The HER2-targeted bispecific investigational antibody zanidatamab, either as monotherapy or in combination with chemotherapy, has shown promising antitumor activity in an ongoing phase 1 study of patients with HER2-expressing biliary tract cancer or gastroesophageal adenocarcinoma, reported Funda Meric-Bernstam, MD, Chair, Department of Investigational Cancer Therapeutics, M.D. Anderson Cancer Center, Houston, TX, at the 2021 ASCO Gastrointestinal Cancers Symposium.
In this ongoing phase 1 study, 33 evaluable patients had a confirmed objective response rate (ORR) of 39% with zanidatamab monotherapy. When used in combination with nab-paclitaxel in 10 response-evaluable patients, the confirmed ORR was 65%, and when used with capecitabine in 14 evaluable patients, the confirmed ORR was 57%.
“HER2 is overexpressed in about 20% of GEA [gastroesophageal adenocarcinoma]. For patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, trastuzumab [Herceptin] in combination with chemotherapy is the only approved HER2-targeted therapy,” said Dr Meric-Bernstam.
Patients enrolled in this phase 1 study had HER2-overexpressing cancers that progressed after standard-of-care therapy and measurable disease. This study had 3 parts. The first part was a 3 + 3 dose-escalation analysis of zanidatamab 10 mg/kg weekly or 20 mg/kg every other week; part 2 assessed zanidatamab monotherapy expansion; and part 3 assessed zanidatamab in combination with chemotherapy (ie, paclitaxel or capecitabine).
Among the patients with gastroesophageal adenocarcinoma, 35 were enrolled in the zanidatamab monotherapy cohort, 11 in the zanidatamab plus paclitaxel cohort, and 17 in the zanidatamab plus capecitabine cohort. The median number of previous therapies was 3 in the zanidatamab monotherapy and in the zanidatamab plus paclitaxel cohorts, and 2 in the zanidatamab plus capecitabine cohort. Approximately 90% of patients in each cohort had previously received HER2-targeted therapies.
Tumor shrinkage was observed in most patients who had response-evaluable measurable disease, both with zanidatamab monotherapy and when used in combination with chemotherapy.
With zanidatamab monotherapy (10 mg/kg weekly or 20 mg/kg every 2 weeks), the 39% ORR consisted of only partial responses, and the disease control rate was 61%, with a median duration of response of 6 months.
In the cohort that received zanidatamab (20 mg/kg every 2 weeks) plus paclitaxel, the responses included 1 (10%) complete response and 4 (40%) partial responses. The cohort that received zanidatamab 20 mg/kg every 2 weeks plus capecitabine resulted in 1 (4%) complete response and 12 (50%) partial responses. The median duration of response in the zanidatamab plus chemotherapy cohorts was 9.1 months with paclitaxel and 5.8 months with capecitabine.
The median progression-free survival was 3.6 months with zanidatamab monotherapy versus 10.9 months with zanidatamab plus paclitaxel and 5.4 months with zanidatamab plus capecitabine.
The rate of treatment-emergent grade 3 or 4 adverse events was 49% in the zanidatamab monotherapy cohort, 59% in the zanidatamab plus capecitabine cohort, and 82% in the zanidatamab plus paclitaxel cohort. The most common grade 3 or 4 adverse events were diarrhea, fatigue, and nausea, the latter mostly related to the use of chemotherapy agents.
“Based on these promising data, zanidatamab is being further evaluated in patients with HER2-expressing GEA in 2 global studies,” said Dr Meric-Bernstam.
Zanidatamab for HER2-Positive Biliary Tract Cancer
In a separate analysis of part 2 of the phase 1 study, 21 patients with HER2-positive biliary tract cancers received zanidatamab monotherapy at the recommended dosage of 20 mg/kg every 2 weeks. The patients received a median of 2 previous therapies, including 5 (24%) patients who had previously received trastuzumab therapy.
Among the 15 trastuzumab-naïve patients, the confirmed ORR was 47% (N = 7) and the overall ORR in the study among the 21 patients was 40% (N = 8). The overall disease control rate was 65%, and the median duration of response was 7.4 months, with several patients still receiving treatment in the study at the time of data cutoff, according to Dr Meric-Bernstam.
Based on these results, a global pivotal phase 2b trial of zanidatamab monotherapy has been initiated in patients with HER2-amplified biliary tract cancer who have previously received treatment with at least 1 gemcitabine-containing systemic chemotherapy regimen.
In November 2020, the FDA granted zanidatamab a breakthrough therapy designation for the treatment of patients with previously treated HER2 gene–amplified biliary tract cancer.