Enhertu Shows Promise in HER2-low & HER2-ultralow Breast Cancer
- A new study, presented at this year’s American Society of Clinical Oncology (ASCO) conference indicated that a drug called trastuzamab deruxtecan (brand name Enhertu) is more effective than the current standard of care, chemotherapy, at treating patients with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer.
- Enhertu is an antibody-drug-conjugate specifically engineered to target to HER2.
- Interestingly, the study also indicated that Enhertu was effective at treating women with a new subgroup of breast cancer known as HER2-ultralow.
- The trial included patients who had already had disease progression after receiving some form of endocrine therapy, or drugs that are given to target the hormone receptors found on patients’ tumors, and the results are quite promising.
Trial results presented at this year's American Society of Clinical Oncology (ASCO) conference indicated that a drug called trastuzamab deruxtecan (brand name Enhertu) is more effective than the current standard of care chemotherapy in women with a specific type of metastatic, or advanced, breast cancer. This exciting advance means more patients may be able to avoid chemo and opt for a frequently less toxic targeted therapy instead. The phase 3 DESTINY-Breast06 Trial examined the use of Enhertu in patients with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer, meaning that the study focussed on patients with tumors that expressed estrogen and/or progesterone receptors and that also expressed the HER2 protein at low levels. Enhertu had already been approved as a second-line treatment for patients with this type of breast cancer, but the new data aims to explore if it is more effective as a first treatment.
What is Enhertu?
Enhertu is an antibody-drug-conjugate that is specifically engineered to target to HER2. Antibody-drug-conjugates are an innovative drug class where the drug is bound to an antibody, a natural substance in the body that helps target the drug to cancerous cells. This causes the drug to bind to receptors on the surface of cancerous cells, increasing its effectiveness while also minimizing toxicity to normal cells. Enhertu was initially approved in August 2022 by the Food and Drug Administration (FDA) as a treatment for HER2-low metastatic breast cancer
after one or more lines of chemotherapy based on the phase 3 DESTINY-Breast03 trial. The DESTINY-Breast06 trial asks whether Enhertu improves outcomes when given instead of standard chemotherapy — and the results are really promising. SurvivorNet spoke to
Dr. Eleonora Teplinsky , a medical oncologist at Valley Health System in New Jersey, about the important goals of the DESTINY-Breast06 trial. “Currently, the way that we sequence treatment is to begin with endocrine therapy followed by chemotherapy if there is disease progression," she explained. "Then, if there is disease progression again during or after chemotherapy, we give anti-HER2 therapies such as Enhertu. This study examines whether we can give Enhertu earlier, before chemotherapy.”
The New HER2-ultralow Breast Cancer Category
Importantly, the trial included not only HER2-low patients, but also HER2-ultralow patients. The HER2-ultralow designation is a fascinating new way of categorizing patients whose tumors express some degree of HER2, but at lower levels than would be required to traditionally meet criteria for HER2-low. Inclusion of this new subgroup means that the investigators are examining whether more patients can potentially benefit from anti-HER2 treatments such as Enhertu. Dr. Teplinsky added how important it is for patients to know their HER2 status and the significance of the new "HER2-ultralow" subgroup. “It is very important for patients to know if they are HER2-ultralow because then they may be candidates for Enhertu. HER2-ultralow is a new category where the pathologist sees some degree of HER2 staining, but less than would qualify as HER2-low," she explained. "This is interesting because the HER2-ultralow category is often not reported on pathology reports. Most of these patients are told they’re HER2 negative. Currently we have a situation where patients sometimes need to advocate for themselves by asking their physicians if the pathologist can go back and look for any degree of HER2 staining, which might qualify them for this treatment."
Dr. Sylvia Adams explains why it's critical for patients to know HER2 status. What Did the Trial Find?
