Numerous studies have confirmed the therapeutic benefits of combining anti-HER2 therapy with endocrine treatment in patients with advanced triple-positive breast cancer (HR+/HER2+). With the enrichment of new endocrine targeting treatments and anti-HER2 treatment schemes in recent years, there has been exploration into other combination schemes, which are hopeful in providing more effective and less toxic "chemotherapy-free" combination treatments for such patients. At the recently held 46th San Antonio Breast Cancer Symposium (SABCS 2023), Professor Santiago Escrivá-de-Romani from the Vall d'Hebron University Hospital/Vall d'Hebron Institute of Oncology in Spain reported a Phase 2a study using a novel HER2 dual-specific antibody (zanidatamab) combined with palbociclib and fulvestrant to treat advanced triple-positive breast cancer, achieving positive anti-tumor activity and good safety.Study Introduction
Primary results from a phase 2a study of zanidatamab (zani) + palbociclib (palbo) + fulvestrant (fulv) in HER2+/HR+ metastatic breast cancer (mBC)
Background:
HER2+ metastatic breast cancer (mBC) is still incurable, and there is a clinical need to develop new anti-HER2 treatments that avoid chemotherapy. About 50% of patients with HER2+ mBC are also hormone receptor-positive (HR+), making the estrogen pathway an additional target for therapy. The CDK4/6 inhibitor Palbociclib combined with the endocrine therapy Fulvestrant has been approved for use in HER2-/HR+ mBC. Targeting these three pathways may further improve the prognosis for patients with HER2+/HR+ mBC. Zanidatamab is a dual-specific HER2-targeted antibody that binds to HER2 in a unique cross-linking structure, driving multiple mechanisms of action. Previous analysis of the current single-arm phase 2a study (NCT04224272) showed that Zanidatamab combined with Palbociclib and Fulvestrant in patients with HER2+/HR+ mBC, who had undergone multiple treatments, demonstrated anti-tumor activity and tolerable safety. This report focuses on the primary endpoint of six months progression-free survival (PFS 6) among other endpoints.
Method:
Eligible patients had unresectable, locally advanced, or metastatic HER2+ (determined by local HER2 testing)/HR+ breast cancer; an Eastern Cooperative Oncology Group (ECOG) score of ≤1; had previously received treatment with at least trastuzumab, pertuzumab, and T-DM1; and had not previously used a CDK4/6 inhibitor. Patients received Zanidatamab (20 mg/kg every two weeks) + Palbociclib + Fulvestrant (standard dose)—the dosage recommendation was determined during the evaluation in part one. The primary endpoint for part two was six-month progression-free survival (PFS6). Other endpoints included median progression-free survival (mPFS), confirmed objective response rate (ORR, according to RECIST v1.1), disease control rate (DCR), and duration of response (DoR); exploratory analysis with PAM50 was conducted; and a post-hoc analysis was performed on the centrally confirmed HER2+ (ccHER2) subgroup.
Results:
As of August 3, 2023, 51 patients (median age [range] 54 years [36-77]) received treatment with Zanidatamab + Palbociclib + Fulvestrant, with a median follow-up time of 16.1 months. Among these 51 patients, 32 (63%) were centrally confirmed HER2+ (ccHER2+). 9 patients (18%) were still on treatment; the median (range) duration of Zanidatamab treatment was 8.4 months (1.0-29.5 months). Patients had received a median (range) of 4 (1-12) previous systemic treatment regimens for metastatic breast cancer, 3 (1-10) previous anti-HER2 treatments, and 1 (0-5) previous endocrine treatments; 12 patients (24%) had previously received T-DXd, and 11 patients (22%) had previously received Fulvestrant.
