was more common with the pertuzumab-containing therapy, affecting 9.8% of patients in the safety analysis versus 3.7% of those who received standard therapy. Von Minckwitz said the incidence of diarrhea occurred predominantly during chemotherapy and more frequently among patients who were administered TCH.

The APHINITY study was funded by Hoffmann-La Roche Ltd, which is developing pertuzumab and trastuzumab along with Genentech, a member of the Roche Group.
von Minckwitz G, Procter MJ, De Azambuja E, et al. APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC). J Clin Oncol. 2017;35(suppl; abstr LBA500).
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