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FAQs: Immunotherapy in BTC
FAQs: Role of Immunotherapy in Biliary Tract Cancer

Released: December 18, 2024

Expiration: June 17, 2025

Tanios Bekaii-Saab
Tanios Bekaii-Saab, MD, FACP
Lipika Goyal
Lipika Goyal, MD, MPhil
Richard Kim
Richard Kim, MD
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Key Takeaways
  • Durvalumab and pembrolizumab, both in combination with gemcitabine/cisplatin, are FDA-approved for patients with previously untreated metastatic biliary tract cancer.
  • Use of immune checkpoint inhibitor–based combinations have demonstrated a manageable safety profile in biliary tract cancer.

In this commentary, Richard Kim, MD, summarizes the overview of currently approved immune checkpoint inhibitor–based therapies for patients with biliary tract cancer (BTC).

Are there any scenarios when you may prefer either durvalumab or pembrolizumab in combination with gemcitabine and cisplatin for your patients with previously untreated metastatic BTC?
Either durvalumab or pembrolizumab can be used for these patients as long as they fit the eligibility criteria for the TOPAZ-1 (durvalumab) or KEYNOTE-966 (pembrolizumab) trials. In my own practice, I tend to use durvalumab more since the TOPAZ-1 regimen received approval before the KEYNOTE-966 regimen. However, both regimens are equally effective. There has been no head-to-head comparison of the 2 regimens. In my opinion, there is really no compelling reason to choose one over the other.

It is however important to note that in the TOPAZ-1 trial, durvalumab in combination with gemcitabine and cisplatin was administered for up to 8 cycles. Thereafter, chemotherapy was stopped and treatment with single-agent durvalumab continued until disease progression, unacceptable toxicity, investigator’s discretion, or if the patient withdraws consent. In the KEYNOTE-966 trial, treatment with pembrolizumab plus gemcitabine and cisplatin was given for 8 cycles, after which cisplatin was discontinued and pembrolizumab and gemcitabine were continued until disease progression, unacceptable toxicity, investigator’s discretion, or if the patient withdraws consent. So, based on these differences, some of my colleagues favor one agent over the other. It is per the treating physician’s discretion and personal preference, not because one of the agents is superior to the other. However, some patients may prefer a "chemotherapy-free holiday" and opt to continue with immunotherapy alone.

Do you perform next-generation sequencing (NGS) testing at diagnosis or after disease progression on first-line therapy for your patients with unresectable, locally advanced, or metastatic BTC?
For patients with extrahepatic cholangiocarcinoma, for example, the tumor sample size is generally very limited. This is in contrast to patients with intrahepatic cholangiocarcinoma, where another biopsy can be done to obtain more tumor sample. If no tissue sample is available, the best option is to do a liquid biopsy with a serum sample using NGS, with the understanding that the serum sample collected from the patient may not contain enough circulating tumor DNA to obtain convincing test results.

In my clinical practice, I send samples for NGS testing as soon as the patient is diagnosed with advanced disease. Of note, the first-line treatment for patients with advanced BTC is gemcitabine and cisplatin in combination with either durvalumab or pembrolizumab. So, I do not need to do a biomarker test for any patient to receive first-line therapy. In the first-line advanced disease setting, treatment with gemcitabine/cisplatin plus an immune checkpoint inhibitor can be initiated without delay. Results from genetic tests using tissue can take weeks to obtain. By the time the patient’s disease progresses, I will have the NGS results to use to make the next treatment decision. This approach may change in the future as there are now several targeted therapies under investigation as first-line therapy for BTC. One example of this is the phase III DESTINY-BTC01 trial of first-line trastuzumab deruxtecan and rilvegostomig, a bispecific antibody targeting PD-1, and TIGIT, in advanced HER2-expressing BTC (NCT06467357).

What are the side effect expectations you set for patients who are about to receive the TOPAZ-1 or KEYNOTE-966 regimen?
We counsel patients on the potential toxicities associated with gemcitabine and cisplatin including fatigue, diarrhea, and hematologic toxicities and provide them with instructions on when to contact us. Of note, adding an immune checkpoint inhibitor to chemotherapy does not cause any significant additional toxicities. Immune checkpoint inhibitors, however, can induce immune-related adverse events (irAEs). So in my practice, our healthcare team informs the patients about these irAEs and that they can impact any organ system. Currently, there is no way to predict patients who will develop irAEs, which typically occur approximately 2 to 3 months after treatment is initiated. These irAEs may persist for up to 2 years after the completion of treatment with immune checkpoint inhibitors. We educate our patients on what to expect before patients initiate immunotherapy. Fortunately, the incidence of irAEs is low. In the TOPAZ-1 trial, irAEs of any grade occurred in 12.7% of patients who received durvalumab, and 22% of patients who received pembrolizumab on the KEYNOTE-966 trial experienced irAEs of any grade. In my experience, the most common toxicities are rash, fatigue, pruritus, and diarrhea. Less common/rare but more serious toxicities can include pneumonitis and endocrinopathies such as hypothyroidism, hyperthyroidism, and adrenal insufficiency.

These immune-mediated side effects are often manageable but may require corticosteroids or other immunosuppressive therapy if severe.

Your Thoughts?
What questions do you have about the use of immunotherapy for patients with advanced BTC? Answer the polling question and join the conversation in the discussion box below.

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In your practice, which of the following immune checkpoint inhibitors do you favor when recommending treatment for your patients with previously untreated metastatic BTC?

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