Dr Gorantla on HER2-Directed Treatment Sequencing in Breast Cancer Brain Metastases

“The concern always becomes: after [patients] progress on T-DXd, are the wheels coming off? Are the patients getting sick because you have selected this clone, which is virulent? [Has the] HER2 expression changed?”

Vikram C. Gorantla, MD, a physician at the University of Pittsburgh Medical Center Hillman Cancer Center, discussed the evolution of treatment sequencing for patients with HER2-positive metastatic breast cancer and brain metastases.

Gorantla emphasized that since the clinical conversation surrounding brain metastases has changed, management objectives have shifted toward strategic sequencing to maximize overall survival. He noted that a critical area of inquiry is treatment crossover: determining whether it is more efficacious to administer fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) followed by a triplet regimen of tucatinib (Tukysa), trastuzumab (Herceptin), and capecitabine (Xeloda), or to use the tucatinib-based regimen first. Gorantla raised concerns regarding the biological behavior of the disease following progression on T-DXd, questioning whether the selection of highly virulent clones or alterations in HER2 expression might lead to rapid clinical deterioration. He noted that the central question remains whether introducing T-DXd in earlier lines fundamentally changes the natural course of the disease or if the addition of the tucatinib-based triplet provides a superior cumulative benefit.

To investigate real-world outcomes with each of these regimens, Gorantla and colleagues conducted a study using patient information from the Integra PrecisionQ Deidentified Database. They identified 255 patients with HER2-positive disease and documented brain metastases who initiated second-line treatment after January 1, 2020. The study cohort included 138 patients treated with T-DXd and 117 patients treated with tucatinib-based therapy. The analysis revealed that T-DXd provided a significant advantage in the primary end point of real-world time to next treatment, with a median of 17 months compared with 11 months for the trastuzumab group (P = .006). Furthermore, the use of T-DXd was associated with a 48% reduced likelihood of requiring subsequent therapy after adjusting for clinical variables (HR: 0.52; 95% CI, 0.37-0.74; P < .001).

Gorantla raised concerns regarding the biological behavior of the disease following progression on T-DXd, questioning whether the selection of highly virulent clones or alterations in HER2 expression might lead to rapid clinical deterioration. He noted that the central question remains whether introducing T-DXd in earlier lines fundamentally changes the natural course of the disease or if the addition of the tucatinib-based triplet provides a superior cumulative benefit.