Tanios S. Bekaii-Saab, MD.
As molecularly targeted and immune-based strategies continue to reshape the treatment paradigm for biliary tract cancers, recent advances in HER2-directed therapy and chemoimmunotherapy have expanded the range of effective options, according to Tanios S. Bekaii-Saab, MD.
“There’s a lot of focus on bringing those therapies that have shown activity in the more refractory setting into the first-line setting, either as single agents or in combination,” he said. “That’s how we’re going to transform the field, while continuing to dig deeper for other targets.”
In an interview with OncLive®, he outlined current treatment standards for advanced biliary tract cancers; highlighted the role of targeted therapies for this patient population; and discussed the need for biomarker-driven immunotherapy selection and other ongoing research.
Saab is a professor of medicine at Mayo Clinic College of Medicine and Science and a consultant in the Division of Hematology and Oncology at Mayo Clinic in Phoenix, Arizona.
OncLive: How would you define the current treatment landscape for biliary tract cancers in 2025?
Bekaii-Saab: Treatment in 2025 biliary tract cancers are an interesting group of cancers. It essentially refers to cancers that involve the bile ducts, and then that also includes gallbladder cancer. All these fall under this denomination.
This is a rare cancer, although if you look across the world, it’s approximately 100,000 patients [diagnosed each year]. In the United States, depending on where you look, it’s approximately 7000 to 12,000 patients [diagnosed each year] with this cancer. If you think about breast cancer, [with] 220,000-plus patients [per year], biliary tract cancer is, relatively speaking, a rare cancer.
What’s unique about this cancer is this is one of the cancers where immunotherapy has a role along with chemotherapy. This is also a very target-rich cancer. There are a number of targets that have been identified that we go after with targeted therapies, and many of them are approved; many are still under study.
Talking first about the landscape, chemotherapy—primarily gemcitabine and cisplatin—had been the backbone for the longest time in treating this cancer in the first line. Over the last few years, we’ve had PD-1 and PD-L1 inhibitors—durvalumab [Imfinzi] first, and then pembrolizumab [Keytruda] came in. When combined with gemcitabine and cisplatin, they appear to do better than gemcitabine/cisplatin alone, and so they became part of our standard of care. Chemoimmunotherapy is our standard in the first line.
[Chemoimmunotherapy] did move the needle. If you look at the 3-year overall survival [OS] for durvalumab, there’s certainly a doubling of the 3-year OS rate, but you can still see that it’s dismal, with only approximately 1 out of 5 patients surviving beyond 3 years.
How often can targeted therapy be utilized for patients with biliary tract cancer?
Approximately 30% to 40% of these cancers have a target that we can match with a proper therapy. For example, for intrahepatic cholangiocarcinoma, approximately 5% to 7% of patients have an FGFR2 fusion. Pemigatinib [Pemazyre] and futibatinib [Lytgobi] both give you a response rate close to 40% and really good long-term outcomes for some patients. Second- and third-generation FGFR inhibitors are being developed that seem to have higher response rates, but also more toxicity.
For gallbladder cancers and extrahepatic cholangiocarcinoma, HER2 amplifications are a major driver. Outside the United States, up to 30% of patients will have HER2 amplifications. We have treatments such as fam-trastuzumab deruxtecan-nxki [Enhertu] and trastuzumab [Herceptin] plus pertuzumab [Perjeta]; more recently, zanidatamab-hrii [Ziihera], which is approved specifically for [previously treated] patients with immunohistochemistry [IHC] 3+ [HER2-positive disease].
We also have rare KRAS G12C mutations, with data for adagrasib [Krazati], which is now included in the National Comprehensive Cancer Network [NCCN] guidelines. We have BRAF V600E mutations, present in approximately 5% to 10% of patients, with dabrafenib [Tafinlar] plus trametinib [Mekinist]. We have IDH1 mutations, present in approximately 20% of patients with intrahepatic cholangiocarcinoma, treatable with ivosidenib [Tibsovo]. Then there are other rare fusions, with more being discovered. Even for a rare cancer, in 30% to 40% of patients—[in addition to chemoimmunotherapy]—we have targeted agents that can induce meaningful responses.
