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Targeted Therapy for BTC
Experts Discuss Key Questions in Targeted Therapy for Advanced Biliary Tract Cancer

Released: July 23, 2024

Expiration: July 22, 2025

Mitesh J. Borad
Mitesh J. Borad, MD
Lipika Goyal
Lipika Goyal, MD, MPhil
James J. Harding
James J. Harding, MD
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Key Takeaways
  • It is critical to test for actionable alterations in advanced BTC, as numerous targeted therapy options are available.
  • Clinical trial enrollment should be considered for patients with advanced BTC whenever possible. 

Immunotherapy and targeted therapy have significantly improved treatment options for many patients with advanced biliary tract cancers (BTC). With new options, healthcare professionals are challenged to understand optimal treatment paradigms and the nuances of using novel therapeutics. In this commentary based on a satellite symposium presented in conjunction with ASCO 2024, Drs Mitesh J. Borad, Lipika Goyal, and James J. Harding discuss key questions surrounding contemporary treatment of advanced BTC. 

For a patient with previously treated advanced BTC with an FGFR2 fusion, would you prefer targeted therapy with futibatinib or pemigatinib or chemotherapy with FOLFOX?

Lipika Goyal, MD, MPhil: Let’s consider the case of a 37-year-old woman who presented with abdominal pain and was found to have a 6.1 centimeter liver mass. Her biopsy showed intrahepatic cholangiocarcinoma, and she underwent resection followed by 6 months of adjuvant therapy. She unfortunately had a recurrence 18 months later and received gemcitabine plus cisplatin plus durvalumab; however, she eventually progressed on this therapy as well. Tumor molecular profiling showed an FGFR2 fusion. What would you recommend for this patient? How do you choose between second-line FOLFOX or an FDA-approved FGFR inhibitor like futibatinib or pemigatinib? 

James J. Harding, MD: I don't think there's much of a choice. I would recommend a targeted therapeutic. The ABC-06 study of FOLFOX was a randomized trial that demonstrated an overall survival (OS) benefit with FOLFOX over active symptom control, but there was minimal to modest antitumor activity with FOLFOX. Although both the pemigatinib and futibatinib approvals are based on single-arm phase II studies, both agents are associated with compelling response rates with durable disease control and favorable OS.

Mitesh J. Borad, MD: I agree. I think with a known driver, the vast majority of physicians and patients would prefer a targeted therapy.

Lipika Goyal, MD, MPhil: I would agree as well. One thing to note: in my practice, of patients who receive first-line therapy, approximately 50% get to a second-line option and only about 25% will receive third-line therapy. As such, I try to use my best options as early as possible, and I always have FOLFOX in reserve if I need it.

As a follow-up on this topic, how do you choose between pemigatinib and futibatinib for patients with BTC with FGFR2 fusions? 

Mitesh J. Borad, MD: From a biologic perspective, futibatinib is associated with a relatively low probability of developing resistance alterations. However, from a clinical, practical perspective, you wouldn't be wrong if you chose either in the correct setting. 

Lipika Goyal, MD, MPhil: There are preclinical data showing that futibatinib can overcome some of the common resistance mutations that can arise with pemigatinib. 

Let’s discuss adverse events (AEs). Hyperphosphatemia is a common class AE with approved FGFR inhibitors, but it is often not clinically significant for patients. Do you really need to monitor for this AE, and how often?  What are some other AEs to be mindful of with this class of drugs? 

James J. Harding, MD: I do monitor for hyperphosphatemia with every cycle of the FGFR inhibitor, and sometimes more frequently at the start of therapy. I generally don't find an elevation of 5 to 7 mg/dL overly worrisome, but as it goes higher than 7 mg/dL, I will often start a phosphate binder and monitor more closely. 

We were asked about nail toxicity with the class of treatment, and this can be challenging to manage. We try to align our patients with our dermatology colleagues, and often over time this AE will improve and stabilize. 

What are some options for patients with HER2-altered advanced BTC?

James J. Harding, MD: Let’s consider the case of a 50-year-old woman with metastatic gallbladder cancer treated with first-line gemcitabine plus cisplatin plus durvalumab. The patient had progression of disease to the lungs and liver and molecular profiling by next-generation sequencing (NGS) showed an ERBB2 amplification, which was confirmed by immunohistochemistry (IHC), showing HER2 IHC 3+. What are some options for this patient?

There are several HER2-targeted regimens that have shown promise for patients like the case patient. These include trastuzumab deruxtecan (a HER2-targeted antibody–drug conjugate); trastuzumab plus pertuzumab; trastuzumab plus tucatinib; and zanidatamab, a bispecific antibody that binds to separate HER2 sites. 

Trastuzumab deruxtecan has been assessed in 2 studies in patients with treatment-refractory HER2-positive advanced BTC, the HERB and DESTINY Pan-Tumor02 studies. These studies have demonstrated overall response rates (ORRs) of approximately 20% to 30% with this agent; when you select for patients with IHC 3+ tumors, a higher ORR is observed, up to over 50%. Although trastuzumab deruxtecan does not have a BTC-specific FDA approval as of June 2024, it does have a tumor-agnostic indication for patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. Trastuzumab deruxtecan, along with off-label trastuzumab plus pertuzumab and trastuzumab plus tucatinib, are listed in national guidelines as options for subsequent-line therapy for HER2-positive BTC if disease progression occurs. 

