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Precision Medicine Approaches in the Management of Cholangiocarcinoma
  • CME
  • CE

Christine Chio, PharmD, BCOP
Lipika Goyal, MD
Caroline Kuhlman, NP
Released: May 13, 2022
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Precision Medicine Approaches in the Management of Cholangiocarcinoma


In this module, Christine Chio, PharmD, BCOP; Lipika Goyal, MD; and Caroline Kuhlman, NP, share how they currently manage patients with cholangiocarcinoma, including initial diagnosis, biomarker testing to guide treatment, adverse event (AE) management, and patient counseling.

The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.

Clinical Care Options plans to measure the educational impact of this activity. Some questions will be asked twice: once at the beginning of the activity and then once again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.

Before continuing with this educational activity, please take a moment to answer the following questions.

Cholangiocarcinoma Treatment: Background

Caroline Kuhlman, NP:
Cholangiocarcinoma is a cancer that arises in the epithelium of the bile ducts of the liver. There are 2 types: intrahepatic cholangiocarcinoma, which arises in the bile ducts within the liver, or extrahepatic cholangiocarcinoma, which occurs in the part of the bile duct closest to the small intestine. Intrahepatic cholangiocarcinoma is considered a primary liver cancer, and it is a surgically curable disease when diagnosed at an early stage. However, if the tumor has metastasized to other organs such as the liver, lungs, or bones, this is considered stage IV disease. At this stage, systemic therapy is the mainstay, rather than local therapy.1

The 3 types of systemic therapies used to treat cholangiocarcinoma are chemotherapy, targeted therapies, and immunotherapies. First-line regimens generally include chemotherapy, sometimes in combination with immunotherapy. Second-line regimens can include chemotherapy, a targeted therapy, or immunotherapy depending on the molecular profile of the tumor.

In our clinic, the initial work-up for a patient with cholangiocarcinoma includes biomarker testing, because learning about the characteristics of a patient’s tumor helps guide treatment options. We do biomarker testing early because it can take several weeks, and even if targeted therapies aren’t part of the first-line therapy, they remain options for subsequent lines of treatment.

First-line Therapy

ABC-02: Gemcitabine + Cisplatin vs Gemcitabine in Advanced BTC

Lipika Goyal, MD:
In 2010, results from the phase III ABC-02 trial established the combination of gemcitabine and cisplatin as the standard first-line treatment for patients with cholangiocarcinoma and other advanced BTCs.2,3 In this study, median overall survival (OS) was 11.7 months with the combination vs 8.1 months with gemcitabine monotherapy (P <.001), and median progression-free survival (PFS) was 8.0 and 5.0 months, respectively (P <.001). Until recently, no other agents have proven superior to this chemotherapy combination for BTC.

Durvalumab and Gemcitabine + Cisplatin in Patients With Advanced BTC (TOPAZ-1): Study Design

Lipika Goyal, MD:
In early 2022, a new chemoimmunotherapy triplet became another first-line standard of care for patients with advanced BTC: gemcitabine/cisplatin plus the PD-L1 checkpoint inhibitor durvalumab.

At the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, Oh and colleagues4 presented interim analysis results from the randomized phase III TOPAZ-1 trial evaluating the combination of durvalumab 1500 mg every 3 weeks plus gemcitabine/cisplatin vs gemcitabine/cisplatin plus placebo in patients with BTC. The trial enrolled 685 patients with untreated, unresectable locally advanced, recurrent, or metastatic BTC. The primary endpoint was OS. Secondary endpoints included PFS, overall response rate (ORR), and safety.


Lipika Goyal, MD:
In this trial, patients who received the triplet regimen with durvalumab had a median OS of 12.8 months vs 11.5 months with the doublet. Of importance, at 2 years, approximately 25% of people were still alive in the triplet arm vs 10.4% of people in the doublet arm. This long-term benefit is evident in the tail on the curve. More mature data will be needed to better assess the long-term benefit of the triplet compared to the doublet.

TOPAZ-1: Tumor Response

Lipika Goyal, MD:
In this interim analysis, the addition of durvalumab to gemcitabine/cisplatin meaningfully improved the tumor response rate (26.7%) compared with placebo plus gemcitabine/cisplatin (18.7%) (P = .011). Like the OS data, the median duration of response (DoR) for patients who achieved an objective response was similar between arms at 6.4 vs 6.2 months, respectively. At 12 months and beyond, 26% of patients receiving the triplet had maintained their response compared with 15% of patients receiving gemcitabine/cisplatin alone.

TOPAZ-1: Safety Summary

Lipika Goyal, MD:
One of the questions many physicians ask is, “How much toxicity does the third agent, durvalumab, add to gemcitabine/cisplatin alone?”

