HER2-Positive Biliary Tract Cancer: Biomarkers, Targeted Therapy, and Managed Care Access

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Welcome to Unscripted: The AMCP Podcast—a look inside managed care pharmacy. Listen in as experts explore the challenges, innovations, and opportunities shaping health care for millions of patients.
This episode of Unscripted: The AMCP Podcast is sponsored by Jazz Pharmaceuticals. Jazz Pharmaceuticals innovates to transform the lives of patients and their families. Today’s discussion will explore the rapidly evolving treatment landscape for HER2-positive biliary tract cancer (BTC) and its implications for managed care decision-making.

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We’ll examine the role of biomarkers like HER2, how molecular profiling guides targeted therapy, and the clinical and economic impact of timely access to HER2-targeted treatments—along with strategies for managed care teams to ensure coverage aligned with guidelines and testing protocols.
To help us with our conversation, we’ll be joined by Jeffrey Dunn, PharmD, MBA. Jeff is the President and CEO of Cooperative Benefits Group.

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Host: Welcome, Jeff.
Jeff: Thank you, Fred. Happy to be here.
Host: It’s really a pleasure to have you on—and this is a fascinating topic. So why don’t we begin: can you provide some background on BTC treatment and the landscape?
Jeff: Yeah. First of all, BTC is extremely rare and aggressive, so payers typically like to see the funnel. One of the first questions we always ask is: what is the prevalence of a disease? So I want to run through that quickly.

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The prevalence is about 4.4 per 100,000 people. Based on the size of the U.S. population, there are about 15,000 people in this country with BTC. Of those, less than 20% have HER2-positive BTC.

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If we take that to the next step—patients with HER2-positive advanced or metastatic disease—that’s about 70% of that number. And then about a third of them receive second-line therapy.
So across the U.S., it’s estimated that about 1,800 adults have advanced or metastatic HER2-positive BTC. And of those, about a third—or about 600—receive second-line therapy.

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So it is extremely rare. The other important point is that it’s very aggressive. The five-year survival rate for BTC patients with distant disease at diagnosis is less than 5%. To reiterate: fewer than 5% of patients survive five years. Very rare, very aggressive, and the long-term prognosis is not very good.

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Host: Given those statistics, what are the NCCN guideline–recommended options for first- and second-line therapy?
Jeff: For first line, NCCN has two preferred regimens. One is gemcitabine + cisplatin + durvalumab (Category 1). The second option uses the same first two components—gemcitabine + cisplatin—but substitutes pembrolizumab for durvalumab.

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Those are the two preferred regimens. Then there are seven or eight other recommended regimens—most are combinations with gemcitabine, but there are a couple of single-agent options. NCCN also lists a handful of agents that are “useful in certain circumstances,” which is where actionable mutations come in—things like NTRK fusions, RET, TMB, and HER2. If we can identify an actionable mutation, targeted therapies may be available.

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For second line, the preferred agent is FOLFOX. There are other recommended regimens as well, and payers typically differentiate between Category 2A and 2B, which often becomes an access “cut line.”

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NCCN again lists targeted therapies as “useful in certain circumstances.” That’s why testing is so important—if there are actionable mutations, we can move away from chemotherapy into more targeted therapies and increase the likelihood of a successful outcome.

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Host: Given the complexity and the unmet need, is this testing and targeting not happening consistently?
Jeff: Absolutely. Historically, there’s been slow uptake of testing—especially next-generation sequencing. Some of that is because many test results used to be non-actionable. But that’s changing: we have more targeted therapies now, so it’s increasingly important to support, promote, and reimburse testing.

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When we look at the data, about 50% of BTC patients have an actionable biomarker. That includes HER2-positive disease, but also other mutations like IDH1 and FGFR2. I also want to point out that HER2 in BTC is different than HER2 in breast cancer. This isn’t the “Herceptin era” dynamic where therapy selection was more routine—here it’s important to identify the driver in BTC so we can match the right therapy.

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Host: And how prevalent is HER2 in BTC?
Jeff: HER2 positivity is about 40% of overall BTC.

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Host: When biomarker testing is ordered and you identify a HER2-targeted pathway, what treatment options do you have?
Jeff: NCCN lists four HER2-targeted regimens. I’ll run through them, including therapy type and route of administration.

