What To Consider Before Treatment with Trastuzumab Deruxtecan (Enhertu) For Early, High-Risk HER2+ Breast Cancer: Results from DESTINY-Breast-05

Determining which patients are most likely to benefit has become a central question after the FDA granted Breakthrough Therapy Designation to trastuzumab deruxtecan (Enhertu) for a high-risk group of early breast cancer patients. 

The designation, based on results from the DESTINY-Breast05 clinical trial, applies to patients with HER2-positive early breast cancer who have residual invasive disease in the breast or axillary lymph nodes following neoadjuvant therapy. Despite surgery and additional post-neoadjuvant treatment, about 20% of these patients will still develop metastatic disease.

Trastuzumab deruxtecan offers a new, potentially curative option for this population, but clinicians say careful patient selection will be essential to support shared decision-making between oncologists and patients as treatment choices grow more complex. 

“It’s obviously a very potent regimen,” said Dr. Harold Burstein at Dana-Farber Cancer Institute. “DESTINY-Breast05 showed that in patients who had presented with very high risk breast cancer did better with trastuzumab deruxtecan than the competing antibody-drug conjugate trastuzumab emtansine. It begs the question: is it better to give the drug up front or use it later for those who are really at high risk?”

What is DESTINY-Breast05?

DESTINY-Breast05 (NCT04622319) is an ongoing phase 3, open-label, international, randomized clinical trial. It compares trastuzumab deruxtecan (T-DXd) with the standard of care trastuzumab emtansine (Kadcyla, T-DM1) as a potentially curative treatment for early-stage, HER2-positive breast cancer with residual invasive disease and node-positive disease at surgery or inoperable disease at diagnosis. Both trastuzumab deruxtecan and trastuzumab emtansine are antibody-drug conjugates. 

DESTINY-Breast05 is a large clinical trial, with 1,635 patients randomly assigned 1:1 to receive trastuzumab deruxtecan (818 patients) or trastuzumab emtansine (817 patients). Median follow-up was 30 months for both groups. Important results include: 

• Invasive-disease events or death: 51 patients (6.2%) in the trastuzumab deruxtecan group and 102 patients (12.5%) in the trastuzumab emtansine group. Patients treated with trastuzumab deruxtecan had a 53% lower risk of invasive disease or death. 
• Three-year invasive disease-free survival was 92.4% in the trastuzumab deruxtecan group and 83.7% in the trastuzumab emtansine group. 
• Interstitial lung disease (ILD) is a serious side effect of trastuzumab deruxtecan, with 9.6% of patients developing the condition. Two patients treated with trastuzumab deruxtecan who developed interstitial lung disease died. 
• The most common grade 3/4 side effects were low neutrophils and low white cell count.

Interstitial lung disease risk and monitoring for patients treated with trastuzumab deruxtecan

ILD is a known, potentially life-threatening side effect of trastuzumab deruxtecan. Screening patients before treatment with trastuzumab deruxtecan to determine their risk of ILD, monitoring with low-dose CT scans, patient education, and early detection can help reduce the severity of this side effect. 

The rates of ILD have varied in studies trastuzumab deruxtecan, but in DESTINY-Breast05, 9.6% of patients developed ILD of all grades and two patients died. The severity of the ILD varied: 

• Grade 1: 16 patients (2%)
• Grade 2: 52 patients (6.5%)
• Grade 3: 7 patients (0.9%)
• Grade 4: 0 patients
• Grade 5 (death): 2 patients (0.2%)

In DESTINY-Breast05, all patients underwent a baseline low-dose, noncontrast CT scan of the chest. This was followed by another low-dose CT at 6 weeks and then every 12 weeks during treatment, and at the 40-day follow-up. Any patients who had radiotherapy had an additional CT scan after radiotherapy was complete.

If ILD was detected on one of these scans, it was treated based on the severity. 

• Grade 1 ILD or pneumonitis was treated with systemic steroids and trastuzumab deruxtecan treatment was paused. If ILD resolved in less than 28 days, trastuzumab deruxtecan could be resumed. If it took longer, the dose of trastuzumab deruxtecan was reduced. If ILD did not resolve after 126 days, trastuzumab deruxtecan was permanently discontinued. 
• Grade 2 ILD or pneumonitis was treated with steroids and trastuzumab deruxtecan treatment was stopped permanently. 
• Grade 3 and 4 ILD or pneumonitis was treated in the hospital with high-dose methylprednisolone IV treatment and steroids and study treatment was permanently discontinued. If it did not improve after 3 to 5 days, alternative treatment options for ILD were considered.  

For patients with early-stage breast cancer, the additional monitoring with CT scans is a “different paradigm” according to Dr. Heather McArthur, the Clinical Director of Breast Cancer and Komen Distinguished Chair in Clinical Breast Cancer Research at University of Texas Southwestern (UTSW) Medical center. “The scanning is going to be challenging for the community to adopt, but I think [trastuzumab deruxtecan] is practice-changing for selected patients,” she added. 

“In the metastatic setting we stage frequently, patients are already getting scans,” said Dr. Maysa Abu-Khalaf of Jefferson Health. “In the adjuvant setting, these are patients that don’t come in as frequently and don’t need scans at all. If we follow the guidelines, there is radiation exposure. It’s always good to have more treatment options to select from, but there’s a lot of shared-decision making when we bring up these new drugs.” 

Because ILD is potentially fatal, it is important for oncologists and patients to weigh the potential benefits and individual risk factors when considering trastuzumab deruxtecan. Patients who had a history of noninfectious ILD or pneumonitis involving glucocorticoid treatment were not eligible to participate in the trial.

When to consider trastuzumab deruxtecan

For patients with very high-risk HER2-positive breast cancer after neoadjuvant therapy, trastuzumab deruxtecan does provide a meaningful survival benefit over the current standard of care, and it may be beneficial for other patients as well. “Sometimes we find that patients cannot complete the whole treatment course with trastuzumab emtansine because of toxicity, whether it’s liver toxicity or neuropathy, trastuzumab deruxtecan is a good option to have, even for patients at a lower risk. It’s good to have options to switch to,” said Dr. Abu-Khalaf. 

She emphasized the importance of meaningful shared-decision making conversations with patients about the risks and benefits of trastuzumab deruxtecan.

What’s next for DESTINY-Breast05 and trastuzumab deruxtecan?

Researchers continue to monitor the patients enrolled in DESTINY-Breast05. Long-term results will report on the brain metastasis-free interval and overall survival, which were immature at the time of this reporting. Additional studies are being conducted to understand correlations between biomarker status and how well trastuzumab deruxtecan treats high-risk HER2-positive breast cancer.