Beyond breast and gastric cancer: The expansion of HER2-targeted therapy into rare tumors
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HER2 amplifications and overexpression are frequently seen in gallbladder cancers... They are highly aggressive, probably our most challenging cancer to treat.
—Douglas Rubinson, MD, PhD, Assistant Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School
Tumor profiling for human epidermal growth factor receptor 2 (HER2) using next-generation sequencing (NGS) has a well-established history in breast and gastric cancer.
More recently, GI oncologists have been able to identify targetable HER2 mutations in biliary tract cancers (BTCs), a heterogenous group of malignancies derived from the epithelium of the intrahepatic and extrahepatic bile ducts, along with the gallbladder.[][]
Related: Actionable alterations in BTC: Why genomic profiling can’t wait“HER2 amplifications and overexpression are frequently seen in gallbladder cancers,” said Douglas Rubinson, MD, PhD, Assistant Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School in an exclusive interview with MDLinx. “They are highly aggressive, probably our most challenging cancer to treat.”
Dr. Rubinson noted that the frequency with which HER2 amplifications are found is highly dependent on the anatomic location of the cancer.
Among gallbladder cancers, 15%-30% may be HER2 expressing. In contrast, only 1%-5% of intrahepatic cholangiocarcinomas express HER2. Among extrahepatic cholangiocarcinomas, the rate of HER2 expression is about 5%-20% of tumors. When found, tumors with 3+ HER2 expression on immunohistochemistry (IHC) are eligible for treatment with zanidatamab (Ziihera).
Targeting HER2 in BTC: Clinical evidence
Zanidatamab is a humanized bispecific antibody that simultaneously binds the parts of the HER2 receptor that are targeted by trastuzumab and pertuzumab—the juxtamembrane extracellular domain (ECD4) and the dimerization domain (ECD2) of HER2.
The anti-tumor activity of zanidatamab could be greater than that of trastuzumab both in vitro and in vivo, as indicated by preclinical testing and the results of the HERIZON-BTC-01 trial.[]
HERIZON-BTC-01 assessed the activity of zanidatamab in patients following progression on first-line therapy. Patients with HER2 3+ by IHC or 2+ with amplification were enrolled. The trial showed compelling evidence of zanidatamab activity, particularly in the IHC 3+ cohort. The median OS was 15.5 months—and 18.1 months in the IHC 3+ patient subset. The confirmed objective response rate was 41.3% (52% in IHC 3+ and 6% in IHC 2+). Among responders, the median duration of response was a remarkable 14.9 months.
Drug safety was encouraging. The most common toxicities were diarrhea, infusion-related reactions, and decreased ejection fraction. Grade 3 toxicities were rare. The only grade 3 toxicities reported by more than 2 patients were diarrhea (5% of patients), decreased ejection fraction (3.8%), and anemia (3.8%).
Two patients discontinued zanidatamab due to toxicity. There were no treatment-related deaths.
Ongoing trials show promise
Two patients with an initial partial response later developed a complete response. There was a suggestion of patients with partial response later converting to complete response. Among responders, there was a reported improvement in pain, unsurprisingly greatest among complete responders.
Overall, the investigators found no new safety signals; discontinuation rates were low. The investigators concluded, “These findings support the clinically meaningful benefit of zanidatamab for patients with treatment-refractory HER2-positive BTC.”[]
The phase 3 HERIZON-BTC-302 trial is ongoing and will assess zanidatamab in combination with standard-of-care first-line treatment in patients with HER2-positive BTC (IHC 3+ or IHC 2+/FISH-amplified).
In his experience, Dr. Rubinson has observed positive results in patients administered zanidatamab as monotherapy in second-line treatment. Looking ahead, he says he has high hopes for the upcoming results of the BTC-02 trial. “Given the tolerability of zanidatamab as monotherapy, we hope that adding the drug to standard first-line gemcitabine/cisplatin/durvalumab will lead to deeper and longer responses without causing unacceptable toxicity.”