Neoadjuvant Treatment of Early Breast Cancer

A Conversation With FDA’s Office of Hematology and Oncology Products

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The totality of evidence—not just the magnitude of improvement in pathologic complete response rate—led us to approve pertuzumab for the neoadjuvant indication.

—Suparna Wedam, MD

INSIDE THE BLACK BOX is an occasional column providing insight into the FDA and its policies and procedures. In this first installment, FDA Clinical Reviewers Laleh Amiri-Kordestani, MD, and Suparna Wedam, MD, discuss FDA’s recent approval of pertuzumab (Perjeta) for the neoadjuvant treatment of HER2-positive, high-risk early breast cancer. Dr. Amiri and Dr. Wedam are Medical Officers with the Breast/Gynecologic Cancer Team in the Office of Hematology and Oncology Products.

On September 30, 2013, the U.S. Food and Drug Administration (FDA) granted accelerated approval to pertuzumab (Perjeta) for the neoadjuvant treatment of HER2-positive high-risk early breast cancer. Here Dr. Amiri and Dr. Wedam respond to questions about the processes leading to pertuzumab’s accelerated approval.

Evaluating Neoadjuvant Therapy

What is the rationale for neoadjuvant therapy for breast cancer?

Dr. Amiri: Neoadjuvant therapy for breast cancer was first developed to help make inoperable tumors operable and to increase the rate of breast conservation. Also, neoadjuvant trials provide a unique opportunity to study modulation of tumor biomarkers and have the potential to guide and improve the design of adjuvant trials.

Regimens that are given in the adjuvant setting are commonly used in the neoadjuvant setting, knowing that survival is similar whether chemotherapy is given before or after surgery.1 From a drug development perspective, using pathologic complete response rate as the primary endpoint is very appealing since it can be assessed relatively quickly.


Please explain the FDA’s view on evaluating new drugs in the neoadjuvant setting. Why is the agency interested in this?

Dr. Wedam: Typically, drug development is a lengthy and expensive process. Demonstration of an improvement in disease-free survival or overall survival for a new treatment for patients with early breast cancer in the adjuvant setting requires a large trial that takes many years to complete. Thus, pharmaceutical companies first test drugs in the metastatic setting, where endpoints can be obtained faster.

Despite many recent approvals in the treatment of metastatic breast cancer, the process of drug development for patients with early breast cancer—especially for high-risk or poor prognosis populations—has been slow. In the past decade, only one drug has been approved for this early breast cancer high-risk population.2


What is the FDA doing to help facilitate this process?

Dr. Amiri: FDA’s accelerated approval regulations are intended to facilitate availability of drugs for treatment of a serious or life-threatening disease that provide meaningful therapeutic benefit over available therapy.3 The agency would like to expedite the process and help patients with high-risk early breast cancer gain access to promising new agents earlier.4 To help facilitate the neoadjuvant drug development pathway, the FDA has released a draft guidance titled, “Guidance for Industry Pathologic Complete Response in Neoadjuvant Treatment of High Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval.”5

With the collaboration of many international groups, FDA conducted a pooled-analysis of many neoadjuvant breast cancer trials.6 Pathologic complete response was shown to correlate well with long-term outcome at a patient level, but not at a trial level. However, this analysis does not preclude the use of pathologic complete response to support an accelerated approval, because the effect sizes in the trials used in the analysis were relatively small. Once accelerated approval is granted based on pathologic complete response, confirmation of clinical benefit (eg, improvement in event-free, disease-free, or overall survival) is required in order to convert to a regular approval.

Surrogate Endpoint

The FDA facilitated a transparent, open discussion about using pathologic complete response as a surrogate endpoint to support accelerated approval for neoadjuvant treatment of early breast cancer. Can you tell us more about that?

Dr. Wedam: Since this is a new pathway, we felt it was important to have as much public dialogue as possible before finalizing the Guidance. FDA in conjunction with ASCO held a workshop in March 2013 to discuss drug development for neoadjuvant treatment of breast cancer.