The primary endpoint, PFS6, was 67% (69% in the ccHER2+ subgroup). The mPFS was 11.7 months (14.9 months in the ccHER2+ subgroup). See Table 1 for other efficacy endpoints. PAM50 subtyping was available for 29 patients (57%) (1 basal-like; 16 HER2-enriched; 12 luminal B). Compared to HER2-enriched, patients with luminal B subtype had numerically better but not statistically significant mPFS (11.7 months vs 9.3 months; P=0.74) and PFS6 (66.7% vs 62.5%).
Table 1. Efficacy of Triplet Regimen (Zani + Palbo + Fulv) for HER2+/HR+ mBC
Cancer Treatment-related adverse events (TRAEs) most commonly (>20%) associated with zanidatamab, palbociclib, and/or fulvestrant included: diarrhea (80%), neutrophil count decreased/neutropenia (59%), nausea (39%), stomatitis (37%), anemia (29%), vomiting (25%), and asthenia (24%). Grade ≥3 TRAEs occurring in two or more cases included: neutrophil count decreased/neutropenia (53%), diarrhea (14%), anemia (10%), thrombocytopenia (6%), hypokalemia (4%), and hypomagnesemia (4%). One serious TRAE (elevated transaminases) was reported. Adverse events of special interest: 6 patients experienced cardiac events (all with LVEF decrease; 5 patients had Grade 1 or 2 events, 1 patient had a Grade 3 event), and two patients experienced infusion-related reactions (both Grade 1). Due to adverse events, three patients discontinued palbociclib; 1 patient discontinued zanidatamab and fulvestrant due to adverse events. No treatment-related deaths were reported.
Researcher’s Commentary
Oncology Frontier: Could you introduce the novel anti-HER2 antibody Zaniratamab and its uniqueness?
Professor Santiago Escriva-de-Romani: Zaniratamab represents a significant advance in the treatment of HER2+ breast cancer. Its uniqueness lies in its dual-antibody approach, allowing Zaniratamab to bind to two different epitopes on the HER2 receptor, playing a key role in the mechanism of HER2+ breast cancer. This dual-binding feature drives multiple mechanisms of action, including receptor dimerization and various immune-mediated effects. The uniqueness of Zaniratamab also lies in its multifaceted interaction with HER2, offering a broader range of treatment options and potential synergistic effects compared to traditional monoclonal antibodies.
Oncology Frontier: Could you share the latest clinical results of Zaniratamab combined with Palbociclib and Fulvestrant?
Professor Santiago Escriva-de-Romani: Our study primarily focused on the main endpoint of six-month progression-free survival (PFS 6). The patient cohort included individuals who had received extensive treatment, with some having undergone up to fourth-line therapy. Additionally, a portion of the patients had previously been treated with T-DXd, a therapy that has garnered significant attention in the HER2+ breast cancer field. 67% of patients achieved the PFS6 primary endpoint, highlighting the potential efficacy of Zaniratamab + Palbociclib + Fulvestrant combination treatment in a heavily treated patient population. The median PFS reached 12 months. The therapy was well-tolerated. The most common grade 3 and 4 adverse events were diarrhea and neutropenia, but overall tolerability was good. These study results suggest that the combination of Zaniratamab + Palbociclib + Fulvestrant is very promising for treating patients with HR+/HER2+ metastatic breast cancer.
Oncology Frontier: How do you view the role of combination therapy in treating patients with HR+/HER2+ metastatic breast cancer?
Professor Santiago Escriva-de-Romani: Patients with HR+/HER2+ metastatic breast cancer are often managed in a manner similar to those with hormone receptor-negative disease. However, there’s a critical need for more personalized, chemotherapy-free combination therapies specifically for HR+/HER2+ patients. Our study results demonstrate the great potential of combining Zaniratamab + Palbociclib + Fulvestrant: introducing new methods, improving treatment outcomes, and reducing dependence on traditional chemotherapy as much as possible. We hope to see more combination therapies emerge that meet the specific needs of this patient group in the future.
Santiago Escriva-de-Romani
Oncologist at the Vall d’Hebron University Hospital/Vall d’Hebron Institute of Oncology in Spain
