Zanidatamab continued to be efficacious in treating patients with previously treated advanced, unresectable, or metastatic HER2-amplified biliary tract cancer, according to follow-up data from the phase 2b HERIZON-BTC-01 trial that were presented during the 2024 ASCO Annual Meeting.
Results showed that the confirmed objective response rate (cORR; percentage of patients whose disease shrinks or disappears) with zanidatamab was 41.3% and the disease control rate (DCR; when cancer is shrinking or stabilized) was 68.8%, which was maintained from the study’s primary analysis. One additional patient achieved a complete response (CR; disappearance of cancer), marking two CRs in the study so far. Furthermore, the median duration of response (DOR) increased to 14.9 months.
The median overall survival (OS; time patients live before death of any cause) in the cohort of patients with immunohistochemistry (IHC) 2+ or 3+ — meaning that a tissue sample showed certain markers associated with biliary tract cancer — was 15.5 months and the six- and 12-month OS rates were 80.3% and 56.2%, respectively.
“In this long-term analysis, zanidatamab monotherapy demonstrated durable and sustained responses in patients with HER2-positive unresectable, locally advanced or metastatic biliary tract cancer who had been previously treated,” lead study author Dr. Shubham Pant, professor in the Department of Gastrointestinal Medical Oncology and in the Department of Investigational Cancer Therapeutics (Phase I Center) at The University of Texas MD Anderson Cancer Center, in Houston, Texas, said in a poster presentation during the meeting.
Biliary tract cancer, which is associated with poor prognosis, comprises less than 1% of all adult cancers. Furthermore, those who progress on frontline therapy and then go on to receive chemotherapy is linked with poor tolerability and a median OS of approximately six to nine months.
Zanidatamab is a HER2-targeted bispecific antibody binding to two HER2-distinct domains. Bispecific antibodies work by binding to a protein found on cancer cells as well as a protein found on immune cells, which brings the two together and allows for the immune cells to fight cancer. Prior results of this agent in HERIZON-BTC-01 showed that at a median follow-up of 12.4 months, the cORR was 41.3% with a manageable safety profile in patients with previously treated HER2-positive biliary tract cancer.
In May 2024, the FDA granted priority review to a biologics license application seeking the approval of zanidatamab as a treatment of patients with previously treated, unresectable, HER2-positive, locally advanced or metastatic biliary tract cancer, based on the initial findings from the trial.The regulatory agency will decide on the approval by Nov. 29, 2024.
In the phase 2 HERIZON-BTC-01 trial, patients with advanced, unresectable, or metastatic HER2-amplified biliary tract cancer were put into two groups: immunohistochemistry (IHC) 2+ or 3+ (80 patients; cohort 1) and IHC 0 or 1+ (seven patients; cohort 2).
To be eligible for enrollment, patients had to be at least 18 years old, have received prior gemcitabine-containing therapy, had at least one measurable target lesion and an ECOG performance status of 0 to 1, meaning that they could perform all their daily tasks independently. They could not have previously received HER2-targeted therapies.
The primary end point (main result measured at the end of a study) was cORR in cohort 1, and select secondary end points included DOR, DCR, progression-free survival (PFS; time from treatment until disease worsening) and OS, as well as safety and tolerability.
At the 2024 ASCO Annual Meeting, Pant presented on the efficacy and safety of zanidatamab in patients with HER2-positive biliary tract cancer with a longer median follow-up of 22 months (range, 16 to 34 months) and a data cutoff date of July 28, 2023.
More specific OS data within cohort 1 showed that in patients with IHC 2+, the median OS was 5.2 months; the six-month OS rate was 41.7% and the 12-month OS rate was 20.8%. In those with IHC 3+, the median OS was 18.1 months, and the six- and 12-month OS rates were 90.1% and 65.0%, respectively.
Regarding safety in cohorts 1 and 2, Pant noted that zanidatamab’s safety profile was generally unchanged with additional follow-up. Most patients experienced treatment-emergent side effects (96.6%). Patients experienced grade 1 or 2 (mild to serious; 51.7%) or grade 3 or 4 (severe to life-threatening; 20.7%) treatment-related side effects; serious treatment-related side effects were reported in 9.2% of patients.
The most common all-grade and grade 3 to 4 treatment-related side effects were diarrhea (36.8%; 4.6%), infusion-related reaction (IRR; 33.3%; 1.1%), decreased efficacy of the left ventricle of the heart (10.3%; 3.4%), nausea (9.2%; 1.1%), increased alanine aminotransferase (ALT), which can indicate organ damage (6.9%; 1.1%), increased aspartate aminotransferase (AST; which can also indicate organ damage (6.9%; 2.3%), vomiting (6.9%; 0%), fatigue (5.7%; 0%) and anemia (4.6%; 3.4%).
Side effects of special interest consisted of IRRs (all-grade, 33.3%; grade 3-4, 1.1%), confirmed cardiac events (5.7%; 3.4%) and noninfectious pulmonary toxicities (1.1%; 1.1%).
Side effects that led to dose reductions included grade 3 diarrhea (one patient), grade 1 diarrhea and grade 1 nausea (one patient) and grade 2 decreased weight (one patient). Pant reported that one patient experienced serious side effect of increased ALT and increased AST since the prior analysis.
No patients discontinued treatment due to side effects since the prior analysis. Overall, this rate was 2.3%.
The ongoing, international, phase 3 HERIZON-BTC-02 trial is evaluating frontline zanidatamab in combination with standard cisplatin or gemcitabine with or without a PD-1/PD-L1 inhibitor in patients with advanced HER2-positive biliary tract cancer.
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