We had a group of experts discuss issues regarding neoadjuvant therapy and the use of pathologic complete response as a surrogate endpoint. Ultimately, the experts felt that pathologic complete response was reasonably likely to predict clinical benefit and could be used to support accelerated approval of neoadjuvant therapy for use in patients with early breast cancer at high risk of relapse or death despite the best available therapies.

Key Studies

Can you describe the neoadjuvant studies that were submitted to support the pertuzumab approval?

Dr. Amiri: The main trial was NEOSPHERE, a randomized, multicenter, open-label trial of 417 patients with HER2-positive, operable, locally advanced, or inflammatory breast cancer who were randomly allocated to receive one of four neoadjuvant regimens prior to surgery as follows: trastuzumab (Herceptin) plus docetaxel; pertuzumab plus trastuzumab and docetaxel; pertuzumab plus trastuzumab; or pertuzumab plus docetaxel. Following surgery all patients received three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) intravenously every 3 weeks, and trastuzumab was administered intravenously every 3 weeks to complete 1 year of therapy. The study’s primary endpoint was pathologic complete response rate, defined as the absence of invasive cancer in the breast (ypT0/is).

An additional neoadjuvant phase II trial (TRYPHAENA) was conducted in 225 patients with HER2-positive, locally advanced, operable, or inflammatory breast cancer and was designed primarily to assess the cardiac safety of pertuzumab in different neoadjuvant regimens. Patients were randomly allocated to receive one of three neoadjuvant regimens prior to surgery as follows: three cycles of FEC followed by three cycles of docetaxel, all in combination with pertuzumab and trastuzumab; three cycles of FEC alone followed by three cycles of docetaxel and trastuzumab in combination with pertuzumab; or six cycles of docetaxel, carboplatin, and trastuzumab (TCH) in combination with pertuzumab. Following surgery all patients received trastuzumab intravenously every 3 weeks to complete 1 year of therapy.

ODAC Meeting

The FDA recently called a meeting of the Oncologic Drugs Advisory Committee (ODAC) to discuss pertuzumab’s use in the neoadjuvant setting. What were the main points of discussion raised by the ODAC?

Dr. Wedam: Several concerns with the application already apparent to us were raised during the ODAC discussion. These concerns included the uncertainty about whether an improvement in pathologic complete response rate would translate into long-term clinical benefit, the appropriate chemotherapy regimen to use with this targeted therapy, the appropriate duration of pertuzumab treatment, and the sequencing of chemotherapy. Additional concerns included an increased rate of cardiac toxicity with pertuzu­mab, the small size of the NEOSPHERE trial, the lack of patients from the United States, the lack of blinded pathology review, and the lack of prespecified pathology guidelines.

In the end, ODAC voted 13 to 0 with 1 abstention that pertuzumab has demonstrated a favorable risk-benefit profile for this indication. However, many members of the committee agreed with us that this should not be considered a precedent for approval of neoadjuvant treatments, but should be viewed instead as a unique situation due to the robust overall supportive data for pertuzu­mab.

These supportive data included a statistically significant and clinically meaningful improvement in overall survival from the metastatic breast cancer trial (CLEOPATRA) and extensive safety data with over 10,000 patients exposed to the drug at this time. Committee members also stated that completion of enrollment to the confirmatory adjuvant trial (APHINITY) increased their level of comfort with an accelerated approval.

Further Concerns

Several ODAC members expressed concern about how pertuzumab would be used in clinical practice, particularly since in the two neoadjuvant trials, pertuzu­mab was not given with the chemotherapy regimens commonly used in the United States. Is the FDA also concerned?

Dr. Amiri: Yes, we expressed our concern with the chemotherapy regimens, at the ODAC meeting. This was a concern we also had from the beginning. The backbone chemotherapy regimen used in the main study (NEOSPHERE) is seldom used in the United States. In addition, the splitting of the chemotherapy regimen before and after surgery is not typically done when neoadjuvant therapy is given.