How do you approach sequencing in patients eligible for HER2-targeted therapy?
Looking at the data globally, the key studies, at least over the last year, that have changed practice were mostly in the HER2-amplified space.
We had an approval by the FDA with zanidatamab based on the phase 2b HERIZON-BTC-01 trial [ NCT04466891]. This agent is bispecific, targeting both trastuzumab- and pertuzumab-like epitopes—and preclinically, at least, it seemed to perform better than trastuzumab [plus] pertuzumab.
We know that pertuzumab plus trastuzumab has a very modest response rate—around 20%—and can have some toxicities. With zanidatamab, we’ve seen is a response rate a little north of 40%, with many of these responses appearing to be quite durable, and even better outcomes in the IHC 3+ subgroup compared with others. This led to the approval of this agent specifically in IHC 3+ patients.
We’ve also seen data with tucatinib [Tukysa] plus trastuzumab [from a phase 2 study (NCT04579380)], again amounting to a decent response rate and ultimately placement on the NCCN guidelines.
Then there is trastuzumab deruxtecan [which has] a tumor-agnostic approval that includes biliary tract cancer. In the biliary tract cancer subgroup, the response rate was around 40%.
Overall, HER2 amplifications have become a very important target, added to the others we already consider. The question is: how do you sequence them in the clinic?
In my practice, after gemcitabine/cisplatin plus durvalumab or gemcitabine/cisplatin plus pembrolizumab, the first two options would be tucatinib plus trastuzumab or zanidatamab. Zanidatamab may be preferred in the IHC 3+ group, but for IHC 2+ and in situ hybridization–positive disease, I would go with tucatinib/trastuzumab, largely based on our experience in colorectal cancer.
That leaves trastuzumab deruxtecan, which I like to keep as a backup option [after patients progress on the] other 2 [options]. Trastuzumab deruxtecan is an antibody-drug conjugate, and it doesn’t rely on HER2 activity, per se. It binds to HER2, is internalized, and then releases deruxtecan into the tumor environment, leading to cancer cell killing.
Importantly, across studies, the response rate with trastuzumab deruxtecan does not appear to be affected by prior HER2-directed therapy, which means we can still see benefit even in pre-exposed patients. This effectively gives us two lines of HER2-directed therapy. Of course, one of the main concerns with trastuzumab deruxtecan remains interstitial lung disease, which continues to require close monitoring.
What does the future hold for biliary tract cancer research?
The key is to try to bring a lot of these targeted therapies into earlier lines of treatment. That’s being done with zanidatamab. We tried to do that with pemigatinib, but had some difficulties because of the rarity of the target. [We] also will see others, like ivosidenib, ultimately making their way in—primarily in combination with chemotherapy, with or without immunotherapy.
The goal here is to try to bring the advantages we’re seeing with [targeted] those therapies into the first-line setting. That is where I think they’ll have a much bigger benefit. We see that across a lot of different malignancies—if you hit the biology sooner, you end up with significantly better outcomes.
Now, the challenge is that these are rare cancers, and those are targets [within these rare cancers]. The question becomes: how do you design your study in a way that will allow you to test that question while also allowing patients to start treatment while you’re waiting on results? Those are designs that are being looked at in many places.
The other element is immunotherapy. With PD-1/PD-L1 inhibitors, only approximately 10% to 20% of patients seem to benefit. We don’t have a biomarker today, but a lot of biomarker discovery is focusing on how we can better select those patients who may benefit—rather than exposing 100 patients to find the 20 or 30 who will respond. Those are the patients we would want to target, and for the rest, we need to identify different pathways.
I think we’re pretty much maxed out on chemotherapy options beyond [gemcitabine/cisplatin]. All other chemotherapy agents have a very modest role, and I don’t think our goal would be to continue developing along the cytotoxic pathway, except with antibody-drug conjugates, where there may be other targets of interest, such as MET, that could be developed in this pathway.