Christine Chio, PharmD, BCOP:
In the TOPAZ-1 study, the addition of durvalumab did not cause any new serious AEs.4 Rates of grade 3/4 AEs were very similar between the arms, at approximately 77% in each. The most common AEs—anemia, neutropenia, and nausea—were related to the chemotherapy. The lack of added toxicity from durvalumab is very encouraging to patients.

Lipika Goyal, MD:
The incidence of immune-mediated AEs was approximately 13% in the durvalumab arm. Approximately 5% of patients in the placebo arm reported immune-mediated AEs with gemcitabine/cisplatin alone, but these likely were not actually immune mediated.

These are encouraging results in this setting, and it is hoped that the FDA will soon approve this combination as first-line therapy for cholangiocarcinoma and other BTCs.

Initial Therapy: Nursing and Pharmacist Considerations

Lipika Goyal, MD:
Patients who come in with nausea or neuropathy from their gemcitabine/cisplatin regimen will need escalated supportive care and also may need dose reductions and dose holds.

Caroline Kuhlman, NP:
Yes. Toxicity that really limits function or impacts quality of life in a way that the patient finds unacceptable means considering dose adjustments and increasing supportive care interventions.

The chemotherapy dose adjustments are fairly standard. The first step might be a hold until recovery (eg, from significant hematologic toxicity, or impaired kidney or liver function) to grade 1 or better and then a 20%-25% dose reduction moving forward. Also, there is flexibility in scheduling. Instead of 2 weeks in a row with a 1-week break, we can sometimes opt to treat the patient every other week. We want patients to continue to function and be with their families, so we need to ensure that their chemotherapy doesn’t make them so sick that they can’t get out of bed.

Patients must be reminded to call their providers if they are having trouble managing any AE or don’t know what to do about an unexpected AE. Calling early can keep them from having a serious problem or needing hospitalization.

Lipika Goyal, MD:
We always tell our patients: “Never worry alone. Call us whenever you’re worrying.”

In our clinic, for cholangiocarcinoma we typically give gemcitabine/cisplatin for 6 months and then consider whether we’re going to continue or stop. In the ABC-02 trial, this combination was given for 6 months. In TOPAZ-1, the triplet with durvalumab plus gemcitabine/cisplatin was given for 6 months, after which patients continued on durvalumab only or received no further anti-cancer therapy. In our experience, few patients are able to receive gemcitabine/cisplatin for 6 months without dose reductions or dose holds, and we set this expectation with patients in the initial discussions about chemotherapy.

2 Key Trials of Gemcitabine/Cisplatin Combination Regimens for BTC: SWOG 1815 and KEYNOTE-966

Lipika Goyal, MD:
Like TOPAZ-1, 2 additional ongoing late-phase clinical trials are seeking to improve efficacy of gemcitabine/cisplatin with a third agent.

SWOG 1815 is a phase III trial evaluating OS with the addition of nab-paclitaxel to gemcitabine/cisplatin in patients with newly diagnosed advanced BTC (enrolled N = 452) (NCT03768414). In a phase II study, this triplet combination was associated with a median OS of approximately 19 months and a response rate greater than 40% vs a historical rate of approximately 25% with gemcitabine/cisplatin alone.5,6 SWOG 1815 is the first randomized phase III trial in BTC in the United States and we look forward to learning the outcome of the trial.

KEYNOTE-966 is an ongoing randomized, double-blind phase III trial evaluating OS with the addition of the PD-1 checkpoint inhibitor pembrolizumab or placebo to gemcitabine/cisplatin in patients with previously untreated advanced BTC (estimated N = 1048) (NCT04003636). The primary endpoint is OS, with secondary endpoints including PFS, responses, and safety.

We are looking forward to the results of these trials and their potential impact on patient care in the future.

Targetable Mutations

Incidence of Select Mutations in Targetable Pathways in Cholangiocarcinoma

Lipika Goyal, MD:
As described earlier, cholangiocarcinoma is usually broken down anatomically into intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, depending on whether the cancer originated in the bile ducts that are inside the liver (the left and right hepatic ducts) or outside the liver (ie, the bifurcation of the left and right hepatic ducts, the common hepatic duct, and the common bile duct). For a long time, this is the way we thought about this cancer.

However, in recent years, the elucidation of the molecular biology of different cancers has allowed classification of patients by genomic alterations. For example, intrahepatic cholangiocarcinomas may harbor FGFR2 fusions or rearrangements, IDH1 mutations, BRAF V600E mutations, HER2 amplifications, or other actionable alterations seen on genomic sequencing. This table shows the relative incidence of select mutations seen in patients with both intrahepatic and extrahepatic cholangiocarcinoma.7 Of particular note, FGFR1-3 aberrations are seen in 11% of patients with intrahepatic cholangiocarcinoma, BRAF substitutions are seen in 5% of patients with intrahepatic cholangiocarcinoma, and ERBB2 amplifications are seen in 11