Zanidatamab Shows Durable Antitumor Activity in HER2-Expressing Gastroesophageal Adenocarcinoma

Funda Meric-Bernstam

Zanidatamab demonstrated promising antitumor activity with favorable tolerability in patients with HER2-expressing gastroesophageal adenocarcinoma (GEA) that has progressed following previous therapies, including HER2-targeted agents, according to results from the 3-part, phase 1 ZW25-101 study (NCT02892123) presented during the 2021 Gastrointestinal Cancers Symposium.¹

The HER2-targeted antibody elicited a confirmed overall response rate (ORR) of 33% and a disease control rate (DCR) of 61% when used as a monotherapy. When used in combination with chemotherapy, the ORR and DCR were higher, at 54% and 79%, respectively.

“Based on these promising data, zanidatamab is being further evaluated in patients with HER2-expressing GEA in 2 global studies,” study author Funda Meric-Bernstam, chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, said during an oral presentation of the data.

HER2 is overexpressed in approximately 20% of patients with GEA, and for those with HER2-overexpressing metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, trastuzumab (Herceptin) in combination with chemotherapy is the only approved HER2-targeted therapy. Additionally, options are limited if progressive disease occurs following HER2-targeted therapy.

Zanidatamab is a biparatopic antibody that simultaneously binds 2 distinct sites on HER2: the ECD4 and the ECD2, which are the trastuzumab-targeted and pertuzumab-targeted domains, respectively. This unique transbinding results in multiple mechanisms of action by zanidatamab, which includes enhanced receptor clustering and internalization and has led to encouraging activity in patients.

Previously, the FDA has granted 2 fast track designations to zanidatamab, one of them being for its frontline use in combination with standard chemotherapy in patients with GEA, and the other for its use as a single agent in patients with refractory biliary tract cancer (BTC). In November 2020, zanidatamab was also granted a breakthrough therapy designation for use in patients with HER2 gene–amplified BTC who had previously received therapy.²

The key objective of the phase 1 study was to characterize the safety, tolerability, and potential antitumor effects of zanidatamab, when used as a single agent or in combination with select chemotherapy.

To be eligible for enrollment, patients had to have HER2-expressing cancers, including GEA, have progressed following standard-of-care treatment, an ECOG performance status of 0 or 1, and have measurable disease per RECIST v1.1 criteria. Patients also had to have fresh or archived tumor tissue available for central review of HER2 status.

The study was conducted in 3 parts. Part 1 was a 3+3 dose-escalation design where investigators examined zanidatamab at different doses and schedules. Part 2 included monotherapy-expansion cohorts, where patients were given the recommended dose of zanidatamab at either 10 mg/kg once weekly or 20 mg/kg every 2 weeks.

In part 3 of the trial, zanidatamab was looked at in combination with chemotherapy in patients with HER2-expressing GEA receiving either paclitaxel or capecitabine at 1 of 3 different dosing schedules: either 10 mg/kg once weekly, 20 mg/kg every two 2 weeks, or 30 mg/kg every 3 weeks.

Thirty-five patients were in the zanidatamab monotherapy cohort, 11 were in the cohort that received zanidatamab plus paclitaxel, and 17 were in the cohort that received zanidatamab and capecitabine.

The median age of participants was 62 years, 81% were male, and the majority, or 59%, were white. Moreover, about 15% of patients had an initial diagnosis of esophageal cancer, 26% had GEJ cancer, and 59% had gastric cancer. The majority of patients had previously received at least 2 prior systemic regimens, including trastuzumab.

In 33 response-evaluable patients who received zanidatamab as a monotherapy, 11 (33%) had a confirmed objective response. In these patients, the DCR was 61%, the median duration of response (DOR) was 6.0 months, and the median PFS was 3.6 months. Of the 10 response-evaluable patients who received zanidatamab plus paclitaxel, the ORR was 50%, the DCR was 90%, and the median DOR was 9.1 months. In this group, the median PFS was 10.9 months. Among the 14 response-evaluable patients who received zanidatamab plus capecitabine, the confirmed ORR was 57%, the DCR was 71%, and the median DOR was 5.8 months. Here, the median PFS was 5.4 months.

Among patients receiving zanidatamab as monotherapy, the majority of patients with response-evaluable measurable disease experienced tumor shrinkage; the same was true for those who received zanidatamab with chemotherapy.

As anticipate, adverse effects (AEs) were more common with zanidatamab plus chemotherapy. Grade 3 or higher effects occurred in 64% of patients who received paclitaxel and 12% of those given capecitabine. Three patients experienced treatment-related serious AEs: one case of grade 3 diarrhea was experienced in the monotherapy cohort, one case of grade 2 creatinine increase was reported in the cohort that received zanidatamab and capecitabine, and one grade 5 case of pneumonitis was reported in the cohort that received zanidatamab and paclitaxel.

Based on these findings, zanidatamab is being investigated further in the phase 2 ZW25-201 trial (NCT03929666) in combination with first-line chemotherapy in patients with HER2-expressing GEA. The agent is also under examination in the phase 1b/2 BGB-A317-ZW25-101 trial (NCT03929666), where it is being looked at in combination with chemotherapy with and without tislelizumab in patients with HER2-positive GEJ adenocarcinoma and breast cancer.

References

1. Meric-Bernstam F, Hamilton EP, Beeram M, et al. Zanidatamab (ZW25) in HER2-expressing gastroesophageal adenocarcinoma (GEA): results from a phase I study. J Clin Oncol. 2021; 39(suppl 3):164. doi:10.1200/JCO.2021.39.3_suppl.164
2. Zymeworks receives FDA breakthrough therapy designation for HER2-targeted bispecific antibody zanidatamab in patients with biliary tract cancer. News release. Zymeworks Inc. November 30, 2020. Accessed February 15, 2021. https://yhoo.it/2Vizh51