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Targeted Therapy for BTC
Key Questions in Targeted Therapy for Biliary Tract Cancer

Released: April 15, 2024

Expiration: April 14, 2025

Mitesh J. Borad
Mitesh J. Borad, MD
Lipika Goyal
Lipika Goyal, MD, MPhil
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Key Takeaways
  • Early molecular profiling is important to ensure that patients with biliary tract cancer have the best opportunity for targeted therapy and enrollment in clinical trials.

The following is a recap of key questions from healthcare professionals during a live webinar in which Mitesh J. Borad, MD, and Lipika Goyal, MD, MPhil, discussed recent advances in targeted therapy for unresectable and metastatic biliary tract cancer.

How do you choose between durvalumab and pembrolizumab when adding an immune checkpoint inhibitor to chemotherapy in the first-line setting? It seems like both are great options, with similarly strong evidence from positive clinical trials.

Mitesh J. Borad, MD:
In my opinion, it often comes down to practical considerations. For instance, healthcare professionals who started using durvalumab may already have treatment plans built around that agent, and may already be familiar with the dosing. I don’t think there is a wrong answer here. I think a key question can come after the patient has been receiving a regimen and benefitting after some months; do you keep the chemotherapy and the immunotherapy?

Lipika Goyal, MD, MPhil:
TOPAZ-1 and KEYNOTE-966 both had similar outcomes for the frontline treatment of advanced biliary tract cancer, so both are good options. One design difference between the trials is in the maintenance regimen after the initial 6 months of triple therapy. KEYNOTE-966 allowed patients to continue gemcitabine along with pembrolizumab while TOPAZ-1 allowed durvalumab only. Overall, we are excited that immunotherapy is now approved for the treatment of advanced biliary tract cancer and chemoimmunotherapy provides a longer tail on the survival curve for several patients.   

What is your decision-making process when choosing between pemigatinib and futibatinib for patients with FGFR2-altered cancers? How do you sequence them? In addition, what do you think about the new FGFR inhibitors?

Lipika Goyal, MD, MPhil:
There have not been any studies comparing pemigatinib and futibatinib head‑to‑head, and both drugs have strong evidence from clinical trials, so I think it is reasonable to consider either drug for patients with previously treated, unresectable, advanced cholangiocarcinoma with an FGFR2 fusion or rearrangement.

FGFR2 fusions are an Achilles heel in cholangiocarcinoma, so targeting with multiple sequential FGFR inhibitors, similar to the approach in EGFR mutant- or ALK fusion-positive lung cancer, has shown prolonged overall survival in some patients. So the question arises whether patients should start with the reversible FGFR inhibitor pemigatinib and save the irreversible FGFR inhibitor futibatinib to manage acquired resistance to pemigatinib. In the ideal scenario, patients would complete 6 to12 months or more of treatment with pemigatinib and then receive another 6 to 12 months or more of futibatinib. However, many tumors acquire resistance to pemigatinib via bypass or off-target mechanisms. In these cases, switching to futibatinib alone is unlikely to provide significant clinical benefit, so not everyone who experiences progression on pemigatinib can be rescued with futibatinib. Additionally, not everyone with disease progression on 1 FGFR inhibitor will be well enough to receive a second FGFR inhibitor, so multiple factors need to be considered when choosing the first FGFR inhibitor.  

With regard to the new FGFR inhibitors designed to overcome resistance to currently approved FGFR inhibitors, the multikinase inhibitor tinengotinib has shown activity in cholangiocarcinoma post-FGFR inhibitor, and is now under evaluation in FGFR2 fusion-positive cholangiocarcinoma vs chemotherapy in FIRST-308, a phase III clinical trial. RLY-4008 is a highly selective FGFR2 inhibitor that is also currently under investigation in REFOCUS, a phase I/II clinical trial, and has shown activity post-FGFR inhibitor. Although the safety and efficacy of these agents remains to be seen, I think it is exciting for the field to have additional options in development right now.

As the prevalence of MDM2 amplification is about 4% to 8% in biliary tract cancer, is it practical to test for this prior to first‑line therapy? 

Lipika Goyal, MD, MPhil:
Even if patients have MDM2‑amplified cholangiocarcinoma, I still will go with chemoimmunotherapy as frontline therapy. However, while these patients are receiving chemoimmunotherapy, I will order tumor genomic profiling so that I can switch to an MDM2 inhibitor on a clinical trial for second-line therapy, as needed. BRIGHTLINE-2 is a registrational phase II study specifically for patients with MDM2-amplified biliary tract cancer; this trial is evaluating brigimadlin and has additional cohorts for pancreatic cancer, lung adenocarcinoma, and bladder cancer. Overall, for advanced biliary tract cancer, I start with chemoimmunotherapy and then consider targeted therapies in the second line, unless patients are enrolling in clinical trials.