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1. Zanidatamab — a HER2-directed bispecific antibody (IV)
2. Trastuzumab deruxtecan — an antibody-drug conjugate (IV)
3. Trastuzumab + pertuzumab — dual monoclonal antibody therapy (IV)
4. Tucatinib + trastuzumab — combination oral + IV regimen

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Host: Can you discuss zanidatamab and how it works—its mechanism of action?
Jeff: Zanidatamab is a dual HER2-targeted bispecific antibody. It binds to two different extracellular sites on HER2. That leads to HER2 internalization and clustering, along with immune-mediated mechanisms. It’s differentiated by that dual binding—two binding sites—which drives its clinical benefit.

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Host: Now that we’ve covered clinical considerations, can you discuss how managed care should look at this? I know you were involved in a workgroup with some interesting results.
Jeff: Sure. We had a project running through most of 2025 with three payer-provider working groups—one in the West, one in the North, and one in the South. It was really interesting and helpful.

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Each group included GI oncology specialists, payers, and a patient representative—so we had multiple perspectives. The objective was to identify collaborative opportunities between payers and oncologists. Too often we sit across the table from each other without fully understanding what drives decision-making on the other side. These discussions helped.

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We also discussed therapies and tried to develop specific collaborative strategies to improve appropriate treatment access.

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Host: What challenges were identified?
Jeff: One big challenge is that community settings often have limited access to biomarker testing compared to centers of excellence. In community care, access isn’t consistent—and that needs to improve.

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We also discussed financial toxicity in cancer care and specialty care broadly. Employers, health plans, and members are struggling with affordability and accessibility. Social determinants of health came up too—especially long travel distances. With a cancer this rare, getting patients to centers of excellence can be appropriate, but travel becomes a real barrier.

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Another challenge is inconsistency in payer policies, which confuses providers. Medicaid coverage varies state by state, which is frustrating for both members and providers.

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Building off those challenges, we identified collaborative opportunities. One is developing team-based care models. Another is increasing dialogue between payers and oncologists. One practical recommendation I often give provider offices: identify a specific person at the health plan or PBM you can talk to. That streamlines the process a lot—even though it’s not always easy to find that contact.

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We also discussed payers developing in-house oncology expertise. Many payer-side clinical pharmacists review a huge range of drugs, so the knowledge is broad but may not be deep enough in complex oncology areas. Identifying pharmacists who can focus more deeply on oncology helps.
We can also use claims and clinical data to identify opportunities to better manage patients—what else they’re dealing with, what providers they’re seeing, what medications they’re taking—and share that back with providers as a value-add.

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The cancer journey is extremely challenging for members: labs, nurses, providers, infusion centers—it’s a lot, and it’s frustrating. There are real opportunities to streamline the pathway.

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One major recommendation was to standardize biomarker testing protocols—testing earlier to support earlier, better therapeutic decisions. Earlier intervention generally drives better outcomes.

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We also discussed that data suggest earlier testing and earlier access to targeted therapies can improve overall survival. The operational challenge is that many drugs are IV and run through the medical benefit, while oral therapies run through the pharmacy benefit—and testing is its own lane. Payers need to better integrate medical benefit, pharmacy benefit, and testing to make access smoother for both providers and patients.

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We’re also in a strong position to educate stakeholders. And finally, we talked about team-based approaches—nurses, pharmacists, physicians, and social workers working together. Social workers can help address access barriers and social determinants of health by connecting patients to assistance programs and support services, making the whole process more coordinated and less burdensome.

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Host: Is there anything else payers should prioritize to improve access for HER2-positive BTC patients?
Jeff: I’d summarize it as: right drug, right patient, right time. That’s true in many disease states, but it’s especially important here because this is a very rare, very aggressive disease. The data show that if we can identify the right drug and get the patient on it sooner, outcomes—especially overall survival—can improve.

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We need to review payer policies and ensure testing is integrated—so we’re not acting as a barrier between the provider and the lab. If we can do testing early, we can identify the right therapy sooner. Yes, these drugs are expensive, and there are economic considerations, but the goal is to get patients on the right drug earlier so they can live longer and have better quality of life.

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Host: Fantastic. Thank you so much for joining us, Jeff.
Jeff: Thank you.
Host: And thank you for listening to this episode of Unscripted: The AMCP Podcast. This episode was sponsored by Jazz Pharmaceuticals. For more information about Jazz, visit jazzpharma.com.