CD47 Expression Levels Predict Response to Evorpacept Plus Zanidatamab in HER2+ Breast Cancer
Exploratory analysis from a phase 1/2 trial shows CD47 expression levels predict response to evorpacept plus zanidatamab in heavily pretreated HER2-positive metastatic breast cancer patients, supporting biomarker-driven patient selection.
CD47 expression levels were predictive of response to the CD47 inhibitor evorpacept (ALX148) plus zanidatamab-hrii (Ziihera) in heavily pretreated patients with confirmed HER2-positive metastatic breast cancer, according to findings from an exploratory analysis of a phase 1/2 trial (NCT05027139). The full dataset from the phase 1/2 trial have been submitted for presentation at a future scientific meeting.
Data from the exploratory analysis showed that the responses were largely limited to patients with higher levels of CD47 expression.
The chief medical officer at ALX Oncology stated that these new findings support a CD47-dependent, HER2-driven biology for evorpacept. The company believes that a biomarker-driven approach incorporating CD47 expression may optimize patient selection for evorpacept combinations with HER2-targeted agents. The data from this trial and the phase 2/3 ASPEN-06 clinical trial (NCT05002127) reinforce confidence in the ongoing phase 2 ASPEN-09-Breast trial (NCT07007559).
The trial evaluated the combination in patients with previously treated, unresectable, locally advanced or metastatic HER2-expressing cancers, including breast cancer. Patients needed to have an ECOG performance status of 0 or 1. Those with treated, stable brain metastases were permitted to enroll.
Cohort 1 enrolled patients with HER2-positive breast cancer, defined as immunohistochemistry (IHC) 3+ or IHC 2+ and in situ hybridization positive, who had received at least 3 prior treatment regimens, including trastuzumab (Herceptin); pertuzumab (Perjeta); and ado-trastuzumab emtansine (Kadcyla) or tucatinib (Tukysa) or fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu). Cohort 2 enrolled patients with HER2-low breast cancer, and cohort 3 included those with HER2-positive gastroesophageal adenocarcinoma or other HER2-overexpressing non-breast cancers.
In part 1 safety portion, patients in cohort 1 received zanidatamab at 1200 mg (if weighing < 70 kg) or 1600 mg (if weighing ≥ 70 kg) plus evorpacept at 20 mg/kg (part 1A dose) or 30 mg/kg (part 1B dose) every 2 weeks in 28-day cycles. Patients in cohort 1 in the part 2 expansion portion received the combination at the recommended phase 2 dose, which included the part 1B dose of evorpacept. The primary end point in part 1 was safety. The primary end point in part 2 was confirmed overall response rate (cORR). Key secondary end points in part 2 included progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), and safety.
The biomarker findings among the patients with breast cancer from the phase 1/2 trial bolster data from the ASPEN-06 trial, which investigated evorpacept plus trastuzumab, ramucirumab (Cyramza), and paclitaxel in patients with advanced, HER2-overexpressing gastric/gastroesophageal junction adenocarcinoma. ASPEN-06 also showed that CD47 expression level was predictive of durable response with evorpacept in this patient population.
The ongoing ASPEN-09 trial is investigating evorpacept in combination with other anticancer therapies in patients with advanced or metastatic cancers. The single-arm ASPEN-09-Breast substudy is evaluating the efficacy, safety, and tolerability of evorpacept plus trastuzumab and chemotherapy in patients with HER2-positive metastatic breast cancer who have been previously treated with T-DXd.