Enhertu’s Benefits Confirmed for Metastatic, HER2-Positive Breast Cancer; Could Help Treat Early-Stage Disease
The latest results from the DESTINY-Breast02 and DESTINY-Breast03 studies confirmed the benefits of Enhertu (chemical name: T-DXd or fam-trastuzumab-deruxtecan-nxki) for metastatic, HER2-positive breast cancer that had been previously treated with either Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine) or Herceptin (chemical name: trastuzumab) and taxane chemotherapy.
Metastatic breast cancer is cancer that has spread to parts of the body away from the breast, such as the bones or liver.
Results from the TALENT trial suggest that Enhertu may help treat early-stage, hormone receptor-positive, HER2-low breast cancer when given before surgery.
HER2-low breast cancer has a 1+ score on an IHC test or a 2+ score on an IHC test plus a negative FISH test.
All three studies were presented on Dec. 7, 2022, at the San Antonio Breast Cancer Symposium (SABCS). The results of the DESTINY-Breast03 trial also were published at the same time in The Lancet. Read the abstract of “Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.”
Listen to The Breastcancer.org Podcast episode with Sara Hurvitz, MD, FACP, explaining the DESTINY-Breast03 results. Dr. Hurvitz is professor of medicine at the University of California, Los Angeles (UCLA), and director of breast oncology at the Jonsson Comprehensive Cancer Center at UCLA.
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
a topoisomerase I inhibitor chemotherapy called DXd: topoisomerase I inhibitors work by interfering with a cancer cell’s 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 a port.
Enhertu is approved by the U.S. Food and Drug Administration (FDA) to treat unresectable or metastatic, HER2-positive breast cancer in people who have previously received an anti-HER2 medicine:
for metastatic disease
before or after surgery for early-stage disease that came back (recurred) within six months of completing treatment
Unresectable means the cancer can’t be removed with surgery.
Enhertu also is approved to treat unresectable or metastatic, HER2-low breast cancer in people who have previously received chemotherapy:
for metastatic disease
after surgery for early-stage disease that recurred within six months of completing treatment
DESTINY-Breast02 trial: Enhertu after Kadcyla
The DESTINY-Breast02 trial looked at how effective and safe Enhertu was when used to treat metastatic, HER2-positive breast cancer that had previously been treated with Kadcyla.
The study included 608 people who had previously received Kadcyla for metastatic, HER2-positive breast cancer. More than 70% had received two or three previous treatments for metastatic breast cancer.
The people’s ages ranged from 22 to 88; about 80% were younger than 65. About 99% of the people in the study were women, so a few men were included.
About 80% of the cancers had an IHC score of 3+.
The researchers randomly assigned the people to one of two treatment groups:
406 people received Enhertu
202 people received either Herceptin and Xeloda (chemical name: capecitabine) or Tykerb (chemical name: lapatinib) and Xeloda, whichever their doctor recommended
The researchers compared progression-free survival and overall survival in each group.
Progression-free survival is how long a person lives without the cancer growing. Overall survival is how long a person lives, whether or not the cancer grows.
Progression-free survival was:
17.8 months for people who received Enhertu
6.9 months for people who received their doctors’ recommendation of Xeloda and either Herceptin or Tykerb
Overall survival was:
39.2 months for people who received Enhertu
26.5 months for people who received their doctors’ recommendation of Xeloda and either Herceptin or Tykerb
The differences in progression-free survival and overall survival were statistically significant, which means they were probably because of the difference in treatment and not just due to chance.
“In DESTINY-Breast02, T-DXd demonstrated statistically significant and clinically meaningful improvement in [progression-free survival] and [overall survival] for patients with HER2-positive metastatic breast cancer previously treated with T-DM1,” explained Ian Krop, MD, PhD, during a media briefing on the results. Dr. Krop is chief clinical research officer and associate director at the Yale Cancer Center.
“The overall safety profile was consistent with the established safety of T-DXd, with no new safety signals observed,” he added. “DESTINY-Breast02 confirms the favorable benefit/risk profile of T-DXd in patients with advanced HER2-positive metastatic breast cancer, as previously demonstrated by DESTINY-Breast01.”
Results from the DESTINY-Breast01 study led to Enhertu’s FDA approval.
DESTINY-Breast03: Enhertu versus Kadcyla
Earlier results from DESTINY-Breast03 presented at the 2021 European Society for Medical Oncology Congress showed that Enhertu more than doubled the 12-month progression-free survival rate when used as a second-line treatment in people diagnosed with metastatic, HER2-positive breast cancer versus Kadcyla. These results led to Enhertu being considered the preferred second-line treatment for this type of breast cancer, with Kadcyla becoming an alternative option.