The chemotherapy regimens in the supportive study (TRYPHAENA) were administered entirely prior to surgery; however, two of the treatment arms included FEC, which again is not commonly used in the United States. The third treatment arm in TRYPHAENA combined pertuzumab with the nonanthracycline regimen TCH, an FDA-approved regimen in widespread use in the United States.


What is the agency doing to address these concerns?

Dr. Wedam: In order to address these concerns, we asked the applicant to conduct a new trial as a postmarketing requirement, investigating the combination of pertuzumab with two different anthracycline-based treatment regimens in the neoadjuvant setting. The first arm is similar to the concurrent anthracycline (FEC) treatment arm in TRYPHAENA. This regimen would provide a treatment option for physicians who choose to use an anthracycline-based regimen but also would like to get HER2-targeted therapy started quickly.

The second arm will include dose-dense doxorubicin/cyclophosphamide followed by weekly paclitaxel (ddAC-T) with trastuzumab and pertuzumab. The ddAC-T regimen is widely used in the United States. Both treatment arms would continue trastuzumab and pertuzumab for 1 full year. Additional information will be obtained from the fully accrued adjuvant trial (APHINITY), which includes anthracycline and nonanthracycline regimens. Both of these trials will offer more information regarding the safety, optimal treatment regimens, and duration of treatment with pertuzumab.

Labeling Decision

How did you make the final decision regarding labeling given the concerns of the applicability of the chemotherapy regimens used in the trials?

Dr. Amiri: We chose to include the neoadjuvant regimens from the main experimental arm in NEOSPHERE and two of the treatment regimens from TRYPHAENA. The treatment regimen from NEOSPHERE isolates the effect of pertuzumab. The two treatment regimens from TRYPHAENA include TCH, which is an approved adjuvant regimen in the United States, and the sequential anthracycline (FEC) followed by docetaxel, trastuzumab, and pertuzumab regimen. The third regimen in the TRYPHAENA trial is not recommended because there are insufficient cardiac safety data to recommend concomitant administration of an anthracycline with pertuzumab at this time.

Importantly, two limitations of use were added to the label. These include the statements that safety has not been established with pertuzumab in combination with a doxorubicin-containing chemotherapy regimen and that safety of pertuzumab administration for more than six cycles in early-stage breast cancer has not been established. 7

Final Approval

Why did the FDA ultimately decide to approve pertuzumab for neoadjuvant treatment of early breast cancer?

Dr. Wedam: The totality of evidence—not just the magnitude of improvement in pathologic complete response rate—led us to approve pertuzumab for the neoadjuvant indication. In the main neoadjuvant study, NEOSPHERE, a statistically significant improvement in pathologic complete response rate of 17.8% (P = .0063) was observed in patients receiving pertuzumab plus trastuzumab and docetaxel compared to patients receiving trastuzumab plus docetaxel.

Supportive evidence of unprecedented efficacy in the metastatic setting demonstrates that pertuzumab is an active drug that could potentially contribute to treatment regimens intended to cure a larger number of women with HER2-positive early-stage breast cancer. In addition, there are extensive safety data and the confirmatory adjuvant trial has fully accrued.

This totality of evidence and status of the confirmatory trial are what we will be using to evaluate future applications that seek to use this approach for accelerated approval. ■

Disclosure: Drs. Amiri and Wedam reported no potential conflicts of interest.


1. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis. J Natl Cancer Inst 97:188-194, 2005.

2. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005.

3. U.S. Food and Drug Administration: About the accelerated approval regulations. Available at Accessed October 28, 2013.

4. Prowell TM, Pazdur R: Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med 366:2438-2441, 2012.

5. Guidance for Industry: Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. Available at Accessed October 28, 2013.

6. Cortazar P, Zhang L, Untch M, et al: Meta-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC). Cancer Res 72(24 suppl):S1-S11, 2012.

7. Drug approval package, Perjeta (pertuzumab) injection. Available at Accessed October 28, 2013.