New HERizons: HER2-Positive Breast Cancer and the Legacy of Herceptin

Twenty years ago, no targeted treatments existed for breast cancers with high levels of a protein called HER2 (HER2-positive, or HER2+). The significance of HER2 in breast cancer had only been recognized in 1987, when excessive levels of the protein were identified in about 20% of breast cancers. Oncologists realized that high levels of HER2 mark a type of cancer with a poor prognosis, as compared to the predominant type of breast cancer: estrogen receptor-positive, HER2 negative (HER2-).

The possibility of targeting HER2 to treat cancer was fulfilled in 1998, when the U.S. Food and Drug Administration (FDA) approved Herceptin (generic name trastuzumab), for treatment of metastatic HER2+ breast cancer. Made by Genentech, Herceptin is a type of drug known as a humanized antibody, meaning that it mimics an immune system attack on tumor cells, specifically those with high levels of HER2. Now, 20 years later, it is easier to appreciate the significance of this drug, which literally changed the lives of many HER2+ breast cancer patients, and continues to do so today.

Herceptin has gathered more approvals since 1998, notably in earlier-stage cancers. In combination with chemotherapy, it is a backbone of adjuvant (after surgery) treatment—a usage that the FDA approved in 2006. It can also be used as part of neoadjuvant (before surgery) treatment in combination with the drug pertuzumab, a usage approved in 2013. It remained the only HER2-targeting drug for 14 of the 20 years since its original approval, but things have changed since then. Now, four additional drugs are approved for HER2+ breast cancer, with even more in development.

FDA-approved HER2-targeting drugs:

Lapatinib (brand name Tykerb) is a small-molecule drug that inhibits the activity of HER2 and the related protein EGFR. In 2008, the FDA approved lapatinib in combination with the chemotherapy drug capecitabine for treatment of metastatic breast cancer that progressed after treatment with Herceptin and a taxane drug. In a clinical trial, compared to capecitabine alone, lapatinib prolonged the amount of time between start of treatment and disease progression (progression-free survival) from 18.6 weeks to 27. Lapatinib with capecitabine is a preferred option for patients with brain metastases. (HER2+ breast cancer tends to metastasize to the brain more frequently than HER2- cancers).

Pertuzumab (brand name Perjeta): This antibody drug targets a specific function of HER2: its ability to bind and interact with other proteins in the same family of proteins (the EGFR family). These interactions are essential for the cancer-promoting function of HER2. The FDA approved Perjeta in 2012 for treatment of metastatic HER2+ cancers, in combination with Herceptin and docetaxel, based on the results of the CLEOPATRA trial. Progression-free survival was improved by 6 months with Perjeta in the mix.

In 2013, the FDA approved the combination of Perjeta, Herceptin, and docetaxel as part of neoadjuvant (pre-surgery) treatment, based on results from the NEOSPHERE trial. In that trial, pathologic complete response (pCR, or elimination of detectable cancer) occurred in 39% of patients treated with Perjeta, Herceptin, and docetaxel, compared to 21.5% of patients treated without Perjeta.

In December of 2017, the FDA approved Perjeta for adjuvant treatment of HER2+ breast cancer, in combination with Herceptin and chemotherapy. The very large APHINITY trial showed that addition of Perjeta slightly reduced the risk of disease recurrence: 94.1% of participants who received Perjeta with Herceptin and chemotherapy lived for 3 years with no signs or symptoms of disease (invasive disease-free survival, or iDFS), compared with 93.2% of those who received just Herceptin and chemotherapy —a very small difference indeed.

