Abstract P4-07-53: Adverse events (AEs) in phase III clinical trials of patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC): a meta-analysis
Authors: Henderson Mackenzie , Yalamanchili Priyanka , Wang Eric , Salas Maribel 
Published: March 2023

Abstract
Background. In the last five years, several new drugs have been approved for BC in the United States, many of which target HER2, including neratinib, margetuximab, tucatinib, and trastuzumab deruxtecan. These approvals depend on a drug’s benefits outweighing its risks in clinical trials (CTs). However, limited information on safety is available from single CTs. The objective of this study is to identify recently published phase III CTs that report AEs in patients (pts) with HER2+ BC and perform a meta-analysis to estimate the frequency of the most common AEs reported in ≥2 CTs. Methods. A literature search was conducted (Ovid, ClinicalTrials.Gov) to identify phase III CTs published from 2017-2021. Search terms included BC, HER2+, phase III, CT, and others. Articles were independently screened by two researchers in two levels (title/abstract; full text) and were included if they reported AEs in pts with HER2+ BC. Meta-analysis was performed in Comprehensive Meta Analysis v3 to estimate frequency of AEs using random effects models. Results. Of 519 articles identified, 33 were included for analysis (455 excluded in level 1 screening; 31 excluded in level 2 screening). Most excluded articles were not phase III or did not include only pts with HER2+ BC. BC treatments most commonly included chemotherapy and HER2-targeted agents (e.g., trastuzumab), including antibody-drug conjugates (ADCs; e.g., trastuzumab emtansine). Most trials (N=27) included ≥1 treatment arm with pts who received chemotherapy in combination with a HER2-targeted agent. Fewer trials (N=10) included ≥1 treatment arm with pts who received only a HER2-targeted agent. Across all 33 trials, 181 unique AEs were reported. Specific chemotherapy agents used were not always reported, but included taxanes, anthracyclines, cyclophosphamide, 5-fluorouracil, capecitabine, and carboplatin. In chemotherapy treated pts (with or without reported concomitant HER2-targeted agent), the most frequent any grade AEs were hand-foot syndrome (63.8%, N=1814), alopecia (56.6%, N=9677), and diarrhea (39.9%, N=12628); the most frequent grade ≥3 AEs were neutropenia (21.7%, N=14349), hand-foot syndrome (12.2%, N=2252), and leukopenia (8.4%, N=3852). HER2-targeted agents included trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, and neratinib. In pts treated with any HER2-targeted agent (without reported concomitant chemotherapy), the most frequent any grade AEs were diarrhea (31.7%, N=5518), nausea (30.8%, N=5518), and epistaxis (24.9%, N=3622); the most frequent grade ≥3 AEs were thrombocytopenia (4.8%, N=3980), anemia (4.2%, N=3845), and aspartate aminotransferase increase (3.3%, N=3975). In the subgroup of pts treated with an ADC (trastuzumab emtansine), the most frequent any grade AEs were nausea (41.4%, N=3622), fatigue (31.6%, N=2895), and headache (28.0%, N=3622); the most frequent grade ≥3 AEs were similar to those in pts treated with any HER2-targeted agent. Significant heterogeneity was detected among trials for the outcomes reported here (Q statistic ranged from 12-2176, p&lt; 0.05). No analysis was conducted in pts who received hormone therapy due to limited available information about this group in the included trials. Conclusion. When evaluating pooled data, the most commonly reported AEs in CTs of patients with HER2+ BC varied by drug classes included in treatment regimens. This meta-analysis provides a more comprehensive understanding of the most frequent AEs in this population by pooling patient data from several CTs and will contribute to better contextualize the safety of products used in this population. Future research including real-world studies can be used to better understand the safety profile of these medications.
Citation Format: Mackenzie Henderson, Priyanka Yalamanchili, Eric Wang, Maribel Salas. Adverse events (AEs) in phase III clinical trials of patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC): a meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-53.