# Switching FGFR Inhibitors in Bile Duct Cancer: Can the Right Sequence Extend Treatment Benefit?

This review examined whether giving a second, different type of FGFR inhibitor (a drug that blocks the fibroblast growth factor receptor) after a first one stops working can keep tumors under control for longer in patients with intrahepatic cholangiocarcinoma (cancer of the bile ducts inside the liver). The authors searched PubMed, ASCO, and ESMO records and found 10 publications covering 68 cases of patients treated first with a reversible FGFR inhibitor and then with an irreversible one. In 20 cases with available data, the first drug controlled the cancer for a median of 9.1 months (range 2.9-23.0), and in 23 cases the second drug controlled it for a median of 7.8 months (range 1-23.6) — and in some patients the second drug worked as long as or longer than the first. The authors conclude that strategic sequencing — reversible drug first, irreversible drug second — may extend the total time patients benefit from FGFR blocking, and they propose a hypothetical treatment algorithm to guide future practice.

# Switching FGFR Inhibitors in Bile Duct Cancer: Can the Right Sequence Extend Treatment Benefit?

## Table of Contents

- Key Points
- Background: Why Bile Duct Cancer Is So Hard to Treat
- What Are FGFR2 Fusions and Why Do They Matter?
- The Four Generations of FGFR Inhibitors
- How Well Does Each FGFR Inhibitor Work?
- Which FGFR Inhibitors Are Approved Today?
- Finding the Right Patients: Genomic Testing and Liquid Biopsy
- Why Tumors Fight Back: Resistance Mutations
- How This Review Was Conducted
- Key Findings: What Happened When Patients Switched Drugs
- What This Means for Patients
- Limitations: What This Review Could Not Prove
- Practical Recommendations
- Frequently Asked Questions
- Source Information

## Key Points

- In a review of 68 cases, patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma received a reversible FGFR inhibitor first, then an irreversible one after progression.
- Among 23 cases with data, the second irreversible FGFR inhibitor controlled the cancer for a median of 7.8 months (range 1 to 23.6); some responses matched or exceeded the first drug.
- The evidence comes from case reports and early-phase trials, not randomized studies, so it cannot prove that sequencing is better than not sequencing.
- Resistance mutations form in patterns and may guide drug choice; for example, lirafugratinib remained active against V565 mutations while futibatinib did not.
- Hyperphosphatemia is a common side effect of nonselective FGFR1-4 inhibitors; FGFR2-selective agents such as lirafugratinib were designed to avoid it.

## Background: Why Bile Duct Cancer Is So Hard to Treat

Cholangiocarcinomas (CCAs) are aggressive, genetically varied cancers that arise from the cells lining the bile ducts. They can start inside the liver, called intrahepatic cholangiocarcinoma (iCCA), or in the bile ducts just outside the liver, called perihilar and distal bile duct cancers. The global number of new cases and deaths from CCA — especially iCCA — has been rising for decades.

Surgery is still the only treatment that can cure this disease. Systemic treatments (drugs that travel through the bloodstream, such as chemotherapy) have improved, but complete surgical removal remains the goal. The problem is that even after successful surgery plus chemotherapy, the cancer comes back in up to about 60% of patients — roughly 6 in 10.

For patients whose tumor cannot be removed, the outlook is poor. iCCA resists both chemotherapy and radiation therapy. Among patients diagnosed with locally advanced disease (cancer that has spread into nearby tissue) or metastatic disease (cancer that has spread to distant organs), the median survival is only about 9 to 15 months. "Median survival" means half of patients live longer than that number and half live less.

The discovery of specific gene changes that can be targeted with drugs has changed the picture for some patients. These "targetable genomic alterations" (DNA changes that drugs can attack) include FGFR2 fusions, isocitrate dehydrogenase-1 (IDH1) mutations, BRAF mutations, KRAS p.G12D/C mutations, and human epidermal growth factor 2 (ERBB2) amplification and overexpression (too many copies and too much protein from the ERBB2 gene).

