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.

backgroundZanidatamab, a dual human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody, previously demonstrated encouraging antitumour activity and a manageable safety profile in patients with treatment-refractory HER2-expressing gastro-oesophageal adenocarcinoma. Here, we evaluated the antitumour activity and safety of zanidatamab plus chemotherapy in first-line HER2-positive advanced gastro-oesophageal adenocarcinoma.

methodsThis phase 2 trial enrolled patients in Canada, South Korea, and the USA who were aged 18 years and older with untreated, metastatic, or advanced HER2-positive gastro-oesophageal adenocarcinoma (HER2 IHC 3+ or 2+ by local or central assessment [part 1]; HER2 IHC 3+ or 2+ with FISH+ by central assessment [part 2]). Eligible patients, with an Eastern Cooperative Oncology Group performance status of 0 or 1 received zanidatamab intravenously plus standard chemotherapy (CAPOX [capecitabine plus oxaliplatin], FP [5-fluorouracil [5-FU] plus cisplatin], or modified FOLFOX6 [mFOLFOX6; leucovorin, 5-FU, and oxaliplatin]). In our study, part 1 aimed to characterise the safety and tolerability of zanidatamab and find the recommended dose when administered with combination chemotherapy and part 2 aimed to evaluate the antitumour activity of zanidatamab administered with combination chemotherapy in patients receiving first-line treatment for HER2-expressing advanced gastro-oesophageal adenocarcinoma. Two dosing schemes for zanidatamab were used in this study: a weight-based regimen and a two-tiered flat dosing regimen. In the CAPOX and FP groups, patients received either 30 mg/kg zanidatamab or 1800 mg or 2400 mg (patients weighing <70 kg and ≥70 kg, respectively) every 3 weeks. In the CAPOX group, patients also received 1000 mg/m

findingsBetween Aug 29, 2019, and Feb 18, 2022, 46 patients were enrolled (39 [85%] were male; seven [15%] were female; 28 [61%] were white, 17 [37%] were Asian, and 43 [93%] were not Hispanic or Latino). Median follow-up was 47·9 months (IQR 39·2-53·7); eight (17%) patients were on treatment and 19 (41%) were in survival follow-up. The confirmed objective response rate was 76·2% (95% CI 60·5-87·9) with a median duration of response of 18·7 months (95% CI 10·4-44·1). The median progression-free survival was 12·5 months (95% CI 8·2-21·8) and median overall survival was 36·5 months (23·6-not estimable). The disease control rate was 88·1% (95% CI 74·4-96·0) and clinical benefit rate was 78·6% (95% CI 63·2-89·7). In part 1, there were no dose-limiting toxicities in six patients treated with zanidatamab plus CAPOX. One (50%) of two patients treated with zanidatamab plus FP had dose-limiting toxicities of diarrhoea and acute kidney injury (both grade 3). Two dose-limiting toxicities of diarrhoea (both grade 3) occurred in 2 (15%) of 13 patients receiving 5-FU 400 mg/m

interpretationZanidatamab plus chemotherapy as first-line treatment of HER2-positive advanced gastro-oesophageal adenocarcinoma demonstrated clinically meaningful and durable antitumour activity, with a manageable safety profile.

fundingJazz Pharmaceuticals, Zymeworks.