Results from a phase 2 clinical trial of the use of zanidatamab with standard first-line chemotherapy in patients with HER2-positive GEA show promising disease control rate and duration of response.
HER2 overexpression in metastatic gastroesophageal adenocarcinoma (GEA) is linked to a high morbidity and mortality rate in patients. Up to 20% of patients with this cancer type have tumors that harbor HER2. There are limited effective treatment options for HER2-positive metastatic GEA. As a result, investigations into successful therapies are being actively pursued. Zanidatamab is an antibody that targets the juxtamembrane domain and the dimerization domain of HER2. When it binds to HER2, it downregulates HER2 and inhibits tumor cell proliferation. Promising results have been reported in early-stage clinical trials of patients with HER2-expressing metastatic GEA. At the European Society for Medical Oncology 2021 Congress, the results of a phase 2 study of zanidatamab plus chemotherapy in 36 patients with untreated unresectable locally advanced or metastatic HER2-positive GEA were presented.
Patients in the clinical trial were treated with 1 of 3 regimens: zanidatamab plus capecitabine and oxaliplatin (CapOx) or zanidatamab plus fluorouracil and cisplatin (FP) every 3 weeks or zanidatamab plus fluorouracil/leucovorin/oxaliplatin (modified [m] FOLFOX6) every 2 weeks. The treatment regimen was chosen by the patient’s physician. The study’s primary end points were safety and confirmed objective response rate (cORR), with response assessment performed every 6 weeks. Disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS) were also evaluated. At the time of publication, there were 19 patients still on treatment, with a median treatment duration of 9 cycles. The DCR was 100% in the CapOx and FP groups and 79% in the mFOLFOX6 group. There was a 75% cORR across the treatment groups. In patients treated with zanidatamab and CapOx, the cORR was 92%; those treated with zanidatamab and FP had a cORR of 100%. Median DOR was 16.4 months. Median PFS was 12.0 months.
All patients experienced treatment-related adverse events (TRAEs). Most of the TRAEs were grade 1 or 2, with the most common being nausea, vomiting, diarrhea, diminished appetite, fatigue, peripheral sensory neuropathy, and hypokalemia. Grade 3 TRAEs (as the highest reported grade) were reported in 79% of the group receiving zanidatamab and mFOLFOX6, in 57% of the group receiving zanidatamab and CapOx, and in 50% of the group receiving zanidatamab and FP. The most common grade 3 TRAEs were diarrhea, hypokalemia, and vomiting. Grade 4 hypokalemia and leukopenia were found in 7% of all patients. TRAEs caused 10% of patients to discontinue treatment. All these patients were in the zanidatamab plus mFOLFOX6 treatment group. There were no treatment-related deaths during the reported trial period.
Based on these results a global phase 3 trial of first-line zanidatamab and chemotherapy (CapOx or FP) with or without tislelizumab in HER2-positive GEA is in the planning stage.
Sources: Ku G, Elimova E, Denlinger CS, et al. Phase (Ph) II study of zanidatamab + chemotherapy (chemo) in first-line (1L) HER2 expressing gastroesophageal adenocarcinoma (GEA). Poster presented at ESMO Congress 2021; September 16-21, 2021.
Ku G, Elimova E, Denlinger C, et al. Phase (Ph) II study of zanidatamab + chemotherapy (chemo) in first-line (1L) HER2 expressing gastroesophageal adenocarcinoma (GEA). Ann Oncol. 2021;32(suppl_5):S1044-S1045.