## What Are FGFR2 Fusions and Why Do They Matter?

FGFR2 fusions occur almost exclusively in iCCA, where they are found in up to 10% of patients — about 1 in 10. A "fusion" means two separate genes have broken and joined together, creating an abnormal hybrid gene.

The most common fusion in CCA is FGFR2::BICC1. Normally, the FGFR2 protein only switches on when a signaling molecule called FGF (fibroblast growth factor) attaches to it. In the fused version, the protein pairs up with itself without needing FGF at all. The result is a receptor that is permanently switched on — scientists call this "ligand-independent dimerization" and "constitutive activation" — driving continuous, cancer-promoting signals inside the cell.

Because FGFR2 fusions are a clear driver of the cancer, they are an attractive therapeutic target. That discovery prompted the development of many FGFR inhibitors (FGFRis). All of these drugs are highly potent, selective tyrosine kinase inhibitors (TKIs — drugs that block specific enzymes that drive cell growth). But they differ from each other in several important ways:

-
**Structure** — the physical shape of the drug molecule
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**Mechanism of inhibition** — whether they compete reversibly with ATP (the cell's energy molecule) for the binding site, bind irreversibly by forming a permanent chemical bond, or work at an allosteric site (a location away from the main active site)
-
**Pharmacologic and pharmacodynamic profiles** — how the body processes the drug and how the drug affects the body
-
**Selectivity** — how precisely they hit the four FGFR subtypes (FGFR1 through FGFR4) versus other kinases

Because of these differences, FGFRis can be used in the second line of treatment and beyond for CCA. ("Second line" means after the first treatment has stopped working.) Evidence is now emerging that the order in which these drugs are given — the sequencing — may matter. However, experts still disagree on the best sequence, and there is no consensus yet.

## The Four Generations of FGFR Inhibitors

FGFR inhibitors fall into four broad generations, defined by how precisely they hit their target and by how they bind.

**First generation.** These drugs (for example, derazantinib and erdafitinib) are not specific to FGFR. They also block many other kinases, which causes off-target side effects — problems caused by hitting unintended targets.

**Second generation.** These are FGFR-selective inhibitors, including pemigatinib, infigratinib, and tasurgratinib. They work by reversibly competing with ATP for the binding site, attaching through hydrogen bonds and weaker van der Waals interactions. Because they are more selective, they cause fewer off-target effects — but they are more likely to cause hyperphosphatemia (high phosphate levels in the blood), which is a common "on-target" side effect of blocking FGFR1-4.

Hyperphosphatemia happens because FGFR1 helps regulate phosphate balance in the body through a feedback loop involving FGF23, 1,25(OH)2D3 (activated vitamin D), and parathyroid hormone. Blocking FGFR1 disrupts this loop.

**Third generation.** This group includes futibatinib and lirafugratinib (RLY-4008). These drugs bind *irreversibly* — they form a permanent covalent (chemical) bond to a cysteine residue in the FGFR kinase domain, unlike the reversible second-generation drugs. Futibatinib is a highly selective FGFR1-4 inhibitor. Lirafugratinib was specifically designed to target only oncogenic FGFR2 alterations and resistance mutations. That FGFR2-only selectivity avoids hyperphosphatemia, because the phosphate problem is driven by FGFR1 rather than FGFR2.

**Fourth generation.** Tinengotinib (TT-004020) is a novel multitarget tyrosine kinase inhibitor that blocks Aurora A/B, FGFR1/2/3, vascular endothelial growth factor receptors (VEGFRs), Janus kinase 1 and 2 (JAK1/2), and colony-stimulating factor 1 receptor (CSF1R). What sets it apart from other ATP-competitive FGFRis is that it works by binding to an **allosteric site** — a location far from the main ATP-binding pocket — and blocks FGFR activity indirectly. Tinengotinib is highly effective against many acquired mutations in the FGFR1-3 kinase domain. It has shown promising antitumor activity in phase I and phase II studies of patients with advanced metastatic CCA and FGFR fusions who had already received an FGFRi.

