The HER2-targeted bispecific investigational antibody zanidatamab, either as monotherapy or in combination with chemotherapy, has shown promising antitumor activity in an ongoing clinical trial of patients with HER2-expressing biliary tract cancer or gastroesophageal adenocarcinoma.
In this phase 1 study, 33 evaluable patients demonstrated 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%, reported Funda Meric-Bernstam, MD, Chair, Department of Investigational Cancer Therapeutics, M.D. Anderson Cancer Center, Houston, TX, at the virtual 2021 ASCO Gastrointestinal Cancers Symposium.
“HER2 is overexpressed in about 20% of GEA [gastroesophageal adenocarcinoma]. For patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, trastuzumab in combination with chemotherapy is the only approved HER2-targeted therapy,” said Dr Meric-Bernstam.
Patients enrolled in the trial had HER2-expressing cancers that progressed after standard-of-care therapy and measurable disease. The trial was comprised of 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 cohort, 3 in the zanidatamab plus paclitaxel cohort, 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 with 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, there was 1 complete response and 4 partial responses, and in the cohort that received zanidatamab 20 mg/kg every 2 weeks plus capecitabine, there was 1 complete response and 12 partial responses. The median duration of response in the zanidatamab plus chemotherapy cohorts was 9.1 months (paclitaxel) and 5.8 months (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.
Treatment-emergent grade ≥3 adverse events (AEs) occurred in 49% of patients in the zanidatamab monotherapy cohort and in 59% (capecitabine) and 82% (paclitaxel) of patients in the zanidatamab plus chemotherapy groups. The most common grade ≥3 AEs were diarrhea, fatigue, and nausea, mostly owing to the 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. Patients had received a median of 2 previous therapies and 5 (24%) were previously treated with trastuzumab.
The confirmed ORR in trastuzumab-naïve patients was 47% (7/15) and the overall ORR was 40% (8/20). The overall disease control rate was 65%, and the median duration of response was 7.4 months, with several patients still on 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 breakthrough therapy designation for zanidatamab in patients with previously treated HER2-amplified biliary tract cancer.