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 the people 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
These latest results again looked at progression-free survival, as well as overall survival.
Updated progression-free survival was:
28.8 months for people who received Enhertu
6.8 months for people who received Kadcyla
Median overall survival — meaning half the people were alive and half were not — wasn’t yet met in either treatment group. So the researchers couldn’t present overall survival data in months. But when the researchers looked at graphs of survival rates, they saw there was a 36% improvement in survival for people who received Enhertu.
“There was a p-value that tested this, and it does look like it’s very statistically significant,” Dr. Hurvitz told Breastcancer.org. “T-DXd significantly reduced the risk of death by 36%. [These] updated results demonstrate remarkable [overall survival] and [progression-free survival] benefit with T-DXd, further supporting the use of T-DXd as the second-line standard of care in patients with HER2-positive metastatic breast cancer.”
TALENT: Enhertu before surgery for early-stage hormone receptor-positive breast cancer
Because Enhertu has been so spectacularly successful in treating metastatic HER2-positive and HER2-low breast cancer, researchers wondered whether it could effectively treat early-stage disease.
The small TALENT trial included 58 people diagnosed with stage II or stage III hormone receptor-positive, HER2-low breast cancer that could be removed with surgery.
The people’s ages ranged from 32 to 87. Two of the participants were men.
Nearly 80% of the cancers had an IHC score of 1+.
Before the people had surgery to remove the cancer, the researchers assigned them to one of two treatment groups:
29 people received Enhertu
29 people received Enhertu plus Arimidex (chemical name: anastrozole), an aromatase inhibitor, a type of hormonal therapy
About half the cancers in each treatment group were grade 2.
Doctors call treatments given before surgery neoadjuvant treatments.
The researchers wanted to see how many of the cancers responded to treatment, called objective response rate (ORR). They also wanted to see if there were changes in HER2 expression after treatment.
The results showed:
68% of the cancers treated with Enhertu responded to treatment
58% of the cancers treated with Enhertu and Arimidex responded to treatment
“The addition of [hormonal] therapy to T-DXd didn’t appear to enhance the efficacy,” said Aditya Bardia, MD, MPH, associate professor of medicine at Harvard Medical School and attending medical oncologist at Massachusetts General Hospital, at a media briefing about the research. “But this needs to be interpreted with caution because the numbers were small.”
The results showed that 49% of the cancers had a change in IHC score after treatment. Of the cancers that had a change, 88% had a decrease in HER2 expression.
Three of the 58 people in the study had an Enhertu dose reduction because of side effects. One person had moderate pneumonia. There were no severe cases of pneumonia and no cases of cardiomyopathy, diseases that affect the heart muscle and make it harder for the heart to pump blood to the rest of the body.
The most common side effects in people who received Enhertu alone were:
nausea
fatigue
diarrhea
hair loss
The most common side effects in people who received Enhertu and Arimidex were:
nausea
fatigue
vomiting
hair loss
“Neoadjuvant T-DXd demonstrated preliminary evidence of clinical activity in HER2-low, hormone receptor-positive [early-stage] breast cancer, with a toxicity profile consistent with previous reports,” Dr. Bardia said. “This is the first report of neoadjuvant T-DXd for patients with hormone receptor-positive, HER2-low breast cancer and provides groundwork for future studies with antibody-drug conjugates for patients with early-stage breast cancer.”
What this means for you
There is good news if you’ve been diagnosed with metastatic HER2-positive breast cancer that has grown during the first treatment: The DESTINY-Breast02 and DESTINY-Breast03 studies confirm that Enhertu is a very good second-line treatment.
Patient-reported outcomes from the DESTINY-Breast04 study offer more good news: People receiving Enhertu didn’t see their quality of life deteriorate as fast as the quality of life of people receiving chemotherapy. So when Enhertu is working well, people receiving it tend to have fewer side effects than people receiving chemotherapy. Enhertu also helped delay pain’s effects on people’s everyday lives.
If you’ve been diagnosed with early-stage hormone receptor-positive, HER2-low breast cancer, you may want to discuss the results of the TALENT study, which suggest that Enhertu may help treat early-stage disease, with your doctor. Still, more research is needed.
“Hormonal therapy after surgery will remain a standard treatment after surgery for early-stage hormone receptor-positive disease,” Dr. Bardia explained. “The question is, do some people need chemotherapy and hormonal therapy or do they need Enhertu and hormonal therapy? That is what future studies need to look at.”
— Last updated on May 26, 2023 at 4:57 PM