乌鸦传媒

In the past, human epidermal growth factor receptor 2-positive (HER2+) breast cancer had a poor prognosis and did not respond well to chemotherapy. However, the approval of targeted therapies has revolutionized the treatment of HER2+ disease. These therapies have led to significant improvements in survival rates for patients with HER2+ breast cancer. However, it is important to recognize the adverse events (AEs) associated with these novel agents early, and to develop standardized monitoring and management strategies for them.

T-DXd is an antibody-drug conjugate that consists of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor called deruxtecan. It is approved for the treatment of metastatic HER2-positive and HER2-low breast cancer (BC) in the second-line or later setting. Multiple phase III trials have demonstrated that T-DXd significantly prolongs median progression-free survival (PFS) and overall survival (OS) compared with other agents such as ado-trastuzumab emtansine (T-DM1), and trastuzumab combined with chemotherapy.

One of the most common AEs reported with T-DXd is interstitial lung disease (ILD), which occurred in up to 10.5% and 12.1% of patients in the phase III DESTINY-Breast03 and DESTINY-Breast04 trials, respectively.

Besides T-DXd, other drugs used in this population, like inhibitors of the mechanistic target of rapamycin, checkpoint inhibitors, and cyclin-dependent kinase 4/6 inhibitors can also result in ILD/pneumonitis. For these reasons, it is important to establish institution-specific protocols for ILD monitoring and management.

The DESTINY-Breast03 and DESTINY-Breast04 protocols for monitoring and managing ILD/pneumonitis associated with T-DXd include a baseline evaluation with complete history and physical examination, high-resolution computed tomography (HRCT), baseline oxygen saturation, and pulmonary consultation for patients with significant lung comorbidities. Patients were then monitored for signs and symptoms of pneumonitis at each clinic visit. If ILD was suspected on clinical assessment, T-DXd treatment was interrupted and further evaluation was performed with HRCT, pulmonary function tests, pulse oximetry, infectious workup, and pulmonary consultation.

A recent retrospective study conducted at the Duke Cancer Institute (DCI) adopted a similar institution-specific protocol. Clinicians at the DCI implemented a protocol consisting of baseline evaluation for clinical symptoms of pneumonitis/ILD (such as cough, shortness of breath, dyspnea, and new or worsening respiratory symptoms), chest imaging with HRCT, and pulmonary function tests with diffusing capacity of the lung for carbon monoxide (DLCO) before initiation of T-DXd and every 6 weeks, before cycles 3 and 5. Patients who had DLCO decrease >10% from baseline were referred to pulmonology for further evaluation of pneumonitis/ILD.

Seven patients with HER2-positive (n=6) and HER2-low (n=1) mBC who received T-DXd were monitored from January 1, 2020, through June 30, 2020, per the protocol described above. All patients completed the protocol, and no confirmed cases of ILD/pneumonitis were observed.

Two patients (28.6%) experienced DLCO decreases greater than 10%. However, pulmonary consultation ruled out pneumonitis/ILD, and the patients continued T-DXd treatment without delay or pneumonitis to date. Both patients had a history of lung disease or significant metastatic disease involvement, including asthma and lymphangitic carcinomatosis, which could have contributed to the drop in DLCO.

The comprehensive protocol used in the study appears to be feasible for patients receiving T-DXd and may prevent treatment delay and even discontinuation by the early recognition and management of pulmonary symptoms. However, the study had a small sample size, which may limit the generalizability of the findings.

However, this study underscores the importance of wide adoption of this protocol for monitoring and management of T-DXd-related ILD. Larger and more longitudinal studies may help to develop and formalize an optimal monitoring strategy for all patients receiving T-DXd.

Arun Kumar, MD, is a hematology/oncology fellow PGY-5 at Medstar Georgetown University Hospital/Medstar Washington Hospital Center in Washington, D.C. Ami A. Chitalia, MD, is a hematologist and medical oncologist at Washington Cancer Institute, MedStar Washington Hospital Center, in Washington, D.C.

Read the review paper by Hope Rugo, MD, and co-authors here and an interview about it here.