Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer

Abstract

Purpose Anti-human epidermal growth factor receptor 2 (HER2) therapies are associated with interstitial lung disease (ILD), also referred to as pneumonitis. In this literature review, we describe the incidence of ILD among patients with HER2-positive metastatic breast cancer (MBC) receiving anti-HER2 therapies, and we describe existing recommendations for monitoring and managing drug-induced ILD among these patients. Methods We searched PubMed and Embase to identify clinical trials and postmarket observational studies that investigated anti-HER2 therapies for HER2-positive MBC, reported on ILD, and were published during January 1, 2009 to July 15, 2019. Articles were screened by two researchers; data were extracted from the full-text articles. Results The 18 articles selected for this review assessed 9,886 patients who received trastuzumab (8 articles), lapatinib (4 articles), trastuzumab emtansine (3 articles), trastuzumab deruxtecan (2 articles), or trastuzumab duocarmazine (1 article). The overall incidence of all-grade ILD was 2.4% (n = 234), with 66.7% (n = 156) occurring as grade 1-2 events, 0.5% grade 3-4 (n = 54; incidence), and 0.2% grade 5 (n = 16; incidence). The highest ILD incidence (21.4%) was among patients receiving trastuzumab combined with everolimus and paclitaxel. Ten studies indicated that ILD events were managed via dose interruption, dose reduction, or treatment discontinuation; two studies included detailed guidelines on managing druginduced ILD. Conclusions ILD is a well-described adverse drug reaction associated with several anti-HER2 drugs. Published ILD management guidelines are available for few anti-HER2 treatment regimens; however, guidance for monitoring for anti-HER2 drug-induced ILD is lacking.

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody–MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors

“…Based on previous studies, interstitial lung disease, also referred to as pneumonitis, is a rare but shared adverse event in several anti-HER2 drugs, including trastuzumab(9.9%), lapatinib (0.2%), T-DM1 (0.5%), DS-8201 (9.0%), and trastuzumab duocarmazine (7.7%) [ 17 , 18 ]. However, no treatment-related lung damage was reported in our present phase I trial of RC48.…”

Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects

“…Notably, unlike the other receptor tyrosine kinase inhibitors erlotinib and gefitinib, lapatinib monotherapy has not been associated with pneumonitis, interstitial lung disease or lung fibrosis (Blackwell et al, 2010;Blackwell et al, 2009;Burris et al, 2005;Burstein et al, 2008;Gomez et al, 2008;Hurvitz and Kakkar, 2012;Perez et al, 2008;Toi et al, 2009). The estimated incidence of 0.2% for these adverse effects is based on 8 cases reported in three phase 3 clinical trials and several additional case reports, all in patients receiving lapatinib in combination with other drugs (Bates et al, 2019a;Brenner et al, 2010;Capri et al, 2010;Hackshaw et al, 2020;Jagiello-Gruszfeld et al, 2010;Xu et al, 2011) known to cause pneumonitis and/or lung fibrosis (Bielopolski et al, 2017;Chan et al, 2011;Torrisi et al, 2011), and sometimes also with radiation, for a median duration of 24-45 weeks. We predict that the distinct off-target profile of lapatinib compared with erlotinib and gefitinib accounts for the difference in the occurrence of these adverse events.…”

“…Notably, unlike erlotinib and gefitinib, lapatinib monotherapy has not been associated with pneumonitis, interstitial lung disease or lung fibrosis 4–11 . The estimated incidence of 0.2% for these adverse effects is based on patients receiving lapatinib in combination with other drugs 15–20 known to cause pneumonitis and/or lung fibrosis 21–23 , and sometimes also with radiation, for a median duration of 24-45 weeks. We predict that lapatinib’s distinct off-target profile accounts for this difference in the occurrence of these adverse events.…”

Clinical Development of New Antibody–Drug Conjugates in Breast Cancer: To Infinity and Beyond

“…Other HER2-directed therapies, including trastuzumab, trastuzumab emtansine, and topoisomerase I inhibitors, have been associated with pulmonary toxicity; however, trastuzumab deruxtecan has higher rates, including some grade 5 events [27].…”