Zanidatamab Plus Chemotherapy Yields Promising Antitumor Activity in HER2+ Breast Cancer

Zanidatamab and single agent chemotherapy may hold promise in a population of patients with previously treated HER2-positive breast cancer.

A combination of bispecific antibody zanidatamab and chemotherapy resulted in promising antitumor activity plus a positive safety profile in patients with HER2-positive breast cancer who were heavily pretreated, according to findings from the third part of the phase 1 ZWI-ZW25-101 trial (NCT02892123) presented during the 2021 San Antonio Breast Cancer Symposium.1

At a median follow-up of 7.1 months, the addition of zanidatamab to chemotherapy resulted in a confirmed objective response rate (cORR) of 36.4% (95% CI, 13.9%-54.9%) among 22 patients. When specifically paired with vinorelbine (n = 11), capecitabine (n = 7), or paclitaxel (n = 4), the ORRs were 27.3% (95% CI, 6.0%-61.0%), 42.9% (95% CI, 9.9%-81.6%), and 50.0% (95% CI, 6.8%-93.2%), respectively.

Among all 22 patients, the clinical benefit rate (CBR) was 54.5% (95% CI, 32.2%-75.6%), the disease control rate (DCR) was 86.4% (95% CI, 65.1%-97.1%), and the duration of response (DOR) ranged from 1.6 months to 22.1+ months. The median progression-free survival (PFS) was 7.3 months (95% CI, 3.6–not evaluable).

“These data support further investigation of zanidatamab plus single-agent chemotherapy as a novel therapeutic option for treatment of patients with HER2-positive locally advanced or metastatic breast cancer after 3 or more lines of prior therapy,” lead study author Philippe L. Bedard, MD, FRCPC, of Princess Margaret Cancer Centre, and colleagues, wrote in a poster on the data.

When patients with advanced HER2-positive breast cancer progress on other available HER2-targeted agents, they typically receive a regimen comprised of a HER2-targeted monoclonal antibody, like trastuzumab (Herceptin), and 1 chemotherapy agent. However, this approach has been shown to produce an ORR of less than 25%, a median PFS of shorter than 6 months, and a median overall survival (OS) of less than 2 years.

The humanized, bispecific, immunoglobulin G isotype 1–like antibody zanidatamab is directed against the juxtamembrane domain and the dimerization domain of HER2. The unique binding properties of the agent lead to receptor clustering, internalization, and downregulation; this also results in the inhibition of both growth factor–dependent and -independent cancer cell proliferation, antibody-dependent cellular cytotoxicity and phagocytosis, and complement-dependent cytotoxicity.

Single-agent zanidatamab has been shown to have favorable tolerability and to produce durable responses in heavily pretreated patients with metastatic HER2-positive breast cancer, as well as in those with HER2-expressing diseases such as gastroesophageal adenocarcinoma and biliary tract cancer.

For part 3 of the ongoing phase 1 trial presented at the 2021 SABCS, investigators examined the safety and activity of the bispecific antibody in combination with chemotherapy in patients with HER2-positive metastatic breast cancer.

To be eligible for enrollment, patients needed to have unresectable, locally advanced, or metastatic HER2-positive breast cancer, and have previously received HER2-targeted therapies such as trastuzumab, ado-trastuzumab emtansine (T-DM1; Kadcyla), and pertuzumab (Perjeta). Patients also needed to have an ECOG performance status of 0 or 1. Those with stable brain metastases were permitted.

Patients received either zanidatamab at 20 mg/kg every 2 weeks plus vinorelbine in a 28-day treatment cycle; zanidatamab at 20 mg/kg every 2 weeks or 30 mg/kg every 3 weeks plus capecitabine in a 28- or 21-day treatment cycle; or zanidatamab at a dose of 20 mg/kg every 2 weeks plus paclitaxel in a 28-day treatment cycle.

Treatment was administered until progressive disease, intolerable toxicity, or until other discontinuation criteria were met. Patients who discontinued chemotherapy were able to continue to receive single-agent treatment with zanidatamab.

The primary end point of the trial was safety, and important secondary end points were ORR, CBR, DCR, DOR, and PFS.

