FDA Green Lights Companion Diagnostic for Trastuzumab Deruxtecan in Metastatic HER2-Low Breast Cancer

October 4, 2022

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).

References

Roche receives FDA approval for first companion diagnostic to identify patients with HER2 low metastatic breast cancer eligible for ENHERTU. News release. Roche. October 4, 2022. Accessed October 4, 2022. https://bit.ly/3SQOKF2
FDA approves first targeted therapy for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed October 4, 2022. https://bit.ly/3CvkZ7i
Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
Ueno NT, Jacot W, Yamashita T, et al. Patient-reported outcomes (PROs) from DESTINY-Breast04, a randomized phase III study of trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low metastatic breast cancer (MBC). Ann Oncol. 2022;33(suppl 7):S632-S633. doi:10.1016/j.annonc.2022.07.256