When do you choose an IDH1 inhibitor vs chemotherapy in a patient with IDH1-mutated biliary tract cancer who requires second-line therapy?

Lipika Goyal, MD, MPhil:
I would say that both IDH1 inhibitors and chemotherapy are good options for treatment of refractory IDH1-mutated biliary tract cancer. Ivosidenib may be better tolerated and cause fewer cytopenias than FOLFOX, FOLFIRI, or 5-FU/nanoliposomal irinotecan, so this can be factored in when discussing the patient’s preferences and needs.  Also, disease burden can impact the decision. The response rate with ivosidenib was 2% in the phase III ClarIDHy trail, and the response rate with FOLFOX chemotherapy was similar at 5% in ABC-06. For patients with greater disease burden and/or rapidly progressive disease, I will often suggest cytotoxic chemotherapy first, and for patients with lower burden, less aggressive disease, I will often recommend ivosidenib first.

Mitesh J. Borad, MD:
I think that is a very difficult conundrum, because the long-term benefit rate with ivosidenib is low. I agree that disease burden could be a good way to discriminate whether the patient should be prescribed chemotherapy for rapidly progressing disease or ivosidenib for less aggressive, lower burden disease.

What do you want your next-generation sequencing (NGS) panel to cover? 

Lipika Goyal, MD, MPhil:
Overall, the main targets in biliary tract cancers with either cholangiocarcinoma-specific or disease-agnostic FDA approved agents (and therefore the targets I would like an NGS panel to cover) include: FGFR2 fusions (seen in 10%-15% of intrahepatic cholangiocarcinomas, or ICC), IDH1 mutations (10%-20% of ICC), BRAF V600E mutations (up to 5% of BTC), NTRK fusions (<1% of BTC), RET fusions (<1% of BTC), and microsatellite insufficiency (up to 3% of BTC). Recently, trastuzumab deruxtecan gained a disease-agnostic approval 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. As such, NGS should HER2 amplification (seen in 5%-20% of BTC).

NGS panels these days usually detect a broad variety of genetic alterations including BTC-relevant alterations such as MDM2 amplification, BRCA1/2 mutations, and KRAS mutations.  Detection of uncommon variants allows oncologists to refer patients for clinical trials to improve outcomes for them and also drive drug development. 

Mitesh J. Borad, MD:
It is important to recognize that NGS panels incorporate a wide range of targets, since they were set up not just to characterize biliary tract cancers, but to cover as many cancers as possible. So, even though a target is rare in biliary tract cancers or more common in other cancers, that information is still going to be meaningful for that patient. That being said, I think the current panels do a pretty good job of covering the majority of interesting targets that we know of today.

How difficult is it to enroll patients in biliary tract cancer trials when there is such a small patient population and competing trials? Do you have any suggestions around recruitment? 

Mitesh J. Borad, MD:
I think trial enrollment is not as much of a problem as people think. Some previous trials enrolled over 1000 patients, although those were not biomarker‑selected trials. However, even among the biomarker‑selected trials, there were several that enrolled over 100 patients each. So, I think patient eligibility and availability of clinical trials are not barriers to enrollment. Currently, I think the greatest barrier to enrollment in clinical trials is probably the lack of tumor profiling and being considered for a trial, rather than the trials not existing.

Lipika Goyal, MD, MPhil:
I think the key for getting patients on trials is to refer them to a center with trials early on, so that they have the opportunity to hear about trials and enter the prescreening process while they are still in relatively good health. This is of particular importance as patients often get sick quickly and only have a short window of opportunity for treatment once their tumors start to progress. Early introduction to clinical trials is also key to overcoming hesitancy from patients. Some people have never heard of clinical trials, so it may take a bit of time for them to wrap their mind around doing a research study and going on an investigational agent. 

Of note, I think there is an appetite for enrollment in these trials, as was seen with the SWOG 1815 study comparing gemcitabine, cisplatin, and nab‑paclitaxel vs gemcitabine and cisplatin.  It was the first randomized phase III study in biliary tract cancer in the US and accrued participants very quickly. Currently, I think there is much more awareness of clinical trials and the potential benefits of enrollment in the cholangiocarcinoma community. Of note, the Cholangiocarcinoma Foundation is a great resource for education about clinical trials and about the disease in general for both oncologists and patients. 

Your Thoughts
What is your experience with molecular testing and targeted therapy for patients with biliary tract cancer? Leave a comment to join the discussion.

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In your current practice, how often do you request or verify testing for actionable biomarkers to guide treatment decisions for patients with advanced cholangiocarcinoma?

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