In mid-stage trials, two newer targeted therapies have shown meaningful activity against HER2-positive biliary tract cancers in pretreated patients with advanced disease. According to Shubham Pant, MD, of the MD Anderson Cancer Center in Houston, cohort 1 of the global HERIZON-BTC-01 study, which included 80 treatment-refractory patients, showed that 41.3% responded to zanidatamab, an investigational bispecific monoclonal antibody that targets two distinct HER2 epitopes. In a smaller study, the dual HER2-targeted strategy of tucatinib (Tukysa) plus trastuzumab induced responses in 46.7% of the 30 patients with metastatic disease, as reported by Yoshiaki Nakamura, MD, PhD, of the National Cancer Center Hospital Japan East in Kashiwa. The median duration of response in the phase II trials ranged from 6 months with tucatinib-trastuzumab to 13 months with zanidatamab.
HER2-directed agents in biliary tract cancer
Although no HER2-directed agents are approved in biliary tract cancer, where HER2 is overexpressed up to 20% of the time, several agents are recommended in guidelines. Prior trials in this population have reported response rates of 16% with neratinib (Nerlynx), 23% with trastuzumab plus pertuzumab (Perjeta), and 36% with trastuzumab deruxtecan (Enhertu). However, each trial had differences in eligibility criteria and definitions for HER2-positive disease, with activating HER2 mutations used for eligibility in some tyrosine kinase inhibitor trials. Furthermore, not all types of biliary cancers express HER2 the same way, with overexpression being more frequently observed in extrahepatic cholangiocarcinomas and gallbladder cancer, for example. Therefore, every patient with advanced biliary cancer, whose treatment is planned, should be tested for HER2 expression and mutations.
Studies on zanidatamab and tucatinib-trastuzumab
The HERIZON-BTC-01 trial enrolled 87 patients with locally advanced or metastatic HER2-amplified biliary cancers across 32 sites in Asia, Europe, North America, and South America. Cohort 1 included 80 patients with HER2 expression defined as an immunohistochemistry (IHC) score of 2+ or 3+, with about three-fourths having IHC 3+. Central confirmation of HER2 amplification was required by fluorescence in-situ hybridisation (FISH), and testing was only allowed on tumor tissue. Cohort 2 included seven patients with IHC 0 or 1+; none of these patients responded to treatment. On central review, partial responses were recorded in 32 patients, as was one complete response. Another 22 patients had stable disease, leading to a disease control rate (DCR) of 69%. Responses with zanidatamab were predominantly seen in the IHC 3+ subset, with just one of 18 patients in the IHC 2+ group responding, per central review. Responses were otherwise generally consistent across subgroups.
In the SGNTUC-019 trial, 30 pretreated patients with HER2-positive biliary tract cancer received at least one dose of oral tucatinib and IV trastuzumab. One complete response was observed in the trial along with 13 partial responses, with a median time to response of 2.1 months and median duration of response of 6.0 months. There were also nine cases of stable disease following treatment with the combination, yielding a disease control rate of 76.7%.
Although the results of the trials are impressive and exciting, it is important to note that not all patients with HER2-positive biliary tract cancer will respond to the two targeted therapies. Furthermore, zanidatamab had a manageable and tolerable safety profile, with mostly low-grade diarrhea and infusion-site reactions that were reversible. Serious treatment-related adverse events were reported in 8.8%, and 2.5% stopped treatment due to drug-related toxicity. Grade ≥3 treatment-emergent adverse events included nausea, decreased appetite, and cholangitis each in three patients, diarrhea, anemia, increased alanine transaminase (ALT), and increased aspartate transaminase (AST) each in two patients, and fatigue, hyponatremia, increases in blood creatinine, COVID-19, and abnormal hepatic function in one patient each.
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