Bispecific Antibody Combination Active in Metastatic HR+/HER2+ Breast Cancer

Derick Alison
Derick Alison
6 Min Read

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 variety of antitumor activities including receptor crosslinking, clustering, internalization, and downregulation; inhibition of tumor cell signaling and proliferation; and immune-mediated antitumor effects.

In a phase I study, 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, with or without a CDK4/6 inhibitor, demonstrated a meaningful benefit in patients with HR+/HER2+ metastatic breast cancer. Escrivá-de-Romani reported findings from a single-arm phase IIa trial 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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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Disclosures

The study was supported by Zymeworks, Jazz Pharmaceuticals, and Pfizer.

Escrivá-de-Romani disclosed relationships with AstraZeneca, COR2ED, Daiichi Sankyo, Pierre Fabre, Seagen, Novartis, Pfizer, Roche, SOLTI, Byondis, MEDSIR, Synthon, Zymeworks, and Kern.

Primary Source

San Antonio Breast Cancer Symposium

Source Reference: Escrivá-de-Romani S, et al “Primary results from a phase 2a study of zanidatamab in combination with palbociclib plus fulvestrant in HER2+ HR+ metastatic breast cancer” SABCS 2023; Abstract LB-04.

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