For HER2+ biliary tract cancer patients with hyperbilirubinemia where stenting isn't possible, zanidatumab is a preferable option over TDXD. Zanidatumab lacks significant hepatotoxicity, whereas TDXD's irinotecan-like payload poses a risk in patients with moderate hepatic impairment.
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Relying solely on Next-Generation Sequencing (NGS) is insufficient for HER2 testing in biliary tract cancers. Data shows NGS misses up to 15% of patients with HER2 overexpression detected by immunohistochemistry (IHC). Performing both tests is essential to avoid denying patients effective targeted therapies.
Trastuzumab deruxtecan (TDXD) and datopotamab deruxtecan (Dato-DXd) share the same cytotoxic payload, yet Dato-DXd has a much lower rate of interstitial lung disease (ILD). This indicates the toxicity is driven by the antibody-antigen interaction, not the payload itself.
Positive data from both DESTINY-Breast09 (TDXD-based) and PATINA (CDK4/6i maintenance) create a new dilemma. With similar PFS outcomes, the first-line choice for metastatic HER2+/HR+ patients now hinges on toxicity profiles and patient preference rather than a single efficacy winner.
Unlike T-cell engaging therapies, the bispecific antibody zanidatumab does not cause cytokine release syndrome (CRS). This unique safety feature is because it binds to two distinct sites on the HER2 receptor itself, rather than engaging T-cells, providing a key toxicity advantage.
In the HORIZON-BTC-01 trial, early response to zanidatumab is a powerful prognostic indicator. A landmark analysis showed that patients who responded by week nine had a median overall survival of 25 months, highlighting the importance of early tumor assessment in predicting long-term outcomes.
The HORIZON-GEA-01 trial for zanidatumab in gastric cancer mandated prophylactic loperamide (4mg BID) for all patients. This was necessary to manage the high rates of diarrhea (up to 80% of patients), a significant GI toxicity associated with the drug's mechanism of action.
In HER2-positive colorectal cancer, the choice of targeted therapy depends on RAS mutation status. The tucatinib/trastuzumab combination is effective only in RAS wild-type patients. In contrast, the antibody-drug conjugate trastuzumab deruxtecan (TDXD) shows efficacy regardless of whether a RAS mutation is present.
Contrary to concerns about cross-resistance between HER2 antibody-drug conjugates (ADCs), retrospective data shows TDM-1 remains effective after progression on TDXD. This suggests the different cytotoxic payloads are key, allowing for effective sequencing and challenging the assumption that progression on one ADC class member precludes using another.
In the DESTINY-CRC02 trial, the lower 5.4 mg/kg dose of trastuzumab deruxtecan (TDXD) resulted in a higher response rate in colorectal cancer compared to the 6.4 mg/kg dose used in gastric cancer. This counter-intuitive finding suggests better tolerability led to longer treatment duration and superior outcomes.
In the rare case of a biliary tract cancer with both HER2 positivity and an FGFR2 fusion, clinicians should likely prioritize an FGFR inhibitor. FGFR2 fusions are considered more homogenous and potent early driver events compared to the often heterogeneous expression of HER2.