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Trastuzumab Deruxtecan Shows Promise in HER2-Mutated NSCLC

• Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with previously treated HER2-mutated non-small cell lung cancer (NSCLC). • The DESTINY-Lung01 trial showed a 55% objective response rate in HER2-mutated NSCLC patients treated with T-DXd at 6.4 mg/kg. • A lower dose of T-DXd (5.4 mg/kg) was approved by the FDA in 2022 for HER2-mutant NSCLC due to comparable efficacy and reduced toxicity. • Ongoing research explores the potential of T-DXd as a frontline therapy for HER2-overexpressing or mutated NSCLC.

Trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate (ADC), is showing promise in treating patients with previously treated HER2-mutated non-small cell lung cancer (NSCLC). Data from the phase 2 DESTINY-Lung01 study (NCT03505710) and DESTINY-Lung02 trial (NCT04644237) support its efficacy and safety profile in this patient population, potentially reshaping treatment paradigms.

DESTINY-Lung01 and DESTINY-Lung02 Trials

The DESTINY-Lung01 study evaluated T-DXd in two cohorts: patients with HER2 overexpression and those with HER2 mutations. According to Dr. Noman Ashraf, patients with HER2 mutations who received T-DXd at 6.4 mg/kg experienced a confirmed objective response rate (ORR) of 55% (95% CI, 44%-65%), a median progression-free survival of 8.2 months (95% CI, 6.0-11.9), and a median overall survival of 17.8 months (95% CI, 13.8-22.1). The DESTINY-Lung02 trial further investigated T-DXd dosing, indicating that a lower dose of 5.4 mg/kg yielded comparable efficacy outcomes with reduced toxicity.

FDA Approval and Dosing Considerations

In 2022, the FDA approved T-DXd at a recommended dose of 5.4 mg/kg for treating patients with HER2-mutant NSCLC, based on the findings from the DESTINY-Lung trials. This approval marked a significant advancement in targeted therapy for this specific subset of lung cancer patients. The decision to approve the lower dose was influenced by the observation that it maintained efficacy while reducing the incidence of adverse events.

HER2 Overexpression vs. Mutation

In the DESTINY-Lung01 trial, patients with HER2 overexpression (defined as HER2 expression of 2+ or 3+ per immunohistochemistry) who received T-DXd at 6.4 mg/kg had a lower ORR of 26.5% (95% CI, 15.0%-41.1%) compared to the HER2-mutated cohort. This suggests that HER2 mutation status may be a more predictive biomarker for T-DXd response than HER2 overexpression alone. Both DESTINY-Lung01 and DESTINY-Lung02 administered T-DXd in the second line and beyond, highlighting its utility in later-line settings.

Future Directions and Frontline Potential

There is growing interest in exploring the use of ADCs like T-DXd as frontline therapy for patients with HER2 overexpression or mutations. While current data primarily support its use in later lines of treatment, ongoing research aims to determine its efficacy and safety as an initial treatment option. The potential for ADCs to shift to the frontline setting could redefine the treatment landscape for HER2-positive NSCLC.

Safety Considerations

ADC-related toxicities generally resemble those seen with chemotherapy, including cytopenias and alopecia. However, a unique risk associated with ADCs is interstitial lung disease (ILD), which can be fatal in some cases. Therefore, managing and minimizing ILD risk is crucial to optimize patient outcomes when balancing therapeutic efficacy and safety.
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Reference News

[1]
Dr Ashraf on the Utility of T-DXd in HER2-Mutated NSCLC - OncLive
onclive.com · Nov 7, 2024

Noman Ashraf discusses the benefits of T-DXd in HER2-mutated and -overexpressing NSCLC, noting higher efficacy in HER2-m...

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