by Dr. C.H. Weaver M.D. updated 1/2020
The US Food and Drug Administration (FDA) granted approval to Perjeta (pertuzumab) for use in combination with Herceptin (trastuzumab) and chemotherapy as treatment for patients with HER2-positive breast cancer in the adjuvant, neoadjuvant and metastatic setting because it improves outcomes and delays recurrence when compared to treatment with Herceptin alone. (1-5)
Breast cancer is the second leading cause of cancer-related death among women. This year an estimated 226,870 women will be diagnosed with breast cancer, and 39,510 will die from the disease. Approximately 20-25 percent of breast cancers over-express (make too much of) the human epidermal growth factor receptor 2 (HER2), which is part of a biological pathway involved in growth and spread of cancer cells.
HER2-targeted therapies such as Herceptin and Perjeta have dramatically improved outcomes for women with HER2-positive breast cancer and several newer HER2-targeted therapies have further improved outcomes and expanded treatment option.
Perjeta Approved for the Treatment of Advanced HER2 Breast Cancer
The FDA has approved Perjeta® (pertuzumab) for the treatment of HER2-positive, metastatic breast cancer. The drug is approved for use in combination with Herceptin® (trastuzumab) and docetaxel chemotherapy in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Perjeta is given intravenously and targets a different part of the HER2 protein than Herceptin. Since the two drugs target different regions of HER2, they are believed to work in a way that is complementary to each other.
The approval was based on data from an international, phase III, randomized, double-blind, placebo-controlled study that involved 808 patients with HER2-positive metastatic breast cancer. Patients were randomly assigned to receive Perteja/Herceptin/docetaxel or Herceptin/docetaxel/placebo. The results indicated that patients who received the combination of Perjeta/Herceptin/docetaxel lived longer without their cancer getting worse—median progression-free survival (PFS) in the Perjeta group was 18.5 months compared to 12.4 months in the placebo group.
The drug was reviewed under the agency’s priority review program, which allows an expedited six-month review of drugs that may offer major advances in treatment. (1)
Perjeta is given intravenously and targets the HER2 protein. It was approved in 2012 for the treatment of patients with advanced or late-stage (metastatic) HER2-positive breast cancer. Its new use is intended to be used in combination with Herceptin® and other chemotherapy prior to surgery and, depending upon the treatment regimen used, may be followed by chemotherapy after surgery.
The most common side effects reported in participants receiving Perjeta are
- Hair loss
- A decrease in infection-fighting white blood cells.
- Other significant side effects included decreased cardiac function, infusion-related reactions, hypersensitivity reactions and anaphylaxis and peripheral neuropathy (numbness or tingling in the extremities).
Perteja will include a Boxed Warning, which will alert patients and physicians to the potential risk of death or severe defects to a fetus. It is imperative to confirm a negative pregnancy status prior to starting treatment with Perjeta.
Perjeta in Early Stage Breast Cancer
Approval of Perjeta for early stage breast cancer was based on data from the APHINITY multi-center, clinical trial performed in 4804 patients with HER2-positive early stage breast cancer who had their primary tumor removed by surgery. Patients were then treated with either Perjeta or placebo, in combination with adjuvant Herceptin and chemotherapy.
In the current trial patients were followed for evidence of invasive disease-free survival (IDFS) – defined as the time to first occurrence of cancer recurrence, development of a contralateral invasive breast cancer, or death from any cause.
After a median follow-up of 45.4 months, the proportion of IDFS events was 7.1% for Perjeta compared to 8.7% (n=210) for those receiving placebo. High-risk patients included patients such as those with hormone receptor negative or those with node positive breast cancer. The proportion of IDFS events in patients with hormone receptor negative disease was 8.2% for Perjeta compared to 10.6% for placebo. The proportion of IDFS events for patients with node positive disease was 9.2% for Perjeta and 12.1% for placebo. Overall survival data are not yet mature. (2)
Perjeta Approved for Neoadjuvant Treatment of Early Stage HER2-Positive Breast Cancer
The U.S. FDA granted accelerated approval to Perjeta® for the neoadjuvant treatment of early stage breast cancer before surgery. This is the first drug approved for the neoadjuvant treatment of breast cancer.
