New Data on Trastuzumab Deruxtecan (ENHERTU); Should it Be Administered With Radiation?

The use of Trastuzumab deruxtecan (TDXD) has received FDA approval for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have undergone prior anti-HER2 therapy in the metastatic setting, or in the (neo)adjuvant setting for those whose disease progressed either during treatment or within six months of completing therapy. 

New data from the DESTINY-Breast12 trial has contributed to the expanding evidence supporting the clinical benefit of trastuzumab deruxtecan (brand name: Enhertu). The drug yielded a 12-month progression-free survival rate of 61.6% in patients with brain metastases at baseline. 

Systemic treatment for HER2-positive metastatic breast cancer has strongly evolved in the past few years. Approximately 20 percent of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), and it was associated with an increased risk of disease recurrence and an overall worse prognosis — so the expanded evidence of Enhertu’s benefit is a big deal.

Therapies that target HER2 have become essential agents in the treatment of metastatic breast cancer and have transformed the natural course of HER2-positive breast cancer. Because the use of HER2 targeted therapy can improve survival in these patients, it is standard of care that such patients receive HER2-directed therapy as first-line treatment. 

The current HER2 agents available for use in HER2-positive breast cancer are: 

• Trastuzumab deruxtecan (Enhertu) – A monoclonal antibody that binds the extracellular domain of HER2
• Pertuzumab – A monoclonal antibody that binds the extracellular dimerization domain of HER2 and prevents it from binding to itself or to other members of the EGFR family. It is administered in combination with trastuzumab rather than as a single agent in the treatment of HER2-positive breast cancer. 
• Fam-trastuzumab deruxtecan (T-DXd) – T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. As with T-DM1, this conjugate incorporates a cytotoxic agent, and chemotherapy is not added. 
• Ado-trastuzumab emtansine (T-DM1) – Ado-trastuzumab emtansine (also commonly referred to as T-DM1) is an antibody-drug conjugate composed of trastuzumab, a thioether linker, and the antimicrotubule agent DM1. The HER2-directed antibody-drug conjugates incorporate a cytotoxic agent, and therefore chemotherapy is not added. 
• Tucatinib – Tucatinib is an oral tyrosine kinase inhibitor that is selective for the kinase domain of HER2, with minimal inhibition of EGFR. It is used in combination with capecitabine and trastuzumab. 
• Lapatinib – Lapatinib is a tyrosine kinase inhibitor against EGFR1 and HER2 that results in inhibition of signaling pathways downstream of HER2, used in combinations with trastuzumab or capecitabine.
• Neratinib – Neratinib is an irreversible pan-HER inhibitor, used in combination with capecitabine. 
• Margetuximab – Margetuximab is an Fc-engineered anti-HER2-receptor monoclonal antibody used in combination with chemotherapy.

Navigating Among Potential Therapies 

The initial assessment of a patient with metastatic breast cancer is to define which therapy this patient should receive. A comprehensive analysis of prior treatments or a treatment-naive patient can guide this decision. 

Currently, the regimen of choice for those who did not receive adjuvant therapy at the time of the initial diagnosis is trastuzumab plus pertuzumab in combination with a taxane (docetaxel or paclitaxel). 

On the other hand, for patients who had received prior treatment, the therapy choice is based on what treatment the patient received and the treatment-free interval. For patients with a treatment-free interval of six months or longer, it is recommended to offer a taxane plus trastuzumab and pertuzumab. For patients who relapse on treatment or within six months of completing adjuvant HER2-directed treatment, the next step should be offering second- and later-line HER2-directed therapies, including fam-trastuzumab deruxtecan, and ado-trastuzumab emtansine. 

Targeting Patients With Brain Metastasis 

For most patients with a favorable prognosis (eg, good performance score, age <65 years, controlled primary tumor, and controlled or absent extracranial metastases), aggressive local treatment is indicated. Important factors to consider include number, size, and location of brain metastases; degree of mass effect and edema; presence or absence of symptoms, functional status, and extent of systemic disease; and patient preferences with regard to invasive therapy.

Systemic Therapy for stable/responding extracranial disease

For patients presenting with a new or progressive intracranial lesion while maintaining stable or responding extracranial disease, typically it’s suggested to continue the current systemic therapy, assuming it has been well-tolerated and a viable local treatment option exists for the intracranial condition. 

Systemic Therapy for progressive extracranial disease or no local treatment 

For patients with both new or progressive intracranial disease and extracranial disease progression, typically adjusting systemic therapies following the administration of local treatment to the brain metastases is recommended.

Furthermore, if a patient exhibits progressive intracranial disease but lacks a viable local therapy option or does not require immediate local intervention, a change in systemic therapy to address both intracranial and extracranial disease may be considered.

The New Data for Brain Metastases

Radiotherapy (RT) remains the standard of care for the initial management of newly diagnosed brain metastases. However, the role of systemic therapy is evolving, particularly for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as evidenced by recent data on trastuzumab deruxtecan (TDXD) in the clinical trial DESTINY-Breast12.

“At ESMO 2024, we got updated data from Dr. Nancy Lin on DESTINY-Breast 12, which looked at patients with either stable treated brain metastasis or untreated brain metastasis and they received trastuzumab deruxtecan,” Dr. Stephanie Graff, Director of Breast Oncology at Brown University’s Legorreta Cancer Center, tells SurvivorNet Connect. 

“Dr. Lin was able to demonstrate that there was a really significant intracranial response rate, improved progression-free survival [and] overall survival in the patient’s treated with trastuzumab deruxtecan,” Dr. Graff adds. 

Notably, the results of this clinical trial do not lead to a new indication for Enhertu, as the current label does not exclude patients with brain metastases. However, the new data, which previously had been limited for this patient population, contribute to the expanding evidence supporting Enhertu’s clinical benefit. The drug yielded a 12-month PFS rate of 61.6% in patients with brain metastases at baseline. 

“I think given the depth of response that we’ve seen with trastuzumab deruxtecan for controlling systemic disease … my preference will probably be trastuzumab deruxtecan in the second line setting,” Dr. Graff explains.

Due to the concern of increasing toxicity, the concomitant use of chemotherapy plus radiation therapy has been in constant debate. In the same conference, ESMO 2024, a group of authors published encouraging data on the safety of this combination. 

“Dr. Lin’s answer (concerning using trastuzumab deruxtecan and radionecrosis) was that her clinical [recommendation] was to give most patients about three weeks between trastuzumab deruxtecan and radiation. That also aligns with my clinical practice. I still tend to consider radiation for patients who are good candidates for that,” Dr. Graff adds.