Of the 24 patients enrolled to part 3 of the trial, the median age was 55 years (range, 37-72), all were female, half had an ECOG performance status of 0 and the remainder had a status of 1. All patients had HER2-positive disease, 42% were hormone receptor–positive, and 42% were negative. Thirty-eight percent of patients had a prior history of brain metastases.

The median number of prior systemic regimens received in the metastatic setting was 2.0 (range, 0-6). Among the prior HER2-targeted therapies received were trastuzumab (96%), T-DM1 (96%), pertuzumab (96%), lapatinib (Tykerb; 21%), neratinib (Nerlynx; 8%), tucatinib (Tukysa)/placebo (8%), margetuximab-cmkb (Margenza; 4%), and tucatinib (4%).

Findings were extracted on October 12, 2021 from an unlocked database. Of the 24 patients enrolled to the trial, 42% (n = 10) are still on treatment. Fifty-four percent of patients (n = 13) discontinued treatment because of progressive disease and 1 patient stopped treatment because of treatment-related grade 3 diarrhea.

Additional data showed that among those who received zanidatamab plus vinorelbine achieved a CBR of 27.3% (95% CI, 6.0%-61.0%), a DCR of 81.8% (95% CI, 48.2%-97.7%), and a DOR that ranged from 1.6 months to 3.7 months. In the subset of patients who received the bispecific antibody plus capecitabine, the CBR was 85.7% (95% CI, 42.1%-99.6%), the DCR was 100.0% (95% CI, 59.0%-100.0%), and the DOR ranged from 3.6 months to 16.7+ months. In those who received zanidatamab plus paclitaxel, the CBR was 75.0% (95% CI, 19.4%-99.4%), the DCR was 75.0% (95% CI, 19.4%-99.4%), and the DOR ranged from 18.4 months to 22.1+ months.

Safety was formally evaluated by a safety monitoring committee following the enrollment of the first 6 patients to each cohort. In the first 6 patients who received zanidatamab plus vinorelbine, 2 patients required chemotherapy dose reductions because of grade 3/4 decreased neutrophil count in cycle 1.

Because of this, the committee recommended that the dosing of vinorelbine be adjusted from continuous weekly dosing to dosing on days 1 and 15 of a 28-day cycle. After the dosing modification, 1 of the 6 patients in this cohort experienced grade 4 decreased neutrophil count on cycle 1 day 15.

Eight percent of patients (n = 2) reported 3 serious toxicities, although none of these effects were determined to be associated with the study treatment. One patient experienced upper respiratory infection and pneumonitis, and the other was noted to have pleural effusion.

Collectively, 92% of the 24 total patients reported an any-grade treatment-related adverse effect (TRAE), and 54% reported a TRAE that was grade 3 or higher. Notably, no treatment-related serious AEs were reported. Eight percent of patients experienced TRAEs that resulted in treatment discontinuation (any-grade, n = 1; grade 3 or higher, n = 1).

The TRAEs that were most experienced with zanidatamab plus single-agent chemotherapy were diarrhea (any-grade, 71%; grade 3 or higher, 8%), nausea (33%; 0%), stomatitis (29%; 0%), fatigue (25%; 0%), fatigue (25%; 0%), peripheral neuropathy (25%; 4%), palmar-plantar erythrodysesthesia (25%; 0%), decreased neutrophil count (25%; 25%), and neutropenia (17%; 13%).

AEs of special interest included infection-related reactions (13%; 0%), cardiac events (8%; 0%), and pneumonitis (4%; 0%).

“Diarrhea is the most frequent TRAE observed across regimens and is manageable, the majority [> 90%] being low grade,” the study authors wrote. “Few infusion-related reactions or cardiac events were observed, [and] none [of these were] severe [grade 3 or higher].”

The vinorelbine and capecitabine cohorts are still enrolling patients.

Reference

Bedard PL, Im S-A, Elimova E, et al. Zanidatamab (ZW25), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) for HER2-positive breast cancer (BC): results from a phase 1 study. Presented at: 2021 San Antonio Breast Cancer Symposium; December 8, 2021. Poster P2-13-07.