FDA Approves Neoadjuvant Pertuzumab Regimen

Richard Pazdur, MD

Pertuzumab (Perjeta) in combination with trastuzumab and chemotherapy has become the first FDA-approved neoadjuvant treatment for patients with breast cancer. The pertuzumab-based regimen was specifically approved to treat patients at high risk for metastases or death with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer. Following surgery, patients may still be eligible to receive additional chemotherapy and should continue to receive trastuzumab for one year.

The approval was based on results from the phase II NeoSphere trial, which showed that pertuzumab, a HER dimerization inhibitor, combined with the HER2 inhibitor trastuzumab and the chemotherapy docetaxel, significantly improved pathologic complete response (pCR) when compared with three other neoadjuvant regimens. An approval based on pCR, defined as the absence of invasive cancer in the breast and lymph nodes, is only available under the FDA's accelerated approval program.

“We are seeing a significant shift in the treatment paradigm for early stage breast cancer,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or prevent cancer recurrences.’’

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 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 45.8% (95% CI, 36.1-55.7), compared to 29% (95% CI, 20.6-38.5), 24% (95% CI, 15.8-33.7), and 16.8% (95% CI, 10.3-25.3), for groups A, D, and C, respectively.

The most common grade 3 or higher side effects observed in the pertuzumab and trastuzumab plus docetaxel arm were neutropenia (48 of 107), febrile neutropenia (9 of 107), and leukopenia (5 of 107). The number of serious adverse events was similar in groups A, B, and D but was much lower in group C, which did not receive chemotherapy.

In addition to the NeoSphere trial, data from the phase II TRYPHAENA study and the Phase III CLEOPATRA study were submitted in support of the approval. Based on the results of these trials, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 13-0 with one abstention in support of the regimen at a hearing in mid-September.

In the TRYPHAENA study, 225 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 third arm, common grade 3 or higher adverse events were neutropenia (46.1%), febrile neutropenia (17.1%), and anemia (17.1%).

“A new approval pathway has made Perjeta available to people with HER2-positive early breast cancer several years earlier than previously possible,” said Hal Barron, MD, chief medical officer and head, Global Product Development. “Together with the FDA, we’ve charted new territory. We look forward to working with health authorities around the world to explore additional ways to bring promising medicines to patients more quickly.”

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, progression-free survival was 18.5 months with pertuzumab compared with 12.4 months in the control group (HR=0.62; 95% CI, 0.51-0.75, P < .001).

The FDA mandated confirmatory phase III APHINITY trial is in progress and has enrolled more than 4,800 patients with HER2-positive early stage breast cancer. This trial is comparing pertuzumab, trastuzumab, and chemotherapy with trastuzumab and chemotherapy as an adjuvant treatment. Further data on efficacy, safety and long-term outcomes from this trial are expected in 2016.