New and Evolving: Pretreatment Risk Factors for Pneumonitis and Trastuzumab-Deruxtecan

Each year in the United States, approximately 297,790 women and 2800 men are diagnosed with human epidermal growth factor receptor 2 (HER2)-positive breast cancer.¹ Trastuzumab deruxtecan (T-DXd, Enhertu; Daiichi-Sankyo, AstraZeneca) is an FDA-approved antibody-drug conjugate for treatment of HER2-positive and HER2-low metastatic breast cancer.²

Pneumonitis is inflammation of lung tissue | Image credit: © Sebastian Kaulitzki | stock.adobe.com

T-DXd consists of trastuzumab, a monoclonal antibody that targets HER2, and deruxtecan, a cytotoxic agent released into cancer cells causing DNA damage and cell death.² When compared to traditional chemotherapy or trastuzumab emtansine (Kadcyla; Genentech), studies published in the New England Journal of Medicine conclude that T-DXd decreases the risk of disease progression and lengthens progression-free survival.^3,4 Despite these promising results, this medication may come with significant risks.

T-DXd has a boxed warning for interstitial lung disease (ILD) and pneumonitis.² ILD includes chronic lung conditions leading to inflammation and scarring, whereas drug-induced pneumonitis is inflammation of lung tissue caused by drug therapy. ILD and pneumonitis commonly present as shortness of breath, dry cough, chest pain, fever, and fatigue. Up to 15% of patients treated with T-DXd experience ILD and pneumonitis.²

Established risk factors for patients developing pulmonary toxicity include pulmonary comorbidities (asthma, chronic obstructive pulmonary disease, prior ILD/pneumonitis, etc.), baseline oxygen saturation less than 95%, age younger than 65 years, higher doses of T-DXd, kidney impairment, and longer than 4 years since initial diagnosis.²

A team of researchers from The Ohio State University (OSU) published a study that evaluates pretreatment variables that may increase the risk of developing T-DXd pneumonitis. The retrospective, single academic center study enrolled 179 patients with breast cancer who received at least 1 dose of T-DXd from January 2019 to February 2024.²

Of the study patients, 23 (12.8%) developed pneumonitis after T-DXd therapy. These patients presented with lower baseline oxygen saturations (97% vs 98%) and more frequently received abemaciclib (26.1% vs 9.6%; Verzenio, Lilly) prior to T-DXd. Although the difference between 97% and 98% seems small, these results are statistically significant and indicate that abemaciclib may be a risk factor for T-DXd pneumonitis. Alternatively, abnormalities on pretreatment chest imaging and previous treatment radiation did not increase the risk of T-DXd pneumonitis.²

Few studies have examined the impact of pretreatment chest imaging, prior radiation treatment, and systemic treatment on the development of T-DXd pneumonitis. Researchers at OSU investigated these factors, yet the study’s small size and single-center design limit the study's applicability to a broader population. Larger studies are required to confirm whether prior treatment with abemaciclib is a risk factor for T-DXd pneumonitis.²

References

1. Malhotra P. HER2-Positive Breast Cancer: Testing, Treatment, Research. Breast Cancer Research Foundation. Accessed February 19, 2025. https://www.bcrf.org/about-breast-cancer/her2-positive-breast-cancer-treatment-research/

2. Henricks J, Haddad T, Ahmed O, et al. Evaluating risk factors for trastuzumab-deruxtecan pneumonitis in patients with metastatic breast cancer. Breast Cancer Res. 2025;27(1):16. doi:10.1186/s13058-025-01967-1

3. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386:1143-1154. doi:10.1056/NEJMoa2115022

4. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690