Zanidatamab induces response in refractory HER2-positive biliary tract cancer
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Key takeaways:
- Researchers reported a 41% confirmed ORR among patients with HER2-positive disease.
- No patients with immunohistochemistry 0/1+ status responded to treatment.
CHICAGO — Zanidatamab induced durable responses among patients with previously treated HER2-amplified biliary tract cancer, according to study results presented at ASCO Annual Meeting.
The agent also exhibited a manageable safety profile, investigators who conducted the phase 2b HERIZON-BTC-01 study concluded.
Data derived from Pant S, et al. Abstract 4008. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
“The findings demonstrate that HER2 is a very viable target in this disease, and targeting it can lead to clinically significant responses,” researcher Shubham Pant, MD, MBBS, associate professor in the department of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, told Healio.
Background and methods
Biliary tract cancer is a heterogenous group of malignancies, which include gallbladder cancer, extrahepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma.
Patients with locally advanced or metastatic biliary tract cancer who experience disease progression after first-line treatment typically derive limited clinical benefit from subsequent therapies, according to study background.
There has been a “paradigm shift” in treatment options over the past decade, Pant said, with the introduction of FGFR and IDH1 inhibitors.
HER2-neu positivity rates range from less than 5% for intrahepatic cholangiocarcinoma to as high as 20% for extrahepatic cholangiocarcinoma and gallbladder cancer, Pant said. However, no HER2-targeted therapy is approved for biliary tract cancers.
“Only about 5% of patients with biliary tract cancer respond to second-line chemotherapy, so that is not a great option” Pant told Healio. “We need to do next generation sequencing to identify patients with mutations, fusions or amplifications that could be candidates for targeted therapies.”
A phase 1 trial showed zanidatamab (Jazz Pharmaceuticals/Zymeworks) — a HER2-targeted bispecific antibody — induced durable responses for certain patients with biliary tract cancer. Researchers reported a 41% response rate among patients with HER2 overexpression, defined as 2+/3+ by immunohistochemistry (IHC).
In HERIZON-BTC-01, Pant and colleagues assessed zanidatamab monotherapy — dosed at 20 mg/kg via IV every 2 weeks — for patients with HER2-amplified, locally advanced unresectable or metastatic biliary tract cancer.
All patients had received prior gemcitabine-containing therapy. Trial protocol excluded patients who received prior HER2-targeted therapies.
The study included 87 participants (median age, 64 years; range 32-79; 54% women; 66% Asian). About half (52%) had gallbladder cancer, 30% had intrahepatic cholangiocarcinoma and 18% had extrahepatic cholangiocarcinoma.
Patients received a median one (range, 1-7) prior line of therapy in the locally advanced or metastatic setting.
Researchers assigned patients to one of two cohorts based on IHC status.
Cohort 1 included 80 patients with IHC2+/3+ status, defined as HER2-positive disease. Cohort 2 included seven patients with IHC0/1+ status.
Investigators assessed tumors every 8 weeks per RECIST 1.1.
Objective response rate per independent central review in cohort 1 served as the primary endpoint. Other efficacy outcomes and safety served as secondary endpoints.
Results
Median follow-up was 12.4 months.
In cohort 1, researchers reported a 41.3% (95% CI, 30.4-52.8) confirmed ORR, with one (1.3%) complete response and 32 (40%) partial responses. Twenty-two patients (27.5%) exhibited stable disease and 24 (30%) developed progressive disease, equating to a disease control rate of 68.8% (95% CI, 57.4-78.7).
Median response duration was 12.9 months.
Half (49%) of the 33 responders at data cutoff had ongoing responses, and the majority (81.8%) had response durations of at least 16 weeks.
Researchers reported median time to first response of 1.8 months (range, 1.6-5.5).
“Responses are one part of the puzzle; duration of response also is very important,” Pant told Healio. “Sometimes with targeted agents, a patient achieves a quick response but then develops progression. To me, the median duration of response of 12.9 months is very clinically significant.”
Investigators are continuing to assess PFS and OS outcomes.
In cohort 2, no patients responded to treatment. One patient (14%) exhibited stable disease and three (43%) developed progressive disease.
Nearly three-quarters (72%) of patients in both cohorts developed therapy-related adverse events, including diarrhea (37%) and infusion-related reaction (33%).
Eighteen percent experienced grade 3 treatment-related adverse events, the most common of which included diarrhea (4.6%) and ejection fraction decrease (3.4%).
Adverse events prompted two patients (2.3%) to discontinue zanidatamab. One developed ejection fraction decrease and the other developed noninfectious pneumonitis.
