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Clinicians should be cautious not to conflate the remarkable CNS activity of trastuzumab deruxtecan (T-DXd) in HER2-positive disease with that of other ADCs, like TROP2-ADCs, in HER2-low or negative settings. Data is emerging for TROP2-ADCs, but their CNS activity is expected to be much more modest.
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Contrary to the expectation that large molecules like antibody-drug conjugates (ADCs) cannot penetrate the blood-brain barrier, Trastuzumab-Deruxtecan demonstrates significant CNS activity, with response rates over 40% in lung cancer patients with brain metastases. This finding is changing treatment paradigms and challenging long-held assumptions about drug delivery to the brain.
While Trastuzumab deruxtecan (TDXD) is effective in HER2-low breast cancer, there is no evidence that it benefits patients with HER2-low or HER2-intermediate (IHC 2+/FISH negative) gastric cancer. Its use should be strictly limited to truly HER2-positive cases in this disease.
Beyond overall response rates, a critical area of excitement for new ADCs in lung cancer is their potential to treat brain metastases. Early data showing hints of intracranial efficacy is a significant point of interest, as this addresses a common and difficult-to-treat site of disease progression, offering a potential advantage over other therapies.
Unlike the standard chemotherapy regimen TCHP, the newer drug T-DXd can cross the blood-brain barrier. This is a crucial advantage for high-risk HER2-positive breast cancer patients, as it offers the potential to prevent brain metastases, a common and devastating site of recurrence for this cancer subtype.
The B7H3-targeted antibody-drug conjugate (ADC) ifanatumab deruxtecan shows a high intracranial response rate in SCLC, numerically even better than its systemic response rate. This suggests excellent CNS penetration, offering a promising strategy for managing brain metastases, a common and difficult challenge in SCLC.
The concept of an impermeable blood-brain barrier is less relevant once brain metastases are established. The barrier becomes highly permeable, or 'leaky,' allowing even large molecules like antibody-drug conjugates (ADCs) to penetrate the CNS. This suggests that any therapy systemically active in the periphery has potential CNS activity.
Contrary to expectations, TROP2 expression is not a reliable predictive biomarker for response to TROP2-targeting antibody-drug conjugates (ADCs). These drugs have shown activity across various expression levels, challenging the standard biomarker-driven approach to patient selection.
The differing efficacy and toxicity profiles of TROP2 ADCs like sacituzumab govitecan and Dato-DXD suggest that the drug's linker and payload metabolism are crucial determinants of clinical outcome. This indicates that focusing solely on the target antigen is an oversimplification of ADC design and performance.
Unlike the intact blood-brain barrier, the blood-tumor barrier within brain metastases is permeable. This "leakiness" allows large molecules like the ADC trastuzumab deruxtecan (TDXD) to enter and deliver its payload, providing a mechanism for its high CNS efficacy.
Clinicians are cautioned against oversimplifying ADCs. Factors like linker chemistry, cleavability, and drug-antibody ratio are critical variables. Even with the same target and payload class, these biochemical nuances can lead to profoundly different efficacy and toxicity profiles.
