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SAN ANTONIO -- Combination therapy including a bispecific antibody targeting HER2 showed durable activity in patients with previously treated metastatic hormone receptor-positive (HR+)/HER2+ breast cancer, a preliminary clinical trial showed.

Two-thirds of patients remained progression-free at 6 months (PFS6), and median progression-free survival (PFS) was 12 months with zanidatamab plus palbociclib (Ibrance) and fulvestrant. In a subset of patients with centrally confirmed HER2 status, almost half of the patients had objective responses, including three complete responses.

A majority of patients achieved PFS6 across PAM50 subtyping, including basal-like, HER2-enriched, and luminal B, reported Santiago Escrivá-de-Romani, MD, of Vall d'Hebron Institute of Oncology in Barcelona, at the San Antonio Breast Cancer Symposium.

"Zanidatamab in combination with palbociclib and fulvestrant demonstrated a promising PFS outcome, durable responses, and a manageable safety profile in these heavily pretreated patients," said Escrivá-de-Romani. "These results support further development of this novel chemotherapy-free regimen.

In contrast to other HER2-targeted therapies, zanidatamab simultaneously binds to two non-overlapping extracellular domains of HER2. The dual binding sets in motion a including receptor crosslinking, clustering, internalization, and downregulation; inhibition of tumor cell signaling and proliferation; and immune-mediated antitumor effects.

In a , zanidatamab demonstrated activity across a range of solid tumors with HER2 overexpression or amplification. Earlier this year, a study involving patients with heavily treated HER2-expressing biliary cancer showed a response rate exceeding 40% with the bispecific antibody.

Previous studies of HER2-targeted therapy combined with an estrogen receptor antagonist, , demonstrated a meaningful benefit in patients with HR+/HER2+ metastatic breast cancer. Escrivá-de-Romani reported findings from a single-arm continuing that line of investigation.

Eligible patients had unresectable locally advanced/metastatic HR+/HER2+ breast cancer previously treated with trastuzumab, pertuzumab (Perjeta), and T-DM1 (Kadcyla) but no prior exposure to a CDK4/6 inhibitor. HER2 status was assessed locally at enrollment and reassessed via central testing (ccHER2+). The primary endpoints were safety and PFS6.

The study population comprised 51 patients, including 32 with ccHER2+ status and 18 who were HER2+ by local assessment but HER2- by central review (non-ccHER2+). One patient had missing data. Additionally, 29 patients with adequate tissue samples had PAM50 subtyping.

The patients had a median age of 54, three-fourths had prior endocrine therapy, and a fifth had received fulvestrant in any setting.

Two-thirds of the patients had grade 3/4 treatment-related adverse events (TRAEs), the most common being neutropenia/decreased neutrophil count (53%), diarrhea (14%), and anemia (10%). One serious TRAE occurred, elevated transaminases, which resolved without incident. With respect to adverse events of special interest, six patients had decreased ejection fraction (one grade 3/4) and two had infusion-related reactions.

One patient discontinued treatment because of grade 1 asthenia (attributed to all drugs) and two discontinued palbociclib, one each because of diarrhea and transaminases. Escrivá-de-Romani reported that 14 patients died during treatment, 12 because of disease progression, one of a COVID-19-related adverse event, and one with causation as-yet undetermined.

The PFS6 rate was similar in all 51 patients (67%), the ccHER2+ subset (69%), and the non-ccHER2+ subgroup (63%). Objective response rate was 35% overall, including 48% in the ccHER2+ subgroup. Three patients had complete response, all in the ccHER2+ group. The disease control rate was 91% in all patients, 93% in the ccHER2+ group, and 88% in the non-ccHER2+ group.

Median duration of response was 15 months overall, 14 months in the ccHER2+ group, and not evaluable in the non-ccHER2+ patients. About 80% of the patients has some degree of tumor shrinkage.

In the 29 patients with PAM50 data, 19 (66%) achieved PFS6, including the only patient with basal-like subtype, 10 of 16 with HER2-enriched subtype, and eight of 12 with luminal B subtype.

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