Seven patients experienced serious treatment-related adverse events.
No zanidatamab-related grade 4 adverse events or deaths occurred during the study.
Implications and next steps
Prior basket trials of HER2-targeted agents have included patients with biliary tract cancer, but this is the first such trial conducted specifically for this patient population, Pant said.
The findings support the importance of performing next-generation sequencing and HER2-neu immunohistochemistry in biliary tract cancer — particularly for patients with gallbladder cancer or extrahepatic cholangiocarcinoma, he added.
“Biliary tract cancer is a very genomically rich disease, and we need to do next-generation sequencing and look for HER2-neu with immunohistochemistry,” Pant told Healio. “If you don’t look for it, you won’t find it.”
Researchers intend to examine the potential correlation between co-mutations and outcomes, Pant added.
“These are meaningful results for the patients who benefited from the therapy. We will continue to evaluate patients who did not respond or those who achieved shorter response to determine if co-mutations may have played a part,” Pant said. “We collected tumor and blood samples from a majority of patients, and we need to do a deeper dive into every patient.”
Perspective
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Andrew H. Ko, MD, FASCO
Most biliary tract cancer trials include intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and sometimes ampullary adenocarcinomas. However, each of these entities has its own distinct molecular features. Certain targeted molecular alterations are much more commonly seen in intrahepatic cholangiocarcinoma, HER2 overexpression is observed more frequently — thought not exclusively — in extrahepatic cholangiocarcinoma and gallbladder cancers. It’s also essential to remember the definition of HER2 positivity may differ from one trial to the next, including methods for quantifying this, different thresholds of expression and confirmation for eligibility purposes. Beyond overexpression due to gene amplification, we must be aware that activating HER2 mutations are used for eligibility in some trials of HER2-targeted tyrosine kinase inhibitors, and that these HER2 mutations are occasionally but usually not associated with HER2 overexpression.
HER2-targeting agents include monoclonal antibodies, reversible and irreversible TKIs, bispecific monoclonal antibodies and antibody-drug conjugates.
In this trial, patients had to have IHC2+/3+ expression and have central confirmation of HER2 expression by FISH, with testing only allowed on tumor tissue and not blood-based assays. The waterfall plot shows very impressive responses associated with zanidatamab, including what appears to be a number of particularly deep responses and an encouraging prolonged median duration of response upward of 1 year.
The results of this trial — and another presented at ASCO that evaluated tucatinib plus trastuzumab — compare favorably with other recently published or presented studies of other HER2-targeting agents, acknowledging slight differences in eligibility criteria. But I don’t want to imply that we clearly know whether one HER2-targeted agent or combination is better than another.
What I can say is every patients we have with advanced biliary tract cancer should be tested for HER2 expression and probably HER2 mutation, as well, although more precise pathologic standardization is needed for defining HER2 positivity in this disease — similar to what we have for breast or gastric cancers.
Based on demonstrable efficacy and acceptable safety profiles of HER2-directed therapies, several of these are now included in compendia guidelines for HER2-positive biliary tract cancer. But we still have a lot to learn, including mechanisms of both intrinsic and acquired resistance to these agents and how to overcome them; sequencing of these various therapies, including knowing whether efficacy persists if patients go from one HER2-directed agent to another; and finally, moving HER2-targeted therapies into earlier stages and earlier lines of therapy, as well as combining these agents with chemotherapy and/or immunotherapy.
We may just be at the tip of the iceberg in terms of therapeutic strategies for targeting HER2. There are other novel bispecific antibody strategies targeting HER2 concurrently with other distinct targets, antibody-protein conjugates and even HER2-targeting CAR T cells, so there is a lot of reason for excitement and optimism specific to this particular molecular niche.
Perspective
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Pant and colleagues reported results of the phase 2b HERIZON-BTC-01 trial evaluating zanidatamab, a HER2-directed bispecific antibody that targets two separate epitopes on HER2. The cohort consisted of 80 patients with HER2-positive disease — primarily gallbladder primaries (51.3%) — whose disease progressed on prior gemcitabine-based chemotherapy and who tested 2+ (22.5% or 3+ (77.5%) by immunohistochemistry.
Researchers reported a remarkable centrally confirmed response rate of 41.3%, with median response duration of 12.9 months and median PFS of 5.5 months.
This agent appears highly active in HER2-positive biliary cancer. Zanidatamab appears to have a substantial degree of activity across a spectrum of HER2-positive GI malignancies. HER2 has emerged as a clearly targetable pathway in advanced biliary cancers, and an earlier-line study of these agents likely will proceed.
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Pant S, et al. Abstract 4008. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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