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The accelerated FDA approval of zanidatamab-hrii (Ziihera) for patients with previously treated HER2-positive biliary tract cancer and an immunohistochemistry (IHC) score of 3+ has filled a need in a space where therapies are limited, and evaluations of the agent in frontline combination therapy regimens are ongoing, according to James J. Harding, MD.

Findings from the phase 2b HERIZON-BTC-01 trial (NCT04466891) supported the 

 and showed that treatment with the bispecific HER2-directed antibody yielded an objective response rate (ORR) of 52% (95% CI, 39%-65%) in patients (n = 62).

 The median duration of response (DOR) was 14.9 months (95% CI, 7.4-not estimable) with 44% of responders experiencing a response for at least 12 months.

“This represents the first accelerated approval in biliary tract cancers for a [dual] HER2-targeted [bispecific antibody],” Harding said in an interview with 

®. “Zanidatamab has shown excellent antitumor activity and tolerability in patients with HER2-amplified biliary tract cancer. It’s extremely exciting and offers a new treatment option for patients with [a] very difficult [to treat] disease.”

In the interview, Harding highlighted data with zanidatamab and how the agent will fit into the treatment paradigm. Harding is an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

: What is the significance of the FDA approval of zanidatamab?

: This is an exciting time for patients with biliary tract cancers, especially those with HER2-amplified and HER2-positive biliary tract cancers….The importance of this approval is that this was the first clinical trial looking solely at biliary tract cancers that are HER2-positive and asking the question, ‘Can zanidatamab lead to meaningful antitumor activity?’ We’re very pleased that the FDA has authorized this in an accelerated way for use in the second-line-plus population, and it will add to the armamentarium for HER2-positive biliary tract cancers. The ongoing phase 3 HERIZON-BTC-301 study [NCT06282575] is happening now to further define the benefit but is looking in the first-line space.

Zanidatamab is a novel bispecific antibody. There are a number of bispecific antibodies that are entering the clinic [and] that have FDA approvals, but they’re different. In this case, this is a bispecific antibody that targets two HER2 epitopes that are not the same, and it was designed to result in multiple mechanisms of actions for its antitumor activity. It can block HER2 signaling, lead to internalization of the HER2 receptor at the cell surface [making it] less available, [and] lead to antibody-dependent cell cytotoxicity and complement mediated destruction of these cells. [Zanidatamab] does not [result in] cytokine release syndrome, which is seen with other bispecific antibodies, because it’s mechanistically quite different. Both the preclinical data and data in patients from the phase 1 trial [NCT02892123] as well as HERIZON-BTC-01 indicate that it does have antitumor activity; we need to define its further use, but I’m excited for patients for this accelerated approval.

What unmet needs does this approval address for patients?

Biliary tract cancers are an uncommon disease. In the US and globally, [they] represent approximately 2% to 3% of all gastrointestinal cancers. We’ve learned that [for] biliary tract cancers there are a number of precision medicine targets, HER2 being one of those potential therapeutic targets. HER2 is overexpressed or amplified in a subset of biliary tract cancers, and that depends on the anatomic site. For example, in gallbladder cancers it’s estimated that up to 30% of patients will have HER2 overexpression [whereas the estimation] is [up to] 20% in extrahepatic cholangiocarcinoma and 5% to 10% in intrahepatic cholangiocarcinoma.

In general, patients with advanced biliary tract cancers are treated with upfront chemoimmunotherapy which is an active therapy. However, most patients will ultimately progress on this treatment and more therapies are needed. This approval allows for a second line [and beyond] option for patients with HER2-amplified or -positive biliary tract cancer, so it accesses that subset.

What patient population was enrolled in HERIZON-BTC-01?

HERIZON-BTC-01 was a multicenter, open-label, phase 2 study [evaluating] zanidatamab [in] patients with biliary tract cancers who had HER2 amplification as defined by central confirmation. The primary end point of the study was ORR confirmed by independent central review [ICR]. The secondary end points [included] progression free survival [PFS], investigator-assessed ORR, overall survival [OS], and safety, as well as a number of correlates.