T-DM1 (ado-Herceptin emtansine, brand name Kadcyla) is an antibody-drug conjugate consisting of the cytotoxic chemotherapy drug DM1 bound to the Herceptin antibody. Thus, it combines the specificity of the antibody with the cytotoxic power of DM1. The FDA approved T-DM1 in 2013 for treatment of metastatic cancer that progressed after treatment with Herceptin and a taxane drug. The EMILY trial compared the efficacy of T-DM1 to that of lapatinib combined with capecitabine, demonstrating overall survival of 31 months in patients who received T-DM1, compared to 25 months for those who received lapatinib plus capecitabine.   Very recent results from the KATHERINE trial suggest that T-DM1 may soon progress to become an adjuvant treatment of choice in women whose early-stage cancer did not respond well to the FDA-approved neoadjuvant treatment (as seen during surgery). With T-DM1 the 3-year disease-free survival rate was 88% versus 77% with Herceptin.

Neratinib (Nerlynx): this is a small-molecule inhibitor of HER2 and EGFR. The FDA approved neratinib for extended adjuvant treatment of patients with early stage, HER2-positive breast cancer following postoperative Herceptin in July 2017. The results of the randomized ExteNET trial showed a small improvement in disease-free survival, but at the cost of fairly severe side effects.

HER2-targeting drugs in clinical trials:

Tucatinib (ONT-380) is a small-molecule HER2 inhibitor that has shown promising results so far. The combination of tucatinib with capecitabine and Herceptin showed an overall response rate (ORR) of 61% in a small trial. Importantly, this combination elicited responses in brain metastases in 42% of patients who had them. In 2017, the FDA granted Orphan Drug status to tucatinib for treatment of HER2+ patients with brain metastases.

ZW25 is an antibody that binds to two different parts of the HER2 protein, and recently showed promise in cancers other than breast cancer that have high levels of HER2. (Yes, high levels of HER2 are seen—albeit infrequently—in other cancers, such as cancers of the stomach, esophagus, uterus, and more.)

Herceptin Deruxtecan (DS-8201) is based on Herceptin, and like T-DM1, it is an antibody-drug conjugate. The main difference is that DS-8201 has a higher ratio of the chemotherapy drug to the antibody, and there is hope that this drug may be active in patients who have stopped responding to T-DM1. Preliminary results are encouraging. Moreover, DS-8201 has activity against cancers in which HER2 levels are not very high and thus cannot be treated with Herceptin.

Margetuximab is also a Herceptin-based drug that is optimized to induce more potent destruction of the cancer cells to which it binds. It is hoped to be active in patients for whom treatment with FDA-approved HER2-targeting drugs failed, and preliminary clinical trial results for it are promising.

Pyrotinib is a small-molecule inhibitor of HER2 and other proteins in the same family. In a clinical trial, patients with HER2+ metastatic breast cancer who received pyrotinib without any other drugs had a 50% overall response rate (ORR). The ORR was 33% in patients who had stopped responding to Herceptin. A combination of pyrotinib and capecitabine versus lapatinib (Tykerb) and capecitabine produced an ORR of 78.5% for the pyrotinib group compared with 57.1% for the lapatinib group, as well as much longer progession-free survival (18 versus 7 months).

Looking ahead:

Of all the new HER2-targeting drugs, those listed above may be farthest along in development. Others include unarmed antibodies, such as MCLA-128. Many are antibody-drug conjugates, such as XMT-1522, ARX788, PF-06804103, A166, and DHES0815A (RG6148). Some are small-molecule drugs, such as poziotinib and TAS0728. One new drug, PRS343, is a so-called bispecific antibody that targets both HER2 and the immune receptor CD137, with the expectation of literally bringing together activated immune cells and antibody-bound cancer cells, so that the immune cells can attack them.

With all the new drugs in development, Herceptin is still the foundation of treatment for HER2+ breast cancer (and other HER2+ cancers). Many of the new drugs are designed to be used along with Herceptin or utilize it as a backbone for further improvement. The patent on Herceptin has expired, and many companies are now developing “biosimilars”; i.e., less expensive versions of the drug. The legacy of Herceptin, the first antibody drug to target a specific alteration in breast cancer, is long lived.

Image Credit: An illustration of part of the herceptin molecule (yellow) bound to part of the HER2 protein (blue). Image credit: Simon Caulton