## How Well Does Each FGFR Inhibitor Work?

The key measure in these studies is the overall response rate (ORR) — the percentage of patients whose tumors shrank by a meaningful amount. Here is what the largest available trials showed.

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**Derazantinib:** ORR 22.3% (95% CI, 14.7 to 31.6) — about 22 in 100 patients. This came from the phase II FIDES-01 substudy of 103 patients with iCCA and FGFR2 fusions.
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**Erdafitinib:** ORR 52% (95% CI, 33 to 70) — about 52 in 100 patients. This came from the CCA cohort of the RAGNAR tumor-agnostic study, with 31 patients.
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**Infigratinib:** ORR 23.1% (95% CI, 15.6 to 32.2) — about 23 in 100. This came from an open-label, single-arm phase II study in patients with advanced or metastatic CCA with FGFR2 fusions or rearrangements (108 patients).
-
**Pemigatinib:** ORR 37.0% (95% CI, 27.9 to 46.9) — about 37 in 100. This came from the phase II FIGHT-202 study in patients with CCA carrying FGFR2 fusions or rearrangements (108 patients).
-
**Zoligratinib (Debio 1347):** ORR 7% (90% CI, 1 to 20) — about 7 in 100. This came from the phase II FUZE basket trial in 30 patients with biliary tract cancer and FGFR fusions.
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**Futibatinib:** ORR 42% (95% CI, 32 to 52) — about 42 in 100. This came from the phase II FOENIX-CCA2 study in 103 patients with unresectable or metastatic FGFR2 fusion-positive or rearranged iCCA.
-
**Lirafugratinib:** ORR 52% (95% CI, 31.3 to 72.2) — about 52 in 100 — in patients who had never received an FGFRi (25 patients). In patients who had received a prior FGFRi (50 patients), the ORR was 14% (95% CI, 5.8 to 26.7%) — about 14 in 100. This came from a phase I/II dose-escalation study.
-
**Tinengotinib:** ORR 26% — about 26 in 100 — in a phase II study of 39 patients with FGFR-altered advanced or metastatic CCA.

The "95% CI" is a confidence interval. It describes the range of values in which the true result probably lies. A narrow interval means the estimate is precise; a wide interval means more uncertainty.

## Which FGFR Inhibitors Are Approved Today?

The regulatory history of these drugs has been active and, in some cases, bumpy.

1.
**Pemigatinib** received accelerated approval from the US Food and Drug Administration (FDA) in 2020 and from the European Medicines Agency (EMA) in 2021, for adults with previously treated, unresectable, locally advanced or metastatic CCA with FGFR2 fusions or other rearrangements detected by an FDA-approved test.
1.
**Infigratinib** also received accelerated FDA approval in 2021, but the approval was withdrawn in 2022 at the sponsor's request. The reason cited was early termination of the confirmatory phase III trial (PROOF-301), which struggled with recruitment.
1.
**Futibatinib** was approved by the FDA in 2022 and by the EMA in 2023, pending confirmatory data. A confirmatory study (FOENIX-CCA4) is ongoing.

Two large studies were terminated early. A phase III trial assessed pemigatinib in the first-line setting versus standard of care (FIGHT-302), but it closed early because enrollment was low — the standard of care had shifted to gemcitabine-cisplatin combined with durvalumab. In a phase II study, the investigational oral ATP-competitive FGFR1-3 inhibitor Debio 1347 showed only limited antitumor activity with manageable side effects in patients with CCA and FGFR fusions. Those results did not support further clinical development.

## Finding the Right Patients: Genomic Testing and Liquid Biopsy

Between 30% and 50% of patients with CCA carry targetable genomic alterations — roughly 1 in 3 to 1 in 2. Comprehensive genomic profiling using next-generation sequencing (NGS, a technology that reads many genes at once) is increasingly used in routine practice. It gives a precise, individualized molecular diagnosis that older testing methods cannot provide. It also helps match patients to the best available targeted treatment for FGFR2 fusion-positive iCCA.

