Zanidatamab Triplet Shows Positive PFS Outcomes in HR+/HER2+ Metastatic Breast Cancer


Zanidatamab in combination with palbociclib and fulvestrant resulted in positive progression-free survival outcomes and exhibited an acceptable safety profile in patients with hormone receptor–positive, HER2-positive metastatic breast cancer.

Santiago Escrivá-de-Romaní, MD

Santiago Escrivá-de-Romaní, MD

Zanidatamab (ZW25) in combination with palbociclib (Ibrance) and fulvestrant (Faslodex) resulted in positive progression-free survival (PFS) outcomes and exhibited an acceptable safety profile in patients with hormone receptor–positive, HER2-positive metastatic breast cancer, according to initial findings from a phase 2a study (NCT04224272) presented during the 2023 San Antonio Breast Cancer Symposium.1

By Aug. 3, 2023, 51 patients in the multicenter study, with a median age of 54 years (range, 36-77) had received treatment with the drug trio, and at a median follow-up of 16 months (range, 2-32) the study’s primary endpoint of six-month progression-free survival (PFS) was 67%, or 34 patients and 69%, or 22 patients, among a subset of 32 patients who were ccHER2–positive.

“Zanidatamab, in combination with palbociclib and fulvestrant demonstrated a promising PFS outcome, durable responses, and a manageable safety profile in this heavily pretreated population. These results support further development of this novel chemotherapy-free regimen,” primary author Santiago Escrivá-de-Romaní, MD, treating physician in medical oncology at Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital in Barcelona, Catalonia, Spain, said during a presentation of the data at the symposium.

Patients with metastatic disease received a median of 4 (range, 1-12) prior systemic treatment regimens, 4 (range, 2-6) previous other HER2-targeted therapies, and 1 (range, 0-5) previous endocrine therapy.

The median PFS was 12 months (95% CI, 8-15) among all patients and 15 months (95% CI, 9-17) among the ccHER2-positive subset. The median duration of response was 15 months (95% CI, 12-25) for all patients and 14 months (95% CI, 11-25) for patients in the ccHER2-positive subset.

Among all patients and the ccHER2-positive subset, disease control rates were 91% (95% CI; 79-98) and 93% (95% CI; 77-99), respectively, and median durations of response were 15 months (95% CI; 12-25) and 14 months (range, 11-25).

Regarding patients with measurable disease — 46 total, 29 in the ccHER2-positive subset—the confirmed objective response rates were 35% (95% CI; 21-50) and 48% (95% CI; 29%-68%), respectively. For those same patients, the confirmed best objective responses occurred for 3 patients in each group who experienced a complete response, 13 and 11 patients who experienced a partial response, and 26 and 13 patients who experienced stable disease, while 4 and 2 patients experienced progressive disease, respectively.

Among the 29 patients with available PAM50 subtyping, the PFS6 rate was 66%, and the median PFS was 9 months (95% CI; 7-14).

Participants in the trial had HER2-positive or HR-positive, unresectable, locally advanced or metastatic breast cancer, with an ECOG performance score of 0 or 1 and had received prior treatment with at least trastuzumab, pertuzumab (Perjeta), and the antibody-drug conjugate trastuzumab emtansine (Kadclya) and had not been previously treated with a CDK4/6 inhibitor.

Treatment-related adverse events (TRAEs) experienced by more than 20% of patients included diarrhea (80%), neutrophil count decrease/neutropenia (59%), nausea (39%), stomatitis (37%), anemia (29%), vomiting (25%), and asthenia (24%).

Grade 3 or higher TRAEs experienced by multiple patients included neutrophil count decrease/neutropenia (53%), diarrhea (14%), anemia (10%), thrombocytopenia (6%), hypokalemia (4%), and hypomagnesemia (4%), and one serious TRAE, increased transaminases, was also reported.

One patient discontinued all treatments due to grade 1 asthenia, 2 patients discontinued palbociclib due to AEs (grade 3 diarrhea and grade 3 increase of transaminases), and 4 patients had dose reductions of zanidatamab due to AEs. There were 14 deaths, although none were known to be related to treatment, with 12 due to disease progression, 1 due to COVID-19, and 1 unknown cause, with causality pending.


Escrivá-de-Romani S, Cejalvo JM, Alba E, et al. Primary results from a phase 2a study of zanidatamab (zani) + palbociclib (palbo) + fulvestrant (fulv) in HER2+/HR+ metastatic breast cancer (mBC). Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract LBO1-04

Related Videos
Jeffery Auletta, MD, The Ohio State University College of Medicine
Betty Hamilton, MD, Cleveland Clinic
Nicholas P. McAndrew, MD, MSCE, University of California, Los Angeles Health
Sarah Sammons, MD
Coral Olazagasti, MD
Samuel Rosner, MD
Sarah Sammons, MD
Balazs Halmos, MD
Wally Curran, MD
Benjamin Levy, MD