In summary, published data suggest that, despite their large molecular size, ADCs may achieve relevant clinical activity in brain metastases, potentially due to a partially disrupted BBB at the metastatic site.
We observed lower sNSE levels in patients responding to trastuzumab deruxtecan than in nonresponders at 4 weeks after treatment initiation, despite similar baseline levels. This finding may relate to reduced brain parenchyma destruction due to the inhibition of metastatic growth as a direct result of systemic therapy.
With regard to toxicity, no new safety signals were observed and side effects were consistent with the toxicity profile expected from the pivotal trials. One patient was diagnosed with grade 2 interstitial lung disease and therefore had to permanently discontinue treatment, but recovered fully with systemic administration of corticosteroids. Global QoL and cognitive functioning were maintained over the duration of treatment.
Despite the strong biological rationale, the stringent response evaluation by RANO-BM criteria with central response assessment, the availability of biomarkers and extensive QoL evaluation, the present study is limited by the unrandomized phase 2 design and the small sample size and, thus, an inclusion bias cannot be fully excluded.