Trastuzumab Deruxtecan Produces Activity in Metastatic Breast Cancer With Brain Mets, Irrespective of HER2 Status

Fam-trastuzumab deruxtecan-nxki (Enhertu) induced meaningful antitumor activity in patients with HER2-positive, HER2-low, or HER2-negative metastatic breast cancer who presented with brain metastases at baseline, according to data from the phase 2 DAISY trial (NCT04132960) presented at the 2022 ESMO Congress.

Among all patients who presented with baseline brain metastases (n = 24), trastuzumab deruxtecan elicited a best objective response rate (BOR) of 62.5% (95% CI, 40.6%-81.2%). Patients with HER2-positive breast cancer (n = 12; cohort 1) achieved a confirmed BOR of 91.7% (95% CI, 61.5%-99.8%). Those with HER2-low breast cancer (n = 10; cohort 2) experienced a BOR of 30% (95% CI, 6.7%-65.2%) while patients with HER2-negative breast cancer (n = 2; cohort 3) had a BOR of 50% in (95% CI, 1.3%-98.7%).

“Efficacy in patients with HER2-low metastatic brain cancer and brain metastases looks promising and warrants further investigation,” lead study author Nicolas Epaillard, MD, of the Department of Medical Oncology at Gustave Roussy in Villejuif, France, and colleagues wrote in a poster presentation of the data.

Trastuzumab deruxtecan has demonstrated high efficacy in patients with HER2-overexpressing breast cancer and in patients that do not overexpress HER2. DAISY investigated the antibody-drug conjugate’s efficacy in patients with HER2-overexpressing, HER2-low, or HER2-negative metastatic breast cancer. Investigators presented a subgroup analysis of patients with baseline brain metastases at ESMO.

The trial enrolled patients who were at least 18 years of age and received at least 1 prior chemotherapy regimen in metastatic setting. Patients with clinically inactive brain metastases at baseline were permitted to enroll.

Patients in cohort 1 were required to have previous taxane treatment and be resistant to trastuzumab (Herceptin) and ado-trastuzumab emtansine (Kadcyla). Patients in cohort 2 needed to have prior treatment with anthracyclines and taxanes, and, if they were hormone receptor (HR)–positive, be resistant to CDK4/6 inhibitors. Those in cohort 3 needed to have prior treatment with anthracyclines and taxanes, and, if they were HR-positive, be resistant to CDK4/6 inhibitors plus hormonal therapy.

All enrolled patients received intravenous trastuzumab deruxtecan at 5.4 mg/kg once every 3 weeks until disease progression or unacceptable toxicity.

The primary end point of the study was confirmed BOR in each cohort by investigator assessment. Secondary end points included progression-free survival (PFS), overall survival, duration of response, clinical benefit rate (CBR), and safety.

The median age of all patients with baseline brain metastases was 58 years (range, 24- 70). Nine patients were premenopausal and 15 were post-menopausal. Ten patients had a WHO performance status of 0 and 14 patients had a WHO performance status of 1. Eleven patients had HR-negative disease and 13 had HR-positive disease.

Prior lines of treatment in the metastatic setting included 1 (n = 1), 2 (n = 3), 3 (n =3), 4 (n = 5), and 5or more (n = 12).

Among the overall population with baseline brain metastases, the CBR was 70.8% (95% CI, 48.9%-87.4%). The median PFS was 8.5 months (95% CI, 4.4-12.2).

In cohort 1, the CBR was 91.7% (95% CI, 61.5%-99.8%) and the median PFS was 13 months (7.1–not reached [NR]). In cohort 2, the CBR and median PFS were 50% (95% CI, 18.7%-81.3%) and 4.1 months (2.3-11.7), respectively. The CBR for cohort 3 was 50% (95% CI, 1.3%-98.7%), and the median PFS was not evaluable (95% CI, 2.0-NR).

Overall, 7 of 24 patients with baseline brain metastases died during the trial, including 3 patients in cohort 1, 4 patients in cohort 2, and no patients in cohort 3.

Among the overall population with baseline brain metastases, 3 patients experienced interstitial lung disease (ILD). Two instances of ILD were due to treatment with trastuzumab deruxtecan, and both were grade 1. The other event was grade 2 and not drug related. No drug-related deaths were reported.

“No new safety signals were reported in patients with previously treated brain metastases,” study authors concluded.

References

Epaillard N, Lusque A, Pistilli B, et al. Antitumor activity of trastuzumab deruxtecan (T-DXd) in patients with metastatic breast cancer (mBC) and brain metastases (BMs) from DAISY trial. Ann Oncol. 2022;33(suppl 7):S656. doi:10.1016/j.annonc.2022.07.299