FDA approvalsPerspective

FDA approves Perjeta for neoadjuvant breast cancer treatment

The FDA today granted accelerated approval to pertuzumab as part of a complete treatment regimen for patients with early-stage breast cancer in the neoadjuvant setting.

Pertuzumab (Perjeta, Genentech) was approved in 2012 for the treatment of patients with advanced or metastatic HER-2–positive breast cancer.

The FDA reviewed pertuzumab’s use for neoadjuvant treatment under the agency’s priority review program, which provides for an expedited review of drugs that may offer major advances in treatment.

The new designation is intended for patients with HER-2–positive, locally advanced, inflammatory or early-stage breast cancer (tumor >2 cm in diameter or with positive lymph nodes) who are at high risk for cancer metastasis or disease-related mortality.

Pertuzumab is intended to be used combined with trastuzumab (Herceptin, Genentech) and other chemotherapy prior to surgery and, depending upon the treatment regimen used, could be followed by chemotherapy after surgery. After surgery, patients should continue to receive trastuzumab to complete 1 year of treatment.

Richard Pazdur, MD 

Richard Pazdur

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

In May 2012, the FDA issued a draft guidance regarding the use of pathologic complete response, defined as the absence of invasive cancer in the breast and lymph nodes, as an endpoint to support accelerated approval of a drug for neoadjuvant treatment of high-risk, early-stage breast cancer. Under the FDA’s accelerated approval program, patients are provided access to promising drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted.

Pertuzumab’s accelerated approval for neoadjuvant treatment is supported by a study designed to measure pathologic complete response. In the study, 417 participants were randomly assigned to one of four neoadjuvant treatment regimens:

  • Trastuzumab plus docetaxel;
  • Pertuzumab plus trastuzumab and docetaxel;
  • Pertuzumab plus trastuzumab; and
  • Pertuzumab plus docetaxel.

About 39% of participants who received pertuzumab plus trastuzumab and docetaxel achieved pathologic complete response vs. about 21% who received trastuzumab plus docetaxel.

The confirmatory trial for this accelerated approval is being conducted in participants with HER-2–positive breast cancers who had prior breast cancer surgery and are at increased risk of having their cancer return. More than 4,800 participants are currently enrolled in this trial, which will provide further data on efficacy, safety and long-term outcomes.

The most common adverse effects reported in participants receiving pertuzumab combined with trastuzumab and docetaxel were hair loss, diarrhea, nausea and a decrease in infection-fighting white blood cells. Other notable adverse effects included anaphylaxis, decreased cardiac function, infusion-related reactions and hypersensitivity reactions.

The FDA today granted accelerated approval to pertuzumab as part of a complete treatment regimen for patients with early-stage breast cancer in the neoadjuvant setting.

Pertuzumab (Perjeta, Genentech) was approved in 2012 for the treatment of patients with advanced or metastatic HER-2–positive breast cancer.

The FDA reviewed pertuzumab’s use for neoadjuvant treatment under the agency’s priority review program, which provides for an expedited review of drugs that may offer major advances in treatment.

The new designation is intended for patients with HER-2–positive, locally advanced, inflammatory or early-stage breast cancer (tumor >2 cm in diameter or with positive lymph nodes) who are at high risk for cancer metastasis or disease-related mortality.

Pertuzumab is intended to be used combined with trastuzumab (Herceptin, Genentech) and other chemotherapy prior to surgery and, depending upon the treatment regimen used, could be followed by chemotherapy after surgery. After surgery, patients should continue to receive trastuzumab to complete 1 year of treatment.

Richard Pazdur, MD 

Richard Pazdur

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

In May 2012, the FDA issued a draft guidance regarding the use of pathologic complete response, defined as the absence of invasive cancer in the breast and lymph nodes, as an endpoint to support accelerated approval of a drug for neoadjuvant treatment of high-risk, early-stage breast cancer. Under the FDA’s accelerated approval program, patients are provided access to promising drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted.

Pertuzumab’s accelerated approval for neoadjuvant treatment is supported by a study designed to measure pathologic complete response. In the study, 417 participants were randomly assigned to one of four neoadjuvant treatment regimens:

  • Trastuzumab plus docetaxel;
  • Pertuzumab plus trastuzumab and docetaxel;
  • Pertuzumab plus trastuzumab; and
  • Pertuzumab plus docetaxel.