Another agent that has been assessed in clinical trials but is not yet FDA approved is zanidatamab, a HER2-targeted bispecific antibody. Zanidatamab has been assessed in the open-label phase IIb HERIZON-BTC-01 study in patients with HER2-amplified locally advanced or unresectable metastatic BTC that progressed on a prior gemcitabine-containing regimen. The majority of patients in the study had some degree of tumor shrinkage, with the ORR for IHC 2 and 3+ BTC being 41.3%. Based on these data, there's now been launched a pivotal confirmatory phase III study, HERIZON-BTC-302, which will assess first-line zanidatamab plus standard of care therapy (eg, gemcitabine plus cisplatin plus durvalumab) for patients with advanced HER2-positive BTC.   

Lipika Goyal, MD, MPhil: If HER2 is amplified by NGS, do you confirm it with FISH or IHC? Do you retest for HER2 positivity at the time of progression?   

James J. Harding, MD: Data indicate that protein overexpression (ie, HER2 IHC 3+) is critical for response to HER2-targeted agents. Amplification often aligns with overexpression, but it is an incomplete readout. I do rebiopsy and retest HER2 at progression to confirm positivity because HER2 has very heterogeneous expression.

Mitesh J. Borad, MD: Those are excellent points. I think something that might come up if you did NGS and it was negative: should you do other tests to see if this patient is HER2 positive? It may make sense to still do an IHC test because there can be false negatives with NGS depending on the tumor cellularity. 

James J. Harding, MD: At our institution, we reflex HER2 testing now in BTC by ISH and IHC, and we also send for NGS.

Lipika Goyal, MD, MPhil: One thing we started doing at our institution after trastuzumab deruxtecan was approved, at least for GI cancers, was to order reflex testing the way we've done for microsatellite instability. All GI cancers get IHC for HER2 now going forward. 

What are some notable emerging targeted therapeutics for advanced BTC?

James J. Harding, MD: There are many classes of targeted therapies in development. Two of interest include KRAS G12C inhibitors and MDM2 inhibitors.

RAS is a key oncoprotein that has been classically referred to as undruggable. However, with advances in small molecule chemistry and protein–protein interaction, we are now able to inhibit KRAS. A key breakthrough was the observation that you can inhibit specific KRAS G12C with a small molecule by bridging a sulfur bond and locking RAS in an inactive form. One KRAS G12C inhibitor, adagrasib, showed an ORR of 41.7% in patients with previously treated advanced BTC with a KRAS G12C mutation in the basket KRYSTAL-1 study. Adagrasib is now listed in national guidelines as an option for subsequent-line therapy for KRAS G12C mutation–positive BTC if disease progression occurs.

We also know that a subset of BTCs display MDM2 amplification. MDM2 is an inhibitor of p53 which, when active, guards the genome by sending prodeath signals to cells in the presence of genomic abnormalities. 

So, if you can inhibit MDM2, you might allow p53 to have anticancer effect. MDM2 is amplified in 5% to 12% of BTC. Brigimadlin is an example of an investigational MDM2 antagonist that demonstrated activity in MDM2-amplified BTC, which has in part prompted the phase II Brightline-2 study of brigimadlin for previously treated, TP53–wild-type, MDM2-amplified advanced BTC and other solid tumors.

Regarding first-line combination therapy with gemcitabine, cisplatin, and an immune checkpoint inhibitor for advanced BTC, is it ever appropriate to pause either the chemotherapy or immunotherapy in a patient with an ongoing response?

Mitesh J. Borad, MD: This question comes up quite frequently. Currently, gemcitabine and cisplatin can be combined with durvalumab or pembrolizumab in the first-line setting based on the positive phase III TOPAZ-1 and KEYNOTE-966 studies, respectively. TOPAZ-1 included a maintenance approach in which patients received durvalumab alone after 8 cycles (or 6 months) of gemcitabine plus cisplatin plus durvalumab. KEYNOTE-966 continued gemcitabine plus cisplatin plus pembrolizumab without a defined maintenance component to treatment. I generally advise healthcare professionals to follow the guidelines but not to be too robotic. Make decisions that are rational and make sense for your individual patients. For example, if a patient experiences nephropathy, you might discontinue cisplatin. If they are not tolerating chemotherapy well at all, you can go to immunotherapy alone.

Lipika Goyal, MD, MPhil: So overall, depending on the patient's situation, you might continue chemotherapy longer or stop chemotherapy sooner. 

Mitesh J. Borad, MD: Precisely. 

How difficult is it to enroll patients with BTC in trials based on targeted alterations that you see on genome profiling? Isn't BTC a small patient population? 

James J. Harding, MD: I believe that clinical trials are critical. I approach every patient as if we have a trial and we can do clinical trial-based medicine. I tell them about trials even if I don't have one specifically available to them at that time. For trials of novel therapies, it is important to get tumor tissue early and establish a diagnosis so that the patient can be aligned with a clinical trial if possible. BTC is a rare disease, but centers of excellence have many ongoing studies, and there are now decentralized studies.

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