EC Approves Neoadjuvant Pertuzumab Regimen for HER2-Positive Early Breast Cancer

Sandra Horning, MD

Sandra Horning, MD

Pertuzumab (Perjeta), in combination with trastuzumab (Herceptin) and chemotherapy, was approved by the European Commission (EC) as a neoadjuvant therapy for adult patients who have HER2-positive, locally advanced, inflammatory, or early stage breast cancer and are at high risk of recurrence.

The decision was based on an improvement in pathological complete response (pCR) with the pertuzumab triplet compared with other regimens in the phase II NeoSphere trial, marking the first approval based on this endpoint by the EC.

In a 5-year analysis of the phase II study presented at the 2015 ASCO Annual meeting¹the 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.

“Today’s approval is a significant milestone in the neoadjuvant treatment of HER2-positive early breast cancer, bringing Perjeta to patients years earlier than typical adjuvant treatment,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Roche, said in a statement. “We are committed to making the Perjeta regimen available to appropriate patients in the EU as early as possible.”

The phase II NeoSphere 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 a 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks, and docetaxel was administered at 75 mg/m², escalating, if tolerated, to 100 mg/m²every 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 disease-free survival (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.

“Treating breast cancer early, before it has spread, may help prevent the disease from returning or reaching an advanced stage,” Horning said, when the findings were presented. “These new results add to the body of data for Perjeta in the neoadjuvant setting.”

The EC decision for the pertuzumab regimen was also supported by evidence from the TRYPHAENA and CLEOPATRA trials. In TRYPHAENA,²225 patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer were evenly randomized to three neoadjuvant regimens. The primary endpoint of the trial was cardiac safety with a secondary endpoint of pCR. However, this trial was not adequately powered to compare each arm.

The first arm of trial received pertuzumab, trastuzumab, and anthracycline-based chemotherapy, followed by pertuzumab, trastuzumab, and docetaxel with a pCR of 56.2%. Patients in the second arm received anthracycline-based chemotherapy, followed by pertuzumab, trastuzumab, and docetaxel with a pCR of 54.7% with left ventricular dysfunction occurring in 4% of patients. The final group received pertuzumab, trastuzumab, docetaxel, and carboplatin with a pCR of 63.6%.

In the United States, the combination of pertuzumab, trastuzumab, and chemotherapy was granted an accelerated approval by the FDA in September 2013 for patients at high risk for metastases or death with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer. This decision was based on an earlier assessment of the NeoSphere trial and TRYPHAENA study.

The FDA initially approved pertuzumab in 2012 based on results from the phase III CLEOPATRA trial in which 808 patients with HER2-positive metastatic breast cancer were randomized to receive pertuzumab and trastuzumab plus docetaxel versus trastuzumab plus docetaxel and a placebo as first-line treatment.

In this trial, the median overall survival was 40.8 months in the placebo arm and 56.5 months in the pertuzumab arm. The median PFS was 18.7 months with pertuzumab compared with 12.4 months in the control group (HR=0.68;P<.0001).³

For the EC and FDA, approvals for the pertuzumab regimen are contingent on data from the ongoing phase III APHINITY study, which is assessing the triplet in the adjuvant setting for patients with HER2-positive early breast cancer. Further data on efficacy, safety and long-term outcomes from this trial are expected in 2016.

References:

1. &nbsp;&nbsp; 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).&nbsp;J Clin Oncol. 2015;33 (suppl; abstr 505).

2. &nbsp;&nbsp; Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).&nbsp;Ann Oncol.Published online ahead of print May 22, 2013. doi:10.1093/annonc/mdt182.

3. &nbsp;&nbsp; Swain S, Ro J, Campone M. Final overall survival analysis from the Cleopatra study of first-line pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. Presented at: the 2014 Congress of the European Society of Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract 350O&shy;_PR.