Getting enough tumor DNA is not always easy. CCAs can be small, grow along the ducts, have a dense fibrous (desmoplastic) composition, and be woven tightly into surrounding tissue. That makes standard biopsies technically difficult. DNA from fixed, paraffin-embedded tissue blocks can also be damaged by cross-linking between DNA and DNA or proteins, fragmentation, heat, fixation time, storage conditions, tissue age, ischemia time (how long the tissue went without blood supply), and the extraction method used.

Liquid biopsy helps overcome some of these problems and is relatively noninvasive, so it allows repeated sampling over time. Researchers can sequence circulating tumor DNA (ctDNA) from blood and bile samples to assess prognosis. A recent study found that lower ctDNA levels were associated with clinical benefit from targeted therapy, including longer progression-free survival (PFS — time until the cancer grows again) and overall survival (OS). Higher circulating free DNA (cfDNA) levels were linked to worse OS, which reflected larger tumor volumes and poorer liver function, leading to slower clearance of cfDNA from the body.

Beyond identifying patients with targetable FGFR2 fusions or point mutations at diagnosis, NGS of ctDNA or cfDNA may allow early detection of "secondary polyclonal mutations" — multiple new mutations that cause acquired resistance to FGFRis. That could mean detecting disease progression earlier than standard imaging scans do.

Liquid biopsy has limits, though. ctDNA may make up only a small fraction of the total cfDNA extracted, which reduces the sensitivity of NGS. Liquid biopsy is also less specific than tissue biopsy, because it may collect nucleic acids shed from multiple different tumors rather than a single lesion. So while liquid biopsy gathers information from many lesions in one test, it cannot easily assess clonality (whether all the cancer cells came from one original cell).

There is one more technical hurdle. Detecting FGFR2 fusions in ctDNA and tissue DNA is difficult because the genomic breakpoint in intron 17 of the FGFR2 gene cannot be predicted and may sit in a highly repetitive region. Even so, these fusions can be detected using highly tiled hybrid capture probes designed to target that intron.

## Why Tumors Fight Back: Resistance Mutations

Resistance to FGFRi treatment — which leads to disease progression — can arise from FGFR mutations acquired through clonal evolution (as cancer cells divide and change over time). These mutations may lower how tightly the drug binds to the kinase domain compared with ATP, so the drug can no longer block the signal effectively.

Acquired FGFR2 resistance mutations following pemigatinib and other reversible FGFRis commonly occur in the kinase domain and include:

- **V565F/I/L**
- **E566A/G**
- **K642R**
- **N550K/H/D/T**
- **K660M**
- **L618V**

Computer-based structural modeling explains why these changes cause resistance.

-
**N550 is the "gatekeeper" residue** — it controls access to the active site. Mutations here are thought to physically block infigratinib from binding. They may also block pemigatinib, which binds very close to N550.
-
**V565, K642, and E566** each participate in hydrogen bonding that holds the hinge region in an autoinhibited state — like a "molecular brake" that keeps the kinase switched off. Mutations at any of these three positions break the hydrogen bond network and switch FGFR2 on permanently.
-
**K660 mutation** activates the kinase by locking the A-loop (a flexible regulatory structure) into its active shape.
-
**L618 mutations** weaken interactions with the DFG motif of the A-loop, causing a shape change that reduces how well FGFRis bind.

A recent comprehensive multimodal analysis showed something clinically important: although all FGFRis triggered similar patterns of resistance mutations, they differed markedly in their laboratory activity against those mutations. For example, despite having similar mechanisms of action, lirafugratinib remained active against FGFR2 molecular brake resistance mutations including V565, while futibatinib did not. In contrast to other FGFRis, tinengotinib showed activity against a wide array of resistance mutations, including N550K and V565F. Preclinical results also show that tasurgratinib retained inhibitory activity against FGFR2 with N550K/H mutations. And lenvatinib, a nonselective tyrosine kinase inhibitor that blocks FGFR2 along with several other kinases, produced a response in one patient with CCA whose tumor had an FGFR2::BICC1 fusion plus an N550K resistance mutation.

