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CHICAGO -- In a pair of mid-stage trials, newer targeted therapies demonstrated meaningful levels of activity against HER2-positive biliary tract cancers in pretreated patients with advanced disease.

Cohort 1 of the global study, which included 80 treatment-refractory patients, showed that 41.3% (95% CI 30.4-52.8) responded to zanidatamab, an investigational bispecific monoclonal antibody that targets two distinct HER2 epitopes, according to Shubham Pant, MD, of the MD Anderson Cancer Center in Houston.

Zanidatamab induced "rapid and durable responses," he said here at the American Society of Clinical Oncology (ASCO) annual meeting. Findings from the trial were published simultaneously in .

And in a smaller study, the dual HER2-targeted strategy of tucatinib (Tukysa) plus trastuzumab induced responses in 46.7% (90% CI 30.8-63.0) of the 30 patients with metastatic disease, reported Yoshiaki Nakamura, MD, PhD, of the National Cancer Center Hospital Japan East in Kashiwa.

"Tucatinib and trastuzumab demonstrated clinically meaningful activity and favorable tolerability," he said. "Furthermore, multiple HER2 testing modalities were shown to be reliable in identifying patients who may be eligible for this treatment regimen."

The median duration of response (DOR) in the phase II trials ranged from 6 months with tucatinib-trastuzumab to 13 months with zanidatamab.

"Impressive," "exciting," said ASCO-invited discussant Andrew Ko, MD, of the University of California San Francisco Cancer Center, in characterizing the results.

Though 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, said Ko. Prior trials in this population have reported response rates of , , and .

Ko cautioned, however, that each trial had differences in eligibility criteria and definitions for HER2-positive disease, with activating HER2 mutations (often not associated with overexpression) used for eligibility in some tyrosine kinase inhibitor trials.

Furthermore, he said, not all types of biliary cancers express HER2 the same way. Overexpression is more frequently observed in extrahepatic cholangiocarcinomas and gallbladder cancer, for example.

"I don't want to imply that we clearly know whether one targeted agent or combination is better than another," he said. "But right now what I can say is that every patient that we have with advanced biliary cancer, whose treatment is planned, should be tested for HER2 expression and probably for HER2 mutations as well."

HERIZON-BTC-01

From September 2020 to March 2022, 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. Patients received zanidatamab at an IV dose of 20 mg/kg every 2 weeks.

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.

The study's primary endpoint was the confirmed response rate in cohort 1, as assessed by independent central review, and the data from cohort 1 was the focus of Pant's presentation.

Median patient age was 64, 56% were women, 65% were Asian, and 29% were white. For tumor type, 51% had gallbladder cancer, 29% had intrahepatic cholangiocarcinoma, and 20% had extrahepatic cholangiocarcinoma. Most (89%) had stage IV disease at baseline, and patients had a median of one prior line of systemic therapy in the locally advanced or metastatic setting.

On central review, partial responses were recorded in 32 patients (40%), as was one complete response (1.3%). Another 22 patients (28%) had stable disease, leading to a disease control rate (DCR) of 69%. Investigator-assessed responses were similar overall, but showed more complete responders.

Responses with zanidatamab were predominantly seen in the IHC 3+ subset (51.6%), with just one of 18 patients (5.6%) in the IHC 2+ group responding, per central review. Responses were otherwise generally consistent across subgroups.

Median DOR per central review reached 12.9 months, and the median time to response was 1.8 months. Median progression-free survival (PFS) was 5.5 months, while median overall survival (OS) data were not mature. The OS rate at 9 months was 70%.

Zanidatamab had a manageable and tolerable safety profile, said Pant, with mostly low-grade diarrhea and infusion-site reactions that were reversible. Serious treatment-related adverse events (TRAEs) were reported in 8.8%, and 2.5% stopped treatment due to drug-related toxicity. Grade ≥3 TRAEs occurred in 19%, and no deaths were deemed related to treatment.

SGNTUC-019

Nakamura presented data from a phase II basket trial (SGNTUC-019) that included 30 pretreated patients with HER2-positive biliary tract cancer. All received at least one dose of oral tucatinib and IV trastuzumab. Median follow-up was 10.8 months.

Participants had a median age of 68.5, 50% were male, and most were Asian (77%). Gallbladder tumors were most common, in 15 patients, followed by extrahepatic cholangiocarcinomas in eight patients and intrahepatic cholangiocarcinomas in seven. Patients had a median of two prior lines of therapy for their metastatic disease, with most (60%) having been initially diagnosed with stage IV disease.

One complete response (3.3%) was observed in the trial along with 13 partial responses (43.3%), with a median time to response of 2.1 months and DOR of 6.0 months (90% CI 5.5-6.9). There were also nine cases of stable disease (30%) following treatment with the combination, yielding a DCR of 76.7%. Overall, 70% of patients had some degree of reduction in tumor burden.

Median PFS and OS were 5.5 months (90% 3.9-8.1) and 15.5 months (90% 6.5-16.7), respectively.

Grade ≥3 treatment-emergent adverse events (TEAEs) included nausea, decreased appetite, and cholangitis each in three patients (10%); diarrhea, anemia, increased alanine transaminase (ALT), and increased aspartate transaminase (AST) each in two patients (6.7%); and fatigue, hyponatremia, increases in blood creatinine, COVID-19, and abnormal hepatic function in one patient each (3.3%).

HER2 positivity in the trial was determined either by amplification in blood or tissue samples. Patients had to have HER2 3+ overexpression or amplification, with the latter assessed either by tumor tissue or next-generation sequencing (NGS) from circulating tumor DNA (ctDNA).

Concordance rates between local and central test results were 87.5% for both FISH and IHC (with reflex to FISH), but just 76% with blood-based NGS. None of the patients found to be HER2-negative on central review responded to treatment, including seven patients that tested positive locally by ctDNA.

"It serves as a reminder that we need to be cautious in interpreting HER2-positive results on ctDNA in clinical practice for biliary cancer," said Ko.