The FDA has approved use of the PATHWAY anti-HER2/neu rabbit monoclonal primary antibody as a companion diagnostic to identify patients with HER2-low metastatic breast cancer who are eligible for treatment with trastuzumab deruxtecan.
The FDA has approved use of the PATHWAY anti-HER2/neu (4B5) rabbit monoclonal primary antibody as a companion diagnostic to identify patients with HER2-low metastatic breast cancer (MBC) who are eligible for treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu).1
Roche, developer of the antibody, announced the approval in a news release October 4, 2022. The FDA approved T-DXd for patients with unresectable or metastatic HER2-low breast cancer in August 2022. It is the first approved therapy targeted to patients with the HER2-low breast cancer subtype.2
Investigators for the DESTINY-Breast04 trial (NCT03734029), data from which were initially presented at the 2022 ASCO Annual Meeting, were the first to identify the concept of HER2-low breast cancer. Low expression of HER2 is defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.3
“Previously, metastatic breast cancer patients with a lower level of HER2 expression were considered to be part of the HER2-negative population and had no HER2-targeted treatment options,” Thomas Schinecker, chief executive officer of Roche Diagnostics, said in a news release. “Now, they may be eligible for a HER2-targeted therapy, significantly increasing the number of patients who could have improved outcomes.”
The PATHWAY anti-HER2 (4B5) test includes a scoring algorithm that helps pathologists to identify “low expressors” of HER2. With this lower cutoff, the test is able to identify patients who may benefit from T-DXd as a treatment option.
In DESTINY-Breast04, Modi et al assigned 557 patients with HER2-low MBC to 5.4 mg/kg of T-DXd every 3 weeks (n = 373) or investigator’s choice chemotherapy (n = 184). The median progression-free survival in the overall cohort was 9.9 months (95% CI, 9.0-11.3) with T-DXd and 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63; P <.001). The median overall survival was 23.4 months (95% CI, 20.0-24.8) in the T-DXd group and 16.8 months (95% CI, 14.5-20.0) in the chemotherapy group (HR, 0.64; 95% CI, 0.49-0.84; P = .001).
Patients remained on treatment for a median of 8.2 months in the T-DXd arm vs 3.5 months in the chemotherapy arm. Patients discontinued treatment because of adverse effects at a rate of 16.2% with T-DXd vs 8.1% in the chemotherapy arm, with dose reductions in 22.6% vs 38.4%, respectively.
More recently, an analysis of patient reported outcomes (PRO) in the DESTINY-Breast04 trial presented at the ESMO Congress 2022 showed that the antibody-drug conjugate may be more tolerable than physician’s choice of therapy. Patients assigned to T-DXd experienced longer time to definitive deterioration (TDD; HR, 0.69; 95% CI, 0.52-0.92; P = .0096), physical functioning TDD (HR, 0.53; 95% CI, 0.40-0.70; P < .0001), emotional functioning TDD (HR, 0.69; 95% CI, 0.50-0.96; P = .0266), and social functioning TDD (HR, 0.59; 95% CI, 0.45-0.77; P = .0001).4
For pain symptoms, the TDD between the experimental and control arms were 16.4 months (95% CI, 13.1-21.5) and 6.1 months (95% CI, 4.2-7.5), respectively. The hazard ratio for pain symptom TDD was 0.40 (95% CI, 0.30-0.54; P < .0001).