(048) Comparison of Toxicity Profile of Fam-trastuzumab Deruxtecan in HER2+ and HER2-low Metastatic Breast Cancer

Poster Abstract: Background and

Objective:
Fam-trastuzumab deruxtecan (Enhertu®) or T-DXd, an antibody-drug conjugate (ADC) that links a HER2-directed monoclonal antibody with a topoisomerase I inhibitor payload, is approved for treating HER2+ and HER2-low metastatic breast cancer based on DESTINY-Breast 03 and 04 trials, respectively. The proposed mechanism of T-DXd for the additional therapeutic benefit in HER2-low breast cancer is hypothesized to be due to the higher drug-to-antibody ratio relative to other ADCs in its class and the bystander effect, where the cytotoxic payload acts on neighboring cells. However, due to both mechanisms, it is also hypothesized that HER2-low patients treated with T-DXd could experience greater toxicity compared to HER2+ patients as a result of non-specific release of the cytotoxic payload. Although a cross-comparison between the DESTINY-Breast 03 and 04 trials demonstrated similar toxicity rates, HER2-low subjects were heavily pre-treated in DESTINY-Breast 04 relative to HER2+ subjects in DESTINY-Breast 03. The heterogeneity in baseline characteristics between these trials makes it difficult to draw meaningful conclusions by comparing the incidences of adverse effects. The objective is to directly compare toxicity rates in HER2+ and HER2-low metastatic breast cancer patients treated with T-DXd.

Methods:
A single-center retrospective chart review will be conducted from August 5th, 2022 to August 5th, 2023 at Fred Hutchinson Cancer Center in Seattle, WA. This study included patients who were ≥18 years or older who received at least 1 dose of T-DXd for the treatment of metastatic breast cancer. Patients who received T-DXd as part of an investigational drug service protocol, received off-label dosing, or treated for any indication other than breast cancer were excluded. Data collection will include baseline characteristics, T-DXd dose, number of cycles received, number of dose reductions, reasons for discontinuation, dose holds/delays, the use of secondary growth factor prophylaxis, and incidences of adverse effects of interest (nausea/vomiting, neutropenia, febrile neutropenia, interstitial lung disease, and cardiotoxicity).

The primary endpoint is the cumulative incidence of T-DXd associated adverse effects of interest in HER2+ and HER2-low metastatic breast cancer patients. The secondary endpoints are the rate of discontinuation, dose holds/delays due to toxicity, incidence of secondary growth factor prophylaxis, and median number of cycles received.

Nominal baseline characteristics will be analyzed using a Chi-square test, while continuous data will be analyzed with an ANOVA test. Primary and secondary outcomes will be analyzed with an ANOVA test with a p-value of < 0.05 indicating statistical significance.

Results:
Results are in progress.

References (must also be included in final poster): 1. Enhertu [package insert]. Basking Ridge, NJ: Daiichi Sankyo. Inc; 2022
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3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. PMID: 35665782; PMCID: PMC10561652.
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