## How This Review Was Conducted

The authors performed a comprehensive but non-systematic literature search to explore the use of pemigatinib or another reversible FGFRi followed by a subsequent irreversible FGFRi in patients with CCA or mixed iCCA/hepatocellular carcinoma.

They searched PubMed using the free-text terms "case report FGFR sequential," "case report FGFR resistance," "FGFR cholangiocarcinoma outcome," and "cholangiocarcinoma futibatinib." They also captured abstracts from the 2025 ASCO and ESMO meetings using the terms "FGFR tasurgratinib," "tinengotinib" (ASCO), and "cholangiocarcinoma resistance" (ESMO).

Studies were included if they were case reports or case series published in English. They were excluded if they were reviews, letters, or commentaries, or if they described treatment with only one FGFRi. The search covered articles published between January 2019 and September 2025 — a window that starts before the first FGFRi approval for CCA (pemigatinib, April 17, 2020) and ends when the search was run.

The screening process worked as follows: 178 records came from PubMed, 38 from ASCO, and 19 from ESMO. Two duplicates were removed before screening. After screening, 176 PubMed records, 38 ASCO records, and 19 ESMO records were assessed, with 169, 36, and 18 excluded respectively. Ten reports were sought for retrieval (7 PubMed, 2 ASCO, 1 ESMO), none were lost, and all 10 were assessed for eligibility. All 10 were included in the final analysis.

The search was designed to test whether sequential treatment with irreversible FGFRis — such as futibatinib or lirafugratinib — is feasible and potentially beneficial in patients with FGFR2 fusion-positive iCCA whose cancer progressed on a prior ATP-competitive reversible FGFRi.

## Key Findings: What Happened When Patients Switched Drugs

The search identified 10 publications reporting 68 cases of iCCA or mixed iCCA/hepatocellular carcinoma treated with a reversible FGFRi followed by an irreversible FGFRi. This total included 39 individual published case studies and 29 cases from a phase II clinical trial of tinengotinib.

Across all 39 individual cases, patients received pemigatinib, infigratinib, erdafitinib, Debio 1347, or derazantinib as their first reversible FGFRi. They were then treated sequentially with the irreversible FGFRi futibatinib or, in some cases, lirafugratinib or tinengotinib.

The timing results are the heart of this review:

- Among 20 cases with available data, the **median PFS on the first reversible FGFRi was 9.1 months** (range, 2.9 to 23.0 months).
- Among 23 cases where PFS was reported, the **median PFS on the second irreversible FGFRi was 7.8 months** (range, 1 to 23.6 months).
- For 13 patients who received futibatinib through a compassionate use program, the **median PFS was 10.7 months** (interquartile range, 6.8 to 14.2 months). The interquartile range describes the middle 50% of patients — half fell within this window.

In some cases, the PFS on the second irreversible FGFRi matched or even exceeded the PFS achieved with the first reversible drug. That is a striking finding, because you would normally expect a second-line drug to work for less time than the first.

The washout period — the gap between stopping the first drug and starting the second — varied widely, with a median of 7.0 months (range, 1.2 to 16 months) across the 10 cases where it was reported. Intervening treatments given during that gap included gemcitabine-cisplatin with durvalumab, reduced-dose capecitabine, and other agents.

Table 2 in the original article also documents individual mutation patterns. For example, one patient who had been on pemigatinib for 23.0 months developed an N549D mutation and later responded to futibatinib for 23.6 months, acquiring an N549K mutation. Another, treated with infigratinib for 12.6 months, developed K660M and K715R mutations, then received futibatinib for 15.8 months, acquiring a V565F mutation. These individual stories illustrate how resistance mutations change with each successive drug — a pattern the authors argue can be exploited by choosing the next drug based on which mutations have appeared.