The trial included patients who had already had disease progression after receiving some form of endocrine therapy, or drugs that are given to target the hormone receptors found on patients' tumors. Specifically, patients had to meet one of two criteria related to previous treatment: (1) disease progression on two or more previous lines of endocrine therapy given for metastatic breast cancer or (2) disease progression within 6 months of starting first line endocrine therapy in combination with a CDK4/6 inhibitor (another class of medicine that can be used to treat HR+ breast cancer) for metastatic disease. The patients included in the study were randomized to receive either Enhertu or the current standard of care, which consisted of one of several different chemotherapy regimens that were chosen by the patient’s oncologist, as is currently done in clinical practice. The primary endpoint which the trial was designed to examine was progression-free survival (PFS), or the amount of time from enrollment until patients’ disease worsened. While the trial did include patients in the new HER2-ultralow subgroup, the primary goal was to determine if Enhertu improved PFS in the HER2-low group. The main secondary endpoints were PFS in the overall population (i.e. HER2-low and HER2-ultralow groups
combined ) and overall survival. The trial was not designed to statistically examine whether Enhertu improved outcomes in the HER2-ultralow subgroup. A total of 866 patients were included in the trial: 713 patients were HER2-low and 153 were HER2-ultralow. Of the 866 patients, 436 were randomized to Enhertu and 430 were randomized to physician’s-choice chemotherapy. Of the patients randomized to physician’s-choice chemotherapy, 59.8% received capecitabine, 24.4% received nab-paclitaxel, and 15.8% received paclitaxel. Approximately 90% of the patients included in the trial had previously received a CD4/6 inhibitor in conjunction with endocrine therapy. The most important finding of the trial was that Enhertu improved PFS as compared to current standard of care chemotherapy. PFS was significantly longer among the HER2-low patients who received Enhertu (median PFS 13.2 months) as compared to physician’s-choice chemotherapy (median PFS 8.1 months). The study authors commented that the results of the trial established Enhertu as a standard of care in this clinical context. A nearly identical improvement in PFS was seen in the overall trial population (i.e. including
both HER2-low and HER2-ultralow patients together). The overall survival data were immature at the time of this analysis, meaning there has not been enough follow-up time yet to say with certainty whether survival was improved by Enhertu. Nevertheless, the 12-month survival rate in the Enhertu group was numerically higher at 87.6% as compared to 81.7% in the physician’s-choice chemotherapy group, which is promising. Again, more follow-up time will be needed to understand if Enhertu definitively improves survival in this situation. “This translates to a 5.1-month improvement in progression-free survival, meaning patients are alive without disease progression," Dr. Teplinsky explained. "That is quite significant and I think that this is something that is practice-changing. It allows patients to delay chemotherapy, which is very important for some patients." In an interview with the ASCO Post, lead study author Dr. Giuseppe Curigliano commented on these main findings, saying, “These results also represent a potential shift in how we classify and treat metastatic breast cancer, as we may have the opportunity to use trastuzamab deruxtecan earlier in the treatment of HR-positive metastatic breast cancer and expand trastuzamab deruxtecan into new metastatic breast cancer patients who previously have not been able to benefit from a targeted medicine post-endocrine therapy.”
What are the Side Effects?
No concerning new safety signals were detected in the DESTINY-Breast06 trial, and the study authors commented that the side-effect profile was similar to what had been observed in previous clinical trials of Enhertu. Serious adverse events occurred in 40.6% of patients receiving Enhertu vs. 31.4% of patients who received chemotherapy. Previous trials of Enhertu have shown that the most common side effects include:
- Nausea
- Fatigue
- Alopecia (hair loss)
- Vomiting
- Constipation
- Decreased appetite
- Musculoskeletal pain
- Diarrhea
Serious interstitial lung disease/pneumonitis is a particularly serious side effect that can occur with Enhertu, and it occurred in 11.3% of patients receiving Enhertu vs. 0.2% who received chemotherapy.
Questions to Ask Your Doctor
- What is my HER2 status?
- Am I eligible for treatment with Enhertu?
- What sort of side effects should I expect?
- Are there tools available to help alleviate these side effects?
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