Patients had to have progressed on a gemcitabine-containing regimen, could [not] have [received] other HER2-targeted therapy, and were enrolled into 1 of 2 cohorts. Cohort 1 [included] patients who had HER2 amplification by a central [laboratory] in situ hybridization assay and had a 2+ or 3+ IHC [score]. Patients who had HER2 amplification by in situ hybridization but did not express HER2 at that level, [and instead had an] IHC 0 or 2+ [score], went into cohort 2. The primary end point was [in] cohort 1 and [was] met, [with data] demonstrating an ORR of [52%] by ICR, [which supported the accelerated approval].

What were the key efficacy findings from HERIZON-BTC-01?

The initial study, when first reported, had a median follow-up of approximately 12 months, and subsequent reports looked at a median follow-up of approximately 20 plus months. The key takeaways from the totality of the data are that zanidatamab demonstrates antitumor activity in HER2-amplified, HER2-positive biliary tract cancers. At the initial data cut, the ORR was approximately 41% and the median DOR was 12.9 months, and [this] increased at further follow-up [to a 52% ORR with a median DOR of 14.9 months]. The median time to response was approximately 1.8 months [at the initial data cut and] we understand from this data set that PFS is approximately 6 months.

In terms of anti-tumor activity, [the drug is] effective in this patient subset [with an IHC 3+ score]. Unanswered questions are: Can we improve that [response rate] with combinatorial therapy? What about the 2+ [population], how does this [drug] fare in that state? Those studies are ongoing.

In general, the agent was very well tolerated. Only 2.5% of the study population needed to discontinue zanidatamab because of an adverse effect [AE]. Most AEs thought to be related to zanidatamab were grades 1 and 2 and those were [most commonly] infusion-related reactions as well as diarrhea. AEs of special interest [observed that are] particularly for HER2-targeted therapies [were] diarrhea—which was minimal and controlled—and heart ejection [fraction]; HER2 targeted therapy can impact the heart and the myocyte. Decrease in [left ventricular] ejection [fraction] was observed in a very small percentage of patients. The safety profile was in line with prior phase 1 [findings] and in indirect cross trial comparison to other HER2 targeted therapies, it was favorable in my perspective.

Where does zanidatamab fit into the biliary tract cancer treatment paradigm?

With this approval, zanidatamab would fit as a second-line-plus option for patients with HER2- amplified, HER2-positive biliary tract cancers who received a prior gemcitabine-containing regimen. That is excellent because it expands the armamentarium in a disease with few active therapies; that’s critical. This is an accelerated approval, and additional data will be required to confirm this antitumor activity. There is [also the] ongoing frontline setting, global, open-label, randomized phase 3 HERIZON-BTC-301 [NCT04466891] study of zanidatamab with [chemotherapy] plus or minus a PD-1 antibody vs [chemotherapy] plus or minus a PD-1 antibody with the primary objectives of PFS [and OS]. The key is that we’re assessing its activity in the treatment naive setting of disease in combination with chemotherapy and immunotherapy. [For] that study, many sites are open, and we’re actively searching to move this [agent] into the frontline space.

There are also other studies that will be looking at correlative science to define what the best patient population is to respond to zanidatamab as well as other exploratory combinations in this space. It’s a very exciting time to continue to illustrate the key importance of molecular profiling in patients with biliary tract [cancers and zanidatamab is] an additional therapy for patients. But more work needs to happen to define the operating characteristics of this agent and solidify a final approval in the years to come.

FDA grants accelerated approval to zanidatamab-hrii for previously treated unresectable or metastatic HER2-positive biliary tract cancer. FDA. Updated November 21, 2024. Accessed December 6, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanidatamab-hrii-previously-treated-unresectable-or-metastatic-her2

Ziihera. Prescribing information. Jazz Pharmaceuticals, Inc; 2024. Accessed December 6, 2024. https://pp.jazzpharma.com/pi/ziihera.en.USPI.pdf

Articles

James J. Harding, MD, details the significance of the approval of zanidatamab and how the agent could fill unmet needs in biliary tract cancers. 

Vol. 26 No. 2 | Oncology Live®

Zanidatamab Proves Efficacious in Pretreated Biliary Tract Cancer With Potential to Move to the Frontline