CHICAGO – Data presented at the American Society of Clinical Oncology's annual meeting on Friday indicate that targeted HER2 therapies may soon become an option for biliary tract cancer patients with HER2-overexpressing or -amplified tumors.
Biliary tract cancer is rare, comprising less than 1 percent of adult cancers. In the second-line setting, guidelines recommend chemotherapy or HER2-targeted therapies off-label, such as Herceptin (trastuzumab) and Genentech's Perjeta (pertuzumab). Between 5 percent and 15 percent of patients with advanced disease respond to these standard second- or later-line treatments and have a median progression-free survival of around four months.
HER2 targeted therapies are currently approved for HER2-positive breast, gastric, lung, and colorectal cancer patients. Even though there are 12,000 HER2-positive biliary tract cancer patients in the US, Europe, and Japan — with HER2 overexpression or amplifications most commonly seen in those with gall bladder cancer but also in some cholangiocarcinoma patients — there are no approved HER2-targeted treatments in this setting.
In the Phase IIb HERIZON-BTC-01 trial, researchers considered the activity of zanidatamab, a bispecific monoclonal antibody that targets two non-overlapping epitopes of the HER2 receptor being advanced by Zymeworks in collaboration with Beigene and Jazz Pharmaceuticals. To be eligible for the trial, patients had to have HER2-amplified tumors (IHC 2+ or 3+) by central testing.
As of the data cutoff in October 2022, there was a 41.3 percent objective response rate among 80 advanced biliary tract cancer patients on zanidatamab monotherapy; the response rates were the same according to independent centralized review and investigator assessment. One patient had a complete response by independent centralized review, 32 had a partial response, and 22 had stable disease.
In presenting the data at the meeting, Shubham Pant, a professor of gastrointestinal medical oncology and investigational cancer therapeutics at MD Anderson Cancer Center, said the disease control rate was 68.8 percent and the majority of evaluable patients, 68.4 percent, saw their tumors decrease in size. Sixteen patients were still responding to zanidatamab at the time of data cutoff, and the median progression-free survival was 5.5 months. Researchers didn't see responses in patients with HER2 IHC 0 or 1+ scores.
Two patients stopped treatment due to adverse events and three had to have their zanidatamab doses reduced due to toxicities. There were no grade 4 adverse events or deaths due to treatment-related toxicities.
These results suggest that zanidatamab has "meaningful clinical benefit" and could potentially be a future treatment option for HER2-positive biliary tract cancer patients, Pant said. He noted that other studies are underway looking at the activity of this drug, including in combination with cisplatin and gemcitabine.
HERIZON-BTC-01 is a pivotal trial of zanidatamab in second-line HER2-positive biliary tract cancer. In parallel with Pant's presentation at the ASCO annual meeting, data from this study were also published in Lancet Oncology. The US Food and Drug Administration has granted breakthrough therapy designation to zanidatamab as a treatment for previously treated HER2-amplified biliary tract cancer.
The findings from HERIZON-BTC-01 "showed a significant improvement over the current standard of care in second-line biliary tract cancer," said Kelvin Tan, chief medical officer at Jazz Pharmaceuticals, in a call with investors on Friday. Jazz acquired exclusive development and commercialization rights to zanidatamab from Zymeworks in the US, Europe, and Japan last year.
Jazz is hoping to file the latest data from HERIZON-BTC-01 in biliary tract cancer with global regulatory authorities. "We are in dialogue with the FDA regarding the potential regulatory path forward for zanidatamab in biliary tract cancer," Rob Iannone, executive VP and global head of R&D at Jazz, said in an email. "We believe that the current body of data is sufficient to support a biologics license application submission."
Jazz is also developing zanidatamab in gastric cancer. Tan told investors that Jazz believes "zanidatamab has the potential to transform the current standard of care in multiple HER2-expressing cancers" and is pursuing opportunities to expand it into other indications.
Combination HER2-targeted regimen
While HERIZON-BTC-01 looked at single-agent HER2-directed treatment, researchers also considered the activity of dual HER2-targeted treatment in biliary tract cancer patients. In the multi-cohort SGNTUC-019 basket trial, researchers are exploring Seagen's HER2 inhibitor Tukysa (tucatinib) plus Genentech's HER2-targeted monoclonal antibody Herceptin in various solid tumors with various HER2 aberrations.
In one cohort with 30 previously treated advanced biliary tract cancer patients, the combination showed a confirmed objective response rate of 46.7 percent. One patient had a complete response, 13 had a partial response, nine had stable disease, and six patients progressed on treatment.
Twenty-one patients saw their tumor shrink to some degree on the Tukysa-Herceptin regimen; the disease control rate was 76.7 percent. Median progression-free survival was 5.5 months, and median overall survival was 15.5 months. Few patients discontinued the combination regimen, and no patients died due to toxicities.
In presenting this data at the meeting, Yoshiaki Nakamura, a researcher at National Cancer Center Hospital, said Tukysa-Herceptin had "meaningful antitumor activity" in HER2-positive advanced biliary tract cancer patients, adding that these results "further validate HER2 as an actionable biomarker" in this setting.
That around 70 percent of patients in this trial showed some reduction in tumor burden "is certainly very encouraging" for the efficacy of Tukysa-Herceptin, said Andrew Ko, a colorectal and gastrointestinal cancer specialist at the University of California, San Francisco Cancer Center, in reviewing the data.
To partake in the study, patients had to have HER2 overexpression or amplification via local testing. Patients in the trial could undergo tissue-based immunohistochemistry testing to gauge if they had HER2 overexpression, or in situ hybridization or next-generation sequencing to assess if they had HER2 amplification. Patients had to be 3+ by IHC or have a fluorescence in situ hybridization or chromogenic in situ hybridization ratio of at least 2.0 or a gene copy number of more than 6.
Since there's no standardized method for gauging HER2 positivity in biliary tract cancer patients, researchers conducted exploratory biomarker analysis comparing concordance rates between local and central HER2 testing on patient's tissue and blood samples using IHC/FISH, FISH, and blood-based next-generation sequencing. Patients were considered HER2-positive if they had IHC scores of 2+ or 3+ and were ISH positive, or positive by FISH analysis using Agilent's HER2 IQFISH pharmDx assay, or positive by Guardant Health's NGS Guardant360 on blood samples.
The concordance rates were 87.5 percent for both centrally and locally done IHC/FISH and FISH tests, but 75.9 percent by blood-based NGS. The fact that around a quarter of patients deemed HER2-positive by blood-based NGS locally were not confirmed as HER2-positive in central testing "serves as a reminder that we need to be cautious when interpreting HER2 results in ctDNA in clinical practice for biliary cancer," especially since centrally tested HER2-negative patients had no response to the regimen, Ko said.
Reflecting the lack of standard HER2 testing in this setting, Ko pointed out that the Tukysa-Herceptin trial allowed local testing by different methods and the zanidatamab trial involved centralized confirmation for enrollment.
"Since there are no current FDA-approved treatments targeting HER2 amplification in biliary tract cancer, clinical standards for testing these patients have not yet been established," Iannone said. "However, we believe the use of zanidatamab, if approved, will help evolve the clinical practice for HER2 testing in biliary tract cancer."