Zanidatamab/Chemo Yields Durable Response in HER2+ Gastroesophageal Cancer

The median OS was 36.5 months for patients taking zanidatamab plus chemotherapy.

The addition of the HER2-targeting bispecific antibody zanidatamab-hrii (Ziihera) to chemotherapy in the first line of treatment for a small cohort of patients with HER2-positive advanced gastroesophageal adenocarcinoma yielded durable and significant response, according to primary data from a phase 2 study (NCT03929666) reported in Lancet Oncology.¹

The study treatment yielded a confirmed objective response rate (ORR) of 76.2% (95% CI, 60.5%-87.9%) among 42 evaluable patients, which included complete responses in 3 patients (7%) and partial responses in 29 (69%). The median duration of response (DOR) was 18.7 months (95% CI, 10.4-44.1), and the post hoc median time to first response was 1.3 months (IQR, 1.3-1.4).

Data showed a median progression-free survival (PFS) of 12.5 months (95% CI, 8.2-21.8), with estimated PFS rates of 57% (95% CI, 40%-70%) at 12 months and 31% (95% CI, 17%-46%) at 24 months. Additionally, treatment elicited a median overall survival (OS) of 36.5 months (95% CI, 23.6-not estimable [NE]), a 12-month OS rate of 87% (95% CI, 72%-94%), and a 24-month OS rate of 65% (95% CI, 49%-77%).

“First-line treatment with zanidatamab plus chemotherapy demonstrated rapid and durable antitumor activity with promising survival outcomes in patients with HER2-positive advanced gastroesophageal adenocarcinoma. Zanidatamab plus chemotherapy in the first-line setting was well tolerated, with a manageable safety profile, when incorporating antidiarrheal prophylaxis in the first 7 days of treatment,” lead study author Elena Elimova, MD, from the Department of Gastrointestinal Medical Oncology at Princess Margaret Cancer Centre in Toronto, Ontario, Canada, wrote with coauthors in the publication.¹ “If these results are confirmed in a large-scale, randomized phase 3 trial, zanidatamab could represent a substantial advancement in the treatment of HER2-positive advanced gastroesophageal adenocarcinoma.”

In the open-label, multicenter phase 2 study, patients received zanidatamab in combination with capecitabine plus oxaliplatin (CAPOX), 5-fluorouracil (5-FU) plus cisplatin (FP), or leucovorin plus 5-FU and oxaliplatin (mFOLFOX6). In the CAPOX and FP groups, patients received zanidatamab at 30 mg/kg, 1800 mg with a weight of less than 70 kg, or 2400 mg with a weight of 70 kg or higher every 3 weeks. In the mFOLFOX6 group, patients received zanidatamab at 20 mg/kg, 1200 mg with a body weight under 70 kg, or 1600 mg with a weight of at least 70 kg every 2 weeks.

In part 1 of the trial, investigators evaluated the safety and tolerability of zanidatamab plus chemotherapy to determine a recommended phase 2 dose; the primary end points of this part were dose-limiting toxicities and dose reductions. In part 2 of the trial, the primary end point was investigator-assessed confirmed ORR per RECIST v1.1 criteria. Secondary efficacy end points across parts 1 and 2 of the trial included disease control rate, DOR, clinical benefit rate, PFS, and OS.

Patients 18 years or older with unresectable, locally advanced, recurrent, or metastatic HER2-expressing gastroesophageal adenocarcinoma and measurable disease per RECIST v1.1 guidelines were eligible for enrollment in the trial.² Other eligibility criteria included having an ECOG performance status of 0 or 1, adequate organ function, and adequate cardiac left ventricular function.

The median patient age was 58 years (IQR, 55-63), and most of the population was male (85%), White (61%), and not Hispanic (93%). Additionally, most patients had an ECOG performance status of 0 (57%), gastric anatomical subtype disease (41%), stage IV disease at initial diagnosis (83%), and measurable disease (93%). Prior neoadjuvant or adjuvant chemotherapy was reported in 11% of patients.

In a subgroup of patients with centrally confirmed HER2-positive disease (n = 41), zanidatamab-based therapy produced a confirmed ORR of 84% (n = 31 of 37; 95% CI, 68.0%-93.8%). Furthermore, the median PFS was 15.2 months (95% CI, 9.5-33.4) in this subgroup and the median OS was 36.5 months (95% CI, 23.6-NE).

In a post hoc analysis of patients who enrolled in the trial before and after the implementation of antidiarrheal prophylaxis, 61% (n = 14 of 23; 95% CI, 38.5%-80.3%) and 95% (n = 18 of 19; 95% CI, 74.0%-99.9%) experienced confirmed responses. Those who received antidiarrheal prophylaxis experienced longer treatment duration and exposure.

Treatment-related adverse effects (TRAEs) affected 100% of patients, with the most common grade 3/4 TRAEs consisting of diarrhea (39%) and hypokalemia (22%). Additionally, 17% of patients had serious TRAEs, the most common of which was diarrhea (7%).

The median duration of grade 1/2 or grade 3 diarrhea was 6.5 days (IQR, 2-29) and 3 days (IQR, 2-5), respectively, among patients who enrolled in the trial before the implementation of antidiarrheal prophylaxis. The median durations were 3 days (IQR, 2-13) and 4.5 days (IQR, 3-8) among those who entered the trial following the implementation of antidiarrheal prophylaxis.

References

1. Elimova E, Ajani J, Burris H, et al. Zanidatamab plus chemotherapy as first-line treatment for patients with HER2-positive advanced gastro-oesophageal adenocarcinoma: primary results of a multicentre, single-arm, phase 2 study. Lancet Oncol. 2025;26(7):847-859. doi:10.1016/S1470-2045(25)00287-6
2. A safety and efficacy study of ZW25 (zanidatamab) plus combination chemotherapy in HER2-expressing gastrointestinal cancers, including gastroesophageal adenocarcinoma, biliary tract cancer, and colorectal cancer. ClinicalTrials.gov. Updated March 13, 2025. Accessed July 1, 2025. https://tinyurl.com/y9d77aay