Perjeta is given intravenously and targets the HER2 protein. It was approved in 2012 for the treatment of patients with advanced or late-stage (metastatic) HER2-positive breast cancer. Its new use is intended for patients with HER2-positive, locally advanced, inflammatory or early stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of having their cancer return or spread or of dying from the disease. It is to be used in combination with Herceptin® and other chemotherapy prior to surgery and, depending upon the treatment regimen used, may be followed by chemotherapy after surgery. Following surgery, patients should continue to receive Herceptin to complete one year of treatment.
The approval was based on data from a study that included 417 patients who were randomly assigned to receive one of four neoadjuvant treatment regimens: Hercpetin plus docetaxel; Perjeta plus Herceptin and docetaxel; Perjeta plus Herceptin; or Perjeta plus docetaxel. About 39 percent of patients who received Perjeta plus Herceptin and docetaxel achieved a complete disappearance of their cancer at surgery compared with about 21 percent who received Herceptin plus docetaxel. (3)
A confirmatory trial is being conducted in patients with HER2-positive breast cancer who had prior breast cancer surgery and are at high risk of having their cancer return. More than 4,800 participants are enrolled in this trial, which will provide further data on efficacy, safety and long-term outcomes.
Impressive Survival Gains with New First-Line Therapy for HER2-Positive Metastatic Breast Cancer
According to recent findings, the combination of targeted agents Herceptin and Perjeta significantly improves survival for patients with HER2-positive metastatic breast cancer when added to chemotherapy. This data was presented at the 2014 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain, September 26–30. (4)
To evaluate the combination of Herceptin and Perjeta plus chemotherapy with Taxotere® as first-line therapy for patients with HER2-postive metastatic breast cancer, researchers have conducted a Phase III clinical study called the CLEOPATRA trial. This trial included 808 patients, who were assigned to receive Herceptin and Perjeta plus chemotherapy or Herceptin-only plus chemotherapy.
In early follow-up, the combination of Herceptin and Perjeta plus chemotherapy appeared promising: patients in this group experienced improved progression-free and overall survival, and overall survival continued to improved at the next follow-up.
Now that final overall survival results are available, the combination of Herceptin and Perjeta plus chemotherapy still appears more effective than Herceptin-only plus chemotherapy. At last follow-up, median overall survival was over 15 months longer in the Perjeta group: over 56 months versus just over 40 months for the Herceptin-only group. In addition, the researchers found no previously unknown safety concerns for this treatment combination. (4,5)
“The results of the study are really outstanding,” said Giuseppe Curigliano, DM, Director of the Division of Experimental Therapeutics in Milan, Italy. He called the more than 56-month median overall survival for Herceptin and Perjeta plus chemotherapy “unprecedented” in the treatment of HER2-positive metastatic breast cancer and added, “The CLEOPATRA trial changes clinical practice. We now have a new standard of care for patients with metastatic HER2-positive breast cancer.”
- FDA approves Perjeta for type of late-stage breast cancer [FDA News Release]. U.S. Food and Drug Administration website.
- FDA approves Perjeta for neoadjuvant breast cancer treatment. [FDA Announcement]. U.S. Food and Drug Administration website.
- Swain S, Kim S,Cortes J, et al. 350O_PR – Final overall survival (OS) analysis from the CLEOPATRA study of first-line (1L) pertuzumab (Ptz), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC). European Society for Medical Oncology (ESMO) Congress 2014: Abstract 350O_PR. Presented September 28, 2014.
- CLEOPATRA Trial Changes Standard Therapy for Metastatic HER2 Positive Breast Cancer [press release]. European Society for Medical Oncology (ESMO) Congress 2014. Available at: . Accessed October 4, 2014.