Options for Metastatic, HER2-Positive Breast Cancer After Previous Treatments Featured at ASCO Annual Meeting

Margetuximab and neratinib have positive showings as third-line therapy
ASCO Coverage
June 5, 2019
Eric Fitzsimmons, Copy Editor and Content Coordinator

Treatment for metastatic breast cancer often involves many courses of therapyinfo-icon. A person starts on one treatment, and when that treatment stops working against the cancer, they switch to another. This process can repeat several times for as long as treatment continues.

Several presentations at the 2019 ASCO Annual Meeting took an interest in how best to treat metastatic, HER2-positive breast cancer after multiple lines of treatment have stopped working. Today, there are standards for the first and second treatments given for HER2-positive metastaticinfo-icon breast cancer:

After these first two lines, there isn’t an accepted standard for selecting the next treatment – though there are many options available, which include chemotherapyinfo-icon with or without HER2-targeted treatments.

On Tuesday, presenters offered new options for treatment after the first two lines stopped working. The HER2-targeted antibody margetuximab and the tyrosine kinase inhibitor neratinib (Nerlynx) both had positive results compared to existing options for third-line treatment of HER2-positive, metastatic breast cancer, and may offer new options for people in this situation.

SOPHIA study shows margetuximab and chemotherapy results in slightly longer progression-free survival than trastuzumab and chemotherapy

Results from the phase III SOPHIA trial found that the combination of margetuximab and chemotherapyinfo-icon resulted in people going nearly 1 month longer without cancer growing than people taking trastuzumab (Herceptininfo-icon) and chemotherapy after the cancer grew on at least two other HER2-targeted therapies.

The SOPHIA trial explored the use of margetuximab, an engineered, HER2-targeted antibody, to treat metastatic, HER2-positive breast cancer that grew during treatment with other HER2-targeted therapies. Researchers wanted to see if it treated the cancer better than trastuzumabinfo-icon, and study how it interacted with certain biomarkers that seem to affect how well trastuzumab works in some people.

Participants in the SOPHIA trial had at least two prior HER2-targeted treatments, and at least one previous treatment for metastaticinfo-icon breast cancer. A total of 536 people were randomized to be given either

  • margetuximab and chemotherapy, or
  • trastuzumab and chemotherapy

Researchers found that people taking margetuximab had the risk of cancer growing lowered by 24 percent. The difference in the time people went without cancer growing was about a month:

  • People taking margetuximab went 5.8 months before cancer grew.
  • People taking trastuzumab went 4.9 months before cancer grew.

Researchers were also interested in the effect of margetuximab on cancer based on a certain tumorinfo-icon biomarker. They tested participant tumors for features of the CD16A geneinfo-icon, specifically whether they found certain alleles, or alternative forms of the gene.

One specific allele of CD16A, the 158F allele, has been associated with lower response to trastuzumab in past studies. But researchers believe it may make cancer more responsive to margetuximab.

In this study, researchers looked at alleles called FF, FV, or VV. For people with FF or FV alleles of CD16A, the time to cancer growing was

  • 6.9 months on margetuximab
  • 5.1 months on trastuzumab

The results are promising for this potential new medicineinfo-icon in metastatic, HER2-positive breast cancer. People taking margetuximab went longer without cancer growing than people taking trastuzumab, and that effect seemed greater in people with certain forms of the CD16A biomarker, as researchers predicted.

There is more to study about this medicine, and more data needed to fully understand the CD16A biomarker. In addition, researchers are interested to see if this medicine will affect how the cancer responds to future treatments. Margetuximab appears to increase the activity of certain immune cells, which could make the cancer more responsive to later lines of treatment. If so, this may be reflected in SOPHIA’s overall survival results more strongly than seen in the results presented Tuesday.

Despite the need for more research, margetuximab did produce positive results in a population for which there is no clear direction for treatment. It is possible the medicine will become available as an option for people who have experienced progressioninfo-icon on two prior lines of treatment.

People given neratinib and capecitabine go longer without cancer growing than people given lapatinib and capecitabine

Results from the NALA study presented at ASCO on Tuesday showed treatment with neratinib and capecitabine resulted in people going 1.7 months longer without cancer growing than people given lapatinib (Tykerbinfo-icon) and capecitabineinfo-icon.

Neratinib and lapatinibinfo-icon are both tyrosine kinase inhibitors, but neratinib affects proteins related to HER2 that lapatinib does not, and binds in a way that can’t be reversed. This led researchers to explore whether neratinib would have a greater effect on HER2-postive breast cancer than lapatinib. Neratinib is already FDAinfo-icon approved as extended treatment for early-stageinfo-icon, HER2-positive breast cancer, and has shown positive results as a neoadjuvant treatment – treatment given before surgeryinfo-icon. It has also had positive results for metastatic breast cancer in past studies.

The NALA trial randomized 621 patients with metastatic, HER2-positive breast cancer to receive either

  • neratinib and capecitabine, or
  • lapatinib and capecitabine

Because neratinib commonly causes diarrhea that can be severe, people in the neratinib arm were also given the anti-diarrheal medicineinfo-icon loperamide with the first cycle of treatment.

The researchers found that people in the neratinib arm went longer without cancer growing

  • people given neratinib went 8.8 months without cancer growing
  • people given lapatinib went 6.6 months without cancer growing

They also noted that people given neratinib lived 1.7 months longer than those given lapatinib, but that result was not statistically significantinfo-icon, which means it may just be a result of chance and not the effect of the medicine.

The NALA researchers took a special interest in the effect on metastases to the brain and central nervous systeminfo-icon and found that when given neratinib, fewer people needed additional therapyinfo-icon to relieve issues caused by brain metastases.

As with margetuximab, the improvements here were modest, but are likely to make neratinib a treatment option for people in a situation where there is no clear standard for the best treatment going forward.

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Targeted Therapy