## What This Means for Patients

The results support a hypothesis: strategically sequencing a reversible FGFRi first, followed by an irreversible FGFRi, may prolong the total duration of benefit from FGFR inhibition compared with non-sequenced treatment. In plain terms, patients may be able to stay on effective targeted therapy longer by switching drugs in the right order rather than stopping after the first drug fails.

The underlying logic rests on resistance mutations. Each FGFRi generates a somewhat different pattern of resistance mutations when it stops working. Some later-generation drugs remain active against mutations created by earlier drugs. For instance:

- Lirafugratinib remains active against molecular brake mutations such as V565, while futibatinib does not.
- Tinengotinib remains active against a broad set of resistance mutations, including N550K and V565F.
- Tasurgratinib retains activity against N550K/H mutations.

This means the mutation profile found at progression could guide which drug to use next — a concept the authors call a hypothetical treatment-sequencing algorithm for reversible and irreversible FGFRis. Patients and their oncologists may increasingly discuss molecular testing at the time of progression, not just at diagnosis.

## Limitations: What This Review Could Not Prove

This is a review of published case reports, not a randomized clinical trial. Case reports describe what happened to individual patients, and they are often published precisely because the outcome was unusual or favorable. That creates a risk of publication bias — the tendency for positive or interesting results to be published while ordinary results are not.

The total number of cases was small. Only 20 cases had PFS data available for the first drug and 23 for the second. The patient group was also heterogeneous: it mixed patients with pure iCCA and patients with mixed iCCA and hepatocellular carcinoma, and it included different first-line drugs, different intervening treatments, and widely varying washout periods ranging from 1.2 to 16 months and beyond.

The review was also deliberately nonsystematic. The authors did not perform a formal meta-analysis or statistical pooling. They analyzed case series alongside early-phase trial data — a design that can suggest a benefit but cannot confirm it.

Finally, liquid biopsy approaches to tracking resistance have real technical limits. ctDNA may represent only a small fraction of total cfDNA, reducing test sensitivity. The FGFR2 breakpoint cannot be predicted and may fall in repetitive DNA, making fusion detection harder. And liquid biopsy cannot easily determine clonality. These constraints affect how reliably clinicians can identify resistance mutations in practice.

## Practical Recommendations

Based on this review, here is what patients with FGFR2-altered cholangiocarcinoma and their care teams should consider.

1.
**Get comprehensive genomic profiling at diagnosis.** Between 30% and 50% of CCA patients have targetable alterations. NGS identifies FGFR2 fusions and other actionable changes that open the door to targeted therapy.
1.
**Ask about repeat molecular testing at progression.** Resistance mutations such as N550K/H/D/T, V565F/I/L, E566A/G, K642R, K660M, and L618V form in predictable patterns and may inform which drug to try next.
1.
**Do not assume the first drug is the only option.** In the reviewed cases, second-line irreversible FGFRis produced a median PFS of 7.8 months, and 10.7 months in a compassionate use cohort — and in some cases matched or exceeded the first drug's benefit.
1.
**Discuss clinical trials.** Confirmatory studies for futibatinib (FOENIX-CCA4) are ongoing, and novel agents like tinengotinib, lirafugratinib, and tasurgratinib are in development for FGFRi-pretreated patients.
1.
**Expect and monitor for hyperphosphatemia.** High phosphate levels are a common side effect of nonselective FGFR1-4 inhibitors. FGFR2-selective agents such as lirafugratinib were designed to avoid this issue.
1.
**Discuss liquid biopsy as a monitoring option.** Blood- and bile-based ctDNA testing is less invasive than tissue biopsy and may detect progression earlier than imaging, though it has sensitivity limitations.

The authors' overall message is measured but hopeful. FGFR inhibitor sequencing is feasible, the biology supports it, and early case data suggest it may extend treatment benefit. But definitive answers will require prospective clinical trials that randomize patients to sequenced versus non-sequenced treatment.

## Frequently Asked Questions

### What is FGFR inhibitor sequencing for bile duct cancer?

It means giving one type of FGFR inhibitor first, then switching to a different type after the first stops working. In a review of 68 cases, patients received a reversible FGFR inhibitor first, followed by an irreversible one. The goal is to extend the total time the cancer stays controlled by blocking FGFR.