About 39% of participants who received pertuzumab plus trastuzumab and docetaxel achieved pathologic complete response vs. about 21% who received trastuzumab plus docetaxel.

The confirmatory trial for this accelerated approval is being conducted in participants with HER-2–positive breast cancers who had prior breast cancer surgery and are at increased risk of having their cancer return. More than 4,800 participants are currently enrolled in this trial, which will provide further data on efficacy, safety and long-term outcomes.

The most common adverse effects reported in participants receiving pertuzumab combined with trastuzumab and docetaxel were hair loss, diarrhea, nausea and a decrease in infection-fighting white blood cells. Other notable adverse effects included anaphylaxis, decreased cardiac function, infusion-related reactions and hypersensitivity reactions.

    Perspective
    Charles L. Vogel, MD, FACP

    Charles L. Vogel, MD, FACP

    Over the past 38 years, I have devoted my professional career to the practice of breast cancer-specific medical oncology. During these years of discovery, I personally feel the most exciting and compelling story began when Dennis Slamon, MD, PhD, recognized the unique clinical behavior of the HER-2/neu–positive variant of breast cancer. I have been fortunate to have participated in most of the clinical trials since about 1994 that have brought four molecules specifically targeting HER-2–positive disease into clinical practice.

    The recent FDA approval of pertuzumab, as the first agent ever approved for neoadjuvant use in selected breast cancer patients, is a welcome addition to its prior approval in the metastatic disease setting. This perspective was written in an attempt to very briefly mention some of the other neoadjuvant trials in this patient subset and to speculate on future developments in HER-2–directed therapies.

    There are other pertinent neoadjuvant trials that include dual blockade. Although the NeoSphere trial dealt with only single-agent docetaxel, the TRYPHAENA trial evaluated more aggressive chemotherapy regimens with pertuzumab and trastuzumab (Herceptin, Genentech). The pathologic complete response rates appeared even more impressive than the single-agent docetaxel trial; however, cross-trial comparisons are difficult to interpret. NeoSphere was presented in San Antonio at the same time as the Neo-ALTTO trial, which used chemotherapy with trastuzumab but with lapatinib (Tykerb, GlaxoSmithKline) instead of pertuzumab. The results were equally impressive in terms of efficacy in the Neo-ALTTO trial as in NeoSphere; however, there was a relatively high patient discontinuation rate in the Neo-ALTTO trial because of drug toxicity related to lapatinib.

    We now have approval for pertuzumab in the metastatic setting and the neoadjuvant setting. Moving forward, the APHINITY trial is a major adjuvant trial evaluating chemotherapy of different types with trastuzumab alone or trastuzumab plus pertuzumab. If that trial is positive, then the next step would be more widespread use of chemotherapy plus dual blockade with curative potential in the adjuvant setting.

    Although pertuzumab is already approved in metastatic disease , we’ve just finished the VELVET trial, in which a less-toxic chemotherapy, vinorelbine, was substituted for docetaxel with trastuzumab and pertuzumab. There are no overall results of this trial yet, but one of my patients has had a beautiful response of widespread liver metastases. The relative lack of toxicity of this regimen was noteworthy.

    Looking to the future, we now have trastuzumab, pertuzumab, lapatinib and ado-trastuzumab emtansine (Kadcyla, Genentech) approved as HER-2–targeting agents, with only pertuzumab approved to date outside of the metastatic disease setting. We’re anxiously awaiting results from the MARIANNE trial, which includes trastuzumab and docetaxel — the standard prior to the availability of pertuzumab — vs. ado-trastuzumab emtansine alone or in combination with pertuzumab.

    In several years, it’s very possible that the backbone of therapy for HER-2–positive disease could ultimately end up being ado-trastuzumab emtansine plus pertuzumab. However, at this time we don’t even have the results of MARIANNE in metastatic disease, nor any adjuvant ado-trastuzumab emtansine data to support this interesting concept. With the increasing use of these targeted agents in combination, it could even be that — for HER-2–positive disease, relatively nontoxic, chemotherapy-free regimens will dominate clinical care within this decade.

    • Charles L. Vogel, MD, FACP
    • Sylvester Comprehensive Cancer Center University of Miami

    Disclosures: Vogel reports past advisory roles with and research support from Amgen, AstraZeneca, Aveo, Bristol-Myers Squibb, Clarient, Genentech, GlaxoSmithKline, Merck Sharp Dome, Novartis and Roche.