Pertuzumab (Perjeta) is a relatively new drug that targets HER2, a protein found at higher-than-normal levels in about 15% to 20% of all breast cancers. Too much HER2 leads to tumor growth. Currently, all newly diagnosed breast cancer patients have their tumors’ HER2 levels tested. Knowing whether a patient’s HER2 levels are abnormally high (HER2-positive) or normal (HER2-negative) is a major factor in choosing a treatment, thanks to the availability of trastuzumab (Herceptin) and, now, other HER2-targeted drugs such as Perjeta, T-DM1 (Kadcyla), and lapatinib (Tykerb). These drugs are all used to treat HER2-positive patients.
HER2 is a member of a family of related proteins. These proteins usually interact with each other to promote tumor growth. HER2 is actually one of several ‘HER’ proteins. Herceptin, the first HER-targeted drug, was designed by the company Genentech. It binds to HER2 and inhibits its cancer-promoting activity. Pertuzumab, also made by Genentech, prevents HER2 from interacting with other proteins of the same family, in particular with HER3.
Like all new drugs, pertuzumab was first tested in people on its own, without being combined with other drugs. These early clinical trials, conducted in 2004–2005, included patients with breast, ovarian, and prostate cancer. (At the time, pertuzumab was known as ‘Omnitarg.’) In these trials, pertuzumab showed little to no evidence of clinical activity. It didn’t help that the patients’ HER2 levels were not tested at the time; otherwise the drug’s benefits for HER2-positive patients might have been clearer.
Later, pertuzumab was tested in more advanced trials in patients with high HER2 levels in their tumors. These trials served as the basis of the two U.S. Food and Drug Administration (FDA) approvals that pertuzumab currently holds.
On June 8, 2012, the FDA approved pertuzumab for the treatment of HER2-positive metastatic breast cancer. The approval was specifically given for a treatment regimen containing pertuzumab, trastuzumab, and docetaxel (PTD). It was based on the results of the randomized, double-blind, multinational, phase III CLEOPATRA trial.
In the CLEOPATRA trial, patients with HER2-positive metastatic breast cancer received either PTD, or a placebo (instead of pertuzumab) plus trastuzumab and docetaxel (TD). Patients who took PTD had longer times without their cancer worsening; a median of 18.5 months compared to12.4 months in the TD group. At the time of analysis, the median overall survival was 37.6 months in the TD group. Enough patients in the PTD group were still alive that an overall survival number could not yet be stated.
A later analysis showed that patients who took PTD had a delay in the development of brain metastases compared to the TD group (brain metastasis are particularly common in HER2-positive breast cancers).
On September 30, 2013, the FDA granted accelerated approval to PTD for the neoadjuvant (before surgery) treatment of patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer. (Early-stage means that either the tumor is greater than 2 cm in diameter or the cancer has spread to the patient’s lymph nodes—’node positive.’) This was a landmark approval, being the first accelerated approval of a drug in a neoadjuvant setting. The trial that provided the winning results to the FDA was called NeoSphere.
NeoSphere enrolled 417 patients at multiple locations. Each patient was randomly assigned to receive one of four neoadjuvant treatments before surgery: pertuzumab plus trastuzumab and docetaxel (PTD), trastuzumab plus docetaxel (TD), pertuzumab plus trastuzumab (PT), or pertuzumab plus docetaxel (PD). NeoSphere was an open-label trial, meaning that all the researchers and patients knew which patients received which treatments. The researchers looked at how many patients in each group had complete disappearance of invasive cancer cells in the breast after treatment. This is known as ‘pathological complete response,’ or pCR. Patients with pCR after neoadjuvant treatment have better overall survival after surgery and adjuvant treatment (treatment after surgery).
39.3% of patients who took PTD had pCR (complete disappearance of invasive tumor cells) compared to 21.5% in the TD group. pCR rates were lower in the two other groups. These results showed that adding pertuzumab to TD could benefit patients, convincing the FDA to approve pertuzumab for neoadjuvant treatment. Interestingly, among patients whose treatment included pertuzumab, those who had hormone receptor-negative (HR-) tumors had better pCR rates than those with hormone receptor-positive (HR+) tumors.
In the NeoSphere trial, the most common side effects of PTD were alopecia (hair loss), diarrhea, nausea, and neutropenia (low white blood cell counts). More than 30% of the patients who took PTD experienced these side effects. After surgery, all patients in the trial completed three cycles of chemotherapy (FEC) and 9 months of trastuzumab injections.
In a second neoadjuvant trial of pertuzumab, TRYPHAENA, patients received different chemotherapy combinations that all included both trastuzumab and pertuzumab. This trial was designed to measure harmful cardiac (heart-related) effects. The pCR data from TRYPHAENA were even better that the ones from NeoSphere, supporting the use of pertuzumab in neoadjuvant treatment. The cardiac effects of pertuzumab were found to be insignificant.
The FDA approval of pertuzumab for use in neoadjuvant treatment was supported by an additional randomized, phase II trial. This trial enrolled 225 patients with HER2-positive, locally advanced, operable, or inflammatory (T2-4d) breast cancer. The trial was designed primarily to assess cardiac safety when FEC or carboplatin is added to neoadjuvant therapy with pertuzumab.
The positive results of all the trials outlined above are how pertuzumab-containing therapies became preferred treatments in HER2-positive breast cancer; but maybe not for long. Expectations are high for the next-generation HER2-targeted drug TDM1, also known as Kadcyla or trastuzumab emtansine. Kadcyla may soon take over as a preferred drug for treatment of HER2-positive advanced and metastatic breast cancer.