### How long did the second FGFR inhibitor control the cancer?

In 23 cases with available data, the second irreversible FGFR inhibitor controlled the cancer for a median of 7.8 months, with a range of 1 to 23.6 months. In some patients, the second drug worked as long as or longer than the first. A median means half of patients had longer control and half had shorter.

### Who might be eligible for this sequential treatment?

Patients with intrahepatic cholangiocarcinoma that has an FGFR2 fusion and whose cancer has progressed on a prior reversible FGFR inhibitor. In the reviewed cases, patients had received pemigatinib, infigratinib, erdafitinib, Debio 1347, or derazantinib first, then an irreversible FGFR inhibitor such as futibatinib, lirafugratinib, or tinengotinib.

### What are the risks or side effects of FGFR inhibitors?

A common side effect of nonselective FGFR1-4 inhibitors is hyperphosphatemia, which means high phosphate levels in the blood. This happens because blocking FGFR1 disrupts phosphate balance. FGFR2-selective agents such as lirafugratinib were designed to avoid this issue. Other side effects depend on the specific drug and its targets.

### How do doctors decide which FGFR inhibitor to use next?

They may test the tumor again at progression to look for resistance mutations, such as N550K/H/D/T, V565F/I/L, E566A/G, K642R, K660M, and L618V. Different FGFR inhibitors remain active against different mutations. For example, lirafugratinib remained active against V565 mutations while futibatinib did not, and tinengotinib showed activity against N550K and V565F.

### Is there proof that switching FGFR inhibitors works better than not switching?

No. The evidence comes from a review of published case reports and early-phase trial data, not a randomized clinical trial. Case reports often describe unusual or favorable outcomes, so there is a risk of publication bias. Only 20 cases had progression-free survival data for the first drug and 23 for the second. Definitive answers need prospective trials.

### What is liquid biopsy and can it help monitor treatment?

Liquid biopsy is a blood or bile test that looks for circulating tumor DNA. It is less invasive than tissue biopsy and may detect resistance mutations earlier than imaging scans. However, it has limits: circulating tumor DNA may be a small fraction of total DNA, reducing sensitivity, and it cannot easily determine whether all cancer cells came from one original cell.

### My bile duct cancer progressed on pemigatinib — should I get a second opinion before starting futibatinib or another FGFR inhibitor?

When an FGFR2 fusion-positive intrahepatic cholangiocarcinoma progresses on a reversible FGFR inhibitor such as pemigatinib, infigratinib, erdafitinib, Debio 1347, or derazantinib, a second opinion can help clarify whether switching to an irreversible FGFR inhibitor is appropriate. In reviewed cases, a second irreversible drug controlled the cancer for a median of 7.8 months, and 10.7 months in a compassionate use cohort, with some patients matching or exceeding the first drug's benefit. Resistance mutations such as N550K/H/D/T, V565F/I/L, E566A/G, K642R, K660M, and L618V form in predictable patterns and may inform which drug to try next. Diagnostic Detectives Network provides independent expert second opinions.

## Source Information

**Original article title:** Sequencing of Fibroblast Growth Factor Receptor Inhibitors in Cholangiocarcinoma

**Authors:** Daniel Dilg, PhD; Mike Blecker, PharmD, BCPS; Ana Vivancos, PhD; Teresa Macarulla, MD, PhD; and Arndt Vogel, MD, PhD

**Publication:** JCO Precision Oncology, volume 10, article e2501099. Accepted July 22, 2026; published September 1, 2026. DOI: https://doi.org/10.1200/PO-25-01099. Published by the American Society of Clinical Oncology.

**Note:** This patient-friendly article is based on peer-reviewed research. It summarizes a review of published case reports and early-phase clinical trial data rather than a randomized controlled trial. Patients should discuss all treatment decisions, including any sequencing strategy, with their own oncology team.


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