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Enhertu Dramatically More Effective Than Kadcyla as Second Treatment for Metastatic HER2-Positive Breast Cancer

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Enhertu (chemical name: fam-trastuzumab-deruxtecan-nxki) more than doubled the 12-month progression-free survival rate than Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine) in people diagnosed with metastatic HER2-positive breast cancer that had been previously treated, according to results from the DESTINY-Breast03 study.

The research was presented on Sept. 18, 2021 at the European Society for Medical Oncology (ESMO) Congress 2021. Read the abstract of “Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study.”

The progression-free survival rate is the percentage of people who are alive without the cancer growing for the specified time period, which was 1 year for this study.

Metastatic breast cancer is cancer that has spread to parts of the body away from the breast, such as the bones, liver, or brain.

About Enhertu
About Kadcyla
About the study
What this means for you

About Enhertu

Enhertu is a targeted therapy made up of three parts:

  • fam-trastuzumab: an anti-HER2 medicine that has the same basic structure as Herceptin (chemical name: trastuzumab)
  • a topoisomerase I inhibitor chemotherapy called DXd: topoisomerase I inhibitors work by interfering with cancer cells’ ability to replicate
  • a compound that links the fam-trastuzumab molecule to the topoisomerase I inhibitor chemotherapy molecule

Doctors call Enhertu an antibody-drug conjugate targeted therapy. The combination of the topoisomerase I inhibitor and the linking compound is called deruxtecan. The linking compound attaches (conjugates) the fam-trastuzumab to the topoisomerase I inhibitor chemotherapy.

Enhertu is given intravenously, which means the medicine is delivered directly into your bloodstream through an IV or port. Enhertu usually is given every 3 weeks unless the cancer grows or unacceptable side effects develop.

In earlier studies, Enhertu was called T-DXd and DS-8201.

Enhertu is approved by the U.S. Food and Drug Administration (FDA) to treat unresectable or metastatic HER2-positive breast cancer that has been previously treated with two or more anti-HER2 treatment regimens.

Unresectable means the cancer can’t be removed with surgery.

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About Kadcyla

Kadcyla is a combination of Herceptin and the chemotherapy medicine emtansine. Emtansine, like some other chemotherapy medicines, disrupts the way cells grow. Emtansine isn’t a targeted medicine, so it can affect healthy cells as well as cancer cells.

Kadcyla was designed to deliver emtansine to cancer cells in a targeted way by attaching emtansine to Herceptin. Herceptin then carries emtansine to the HER2-positive cancer cells.

Kadcyla is approved by the FDA to treat:

  • HER2-positive, metastatic breast cancer that has previously been treated with Herceptin and a taxane chemotherapy
  • early-stage HER2-positive breast cancer after surgery if residual disease is found after neoadjuvant (before surgery) treatment with Herceptin and taxane chemotherapy

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About the study

The DESTINY-Breast03 study compared Enhertu and Kadcyla head-to-head as a second-line treatment for metastatic HER2-positive breast cancer that grows after being treated with an anti-HER2 medicine and taxane chemotherapy.

The study included 524 people; more than 99% were women. About half the people were older than age 54 and half were younger.

Of the people in the study:

  • about 20% had brain metastases
  • about 70% had visceral metastases, which means the breast cancer had spread to places in the body other than the bones, skin, and lymph nodes, such as the liver or lungs
  • about 90% had previously received treatment for metastatic breast cancer; more than 99% had previously received treatment with Herceptin

The researchers randomly assigned everyone to one of two treatment groups:

  • 261 people were assigned to the Enhertu group; 257 people actually received Enhertu
  • 263 people were assigned to the Kadcyla group; 261 people actually received Kadcyla

Half the people treated with Enhertu were followed for less than 16.2 months, and half were followed for a longer period of time.

Half the people treated with Kadcyla were followed for less than 15.3 months, and half were followed for a longer period of time.

The researchers looked to see which medicine offered better progression-free survival and overall survival.

Overall survival is how long people live, whether or not the cancer grows.

The estimated 12-month progression-free survival rates were:

  • 75.8% for people who received Enhertu
  • 34.1% for people who received Kadcyla

This difference was statistically significant, which means that it was likely due to the difference in treatment and not just because of chance.

People who received Kadcyla had a median progression-free survival of 6.8 months. This means that half the people lived longer than 6.8 months, and half lived for shorter periods of time before the cancer grew.

People who received Enhertu did not reach median progression-free survival. This means that too few people had the cancer grow during treatment with Enhertu, and the researchers couldn’t calculate median progression-free survival.

The estimated 12-month overall survival rates were:

  • 94% for people who received Enhertu
  • 85.9% for people who received Kadcyla

The researchers also looked at how well the breast cancers responded to each treatment:

  • 79.7% of the cancers treated with Enhertu responded to the treatment
  • 34.2% of the cancers treated with Kadcyla responded to the treatment
  • 16.1% of the cancers treated with Enhertu had a complete response compared with 8.7% of the cancers treated with Kadcyla; complete response means the cancer couldn’t be detected after treatment
  • 63.6% of the cancers treated with Enhertu had a partial response compared with 25.5% of the cancers treated with Kadcyla; partial response means the cancer shrunk or stopped growing

The researchers also wanted to know if Enhertu caused more serious side effects that Kadcyla.

Grade 3 or higher side effect rates were similar in the two treatment groups: 45.1% of people who received Enhertu and 39.8% of people who received Kadcyla had a grade 3 or higher side effect.

Still, more people stopped Enhertu treatment or had a dose reduction because of side effects:

  • 12.8% of people who received Enhertu stopped treatment because of side effects
  • 5.0% of people who received Kadcyla stopped treatment because of side effects
  • 21.4% of people who received Enhertu had a dose reduction because of side effects
  • 12.6% of people who received Kadcyla had a dose reduction because of side effects

The most common side effects linked to people stopping treatment were:

  • interstitial lung disease or pneumonia for Enhertu
  • low platelet levels for Kadcyla

Interstitial lung disease is a general term for disorders that cause inflammation and scarring in the lungs. The scarring makes the lung tissue stiff, which makes it difficult to breathe. Interstitial lung disease is a known side effect of Enhertu, and the medicine has a warning on its label about it.

About 10.5% of people who received Enhertu had either interstitial lung disease or pneumonia. Still, no one had grade 4 or 5 of these side effects, and only 0.8% of people had grade 3 cases.

The most common side effects linked to people reducing their doses were:

  • nausea and low white blood cell counts for Enhertu
  • low platelet levels and liver enzyme problems for Kadcyla

“These data support [Enhertu] becoming the standard of care for second-line HER2-positive metastatic breast cancer,” said Javier Cortés, M.D., PhD, of the International Breast Cancer Center, Quiron Group, in Barcelona, Spain, who presented the study. “There was a highly clinically meaningful and statistically significant improvement in progression-free survival compared with [Kadcyla] in patients with HER2-positive metastatic breast cancer.”

Shanu Modi, M.D., of Memorial Sloan Kettering Cancer Center, said the Enhertu effectiveness results from the study were “unprecedented.” Dr. Modi discussed the results of the study after Dr. Cortés’s presentation.

“These progression-free curves from DESTINY03 are absolutely startling,” she added.

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What this means for you

If you’ve been diagnosed with metastatic HER2-positive breast cancer that has grown while being treated with an anti-HER2 medicine and chemotherapy, and you and your doctor are considering second-line treatments, these results are extremely promising. You may want to bring up this study and ask if Enhertu is a good option for you.

If you decide that Enhertu is right for you and your unique situation, it’s important to know that interstitial lung disease can be a severe side effect of the medicine. You should be closely monitored for signs of interstitial lung disease and tell your doctor right away if you experience:

  • shortness of breath
  • dry cough

Learn more about what to expect during Enhertu treatment.

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Written by: Jamie DePolo, senior editor


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