Zanidatamab Plus Evorpacept Shows Early Activity, Tolerability in Pretreated HER2+ Breast Cancer

Zanidatamab-hrii (Ziihera), which has a novel mechanism of action and shows initial signals of clinical activity when combined with evorpacept in patients with HER2-positive breast cancer, could address the need for less-toxic, equally effective alternatives to chemotherapy-based regimens and offer a viable treatment option for patients who have progressed on standard HER2-targeted therapies, according to Alberto Montero, MD, MBA, CPHQ.

Early data from a phase 1b/2 study (NCT05027139) evaluating the combination of the dual HER2-expressing bispecific antibody and evorpacept in patients with HER2-expressing breast cancer and other diseases were presented at the 2024 San Antonio Breast Cancer Symposium (SABCS). In cohort 1 (n = 21), which included patients with HER2-positive metastatic breast cancer, the confirmed overall response rate (cORR) was 33.3% (95% CI, 14.6%-57.0%) and comprised entirely partial responses. The disease control rate was 71.4% (95% CI, 47.8%-88.7%), the median duration of response was not evaluable (NE; range, 3.6-25.9), and the median progression-free survival (PFS) was 3.6 months (95% CI, 1.8-11.0).

Although efficacy outcomes were most pronounced in patients with HER2-positive disease, the cORR and median PFS were 20.0% (95% CI, 4.3%-48.1%) and 1.9 months (95% CI, 1.6-3.9), respectively, for patients with HER2-low metastatic breast cancer, which comprised cohort 2 (n = 15).

“In a heavily pretreated population of patients with breast cancer [who had previously received] fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd], we saw an impressive response rate [with zanidatamab plus evorpacept] that we normally would not expect, alongside little toxicity,” said Montero, clinical director of the Breast Cancer Medical Oncology Program and the Diana Hyland Chair for Breast Cancer at University Hospitals Seidman Cancer Center, as well as an associate professor of medicine at Case Western Reserve University School of Medicine in Cleveland, Ohio. “This mechanism of augmenting antibody-dependent phagocytosis through blocking CD47 with a fusion protein is an interesting and novel mechanism of action that hasn’t been widely tested in breast cancer.”

In an interview with OncLive®, Montero highlighted the synergistic mechanism of action of zanidatamab in combination with evorpacept, reviewed early efficacy and safety findings with the combination in heavily pretreated HER2-positive breast cancer, and outlined potential next steps to optimize its use across HER2-positive cancers.

OncLive: What are some key unmet needs in metastatic HER2-positive breast cancer?

Montero: There are a couple important unmet needs in metastatic HER2-positive breast cancer. One is to have drugs that [are not associated with] significant toxicity, unlike chemotherapy. Second, even though we have a lot of great drugs [available] for [managing] metastatic HER2-positive breast cancer, the disease remains incurable. We need newer treatments that are more effective, particularly for when one of the currently approved HER2-targeted drugs stops working.

What was the rationale for combining zanidatamab with evorpacept in HER2-positive cancers, and what potential advantages might the regimen’s mechanism of action offer?

Zanidatamab is a bispecific monoclonal antibody [directed] against HER2. Much like other HER2-directed antibodies, one of the important mechanisms of action of a monoclonal antibody is antibody-dependent phagocytosis through an immune-mediated effect. Evorpacept augments the effect of antibody-dependent phagocytosis because it’s an anti-CD47 small molecule. Zanidatamab is highly active, so adding evorpacept, because of its immune-mediating mechanism through blocking CD47, enhances its effectiveness.

What were the design and methodology of the phase 1b/2 trial evaluating this combination?

This is a phase 1b trial with cohort expansion. We looked at 2 different dose-escalating levels of evorpacept: 20 mg/kg and 30 mg/kg. [Evorpacept was administered in combination] with a fixed dose of zanidatamab. We saw no dose-limiting toxicities at the lower dose, so the recommended phase 2 dose was [determined to be] 30 mg/kg of evorpacept [administered] intravenously every 2 weeks, along with zanidatamab. Then there was a cohort expansion, [which included] a cohort of patients with HER2-positive or HER2-low metastatic breast cancer [along with patients with] other cancers that were HER2 positive.

What early efficacy and safety results were presented at SABCS?

In patients who were HER2 positive [by central assessment (n = 9)], the cORR was [55.6% (95% CI, 21.2%-86.3%)]. It’s important to note that all the patients with [HER2-positive] breast cancer had received a median of 6 [range, 2-10] prior lines of therapy, and all patients had received T-DXd previously. The median PFS was [7.4 months (95% CI, 0.6-NE) for the cohort of patients who were HER2 positive by central assessment].

When we looked at all the patients with breast cancer, the cORR was [33.3%], and the median PFS was [3.6] months, which is still impressive [considering the fact that the cohort] included patients with lower HER2 expression.

Because [the combination] doesn’t include chemotherapy, [it potentially addresses] an unmet need for novel combinations that [are not associated with] the cytotoxic effects of chemotherapy. Other than infusion reactions with the first infusion that we saw with zanidatamab, there was diarrhea, [although] little grade 3 diarrhea. Otherwise, [the regimen] was well tolerated.

What next steps are planned for the investigation of zanidatamab plus evorpacept?

[It’s important to remember that] this was a small trial and was only phase 1. We’re still following patients. There are still 5 patients on treatment, so the data are premature. We also have correlative data evaluating circulating tumor DNA. Based on those data, we’re going to decide how to move forward and decide whether to use this [combination] as a chemotherapy-free treatment option in metastatic HER2-positive breast cancer or—because there’s not significant toxicity—perhaps combine it with chemotherapy or another [class of] drug.

Reference

Montero AJ, Wisinski KB, Fang B, et al. Zanidatamab in combination with evorpacept in HER2-positive and HER2-low metastatic breast cancer: results from a phase 1b/2 study. Presented at: 2024 San Antonio Breast Cancer Symposium; San Antonio, TX, December 10-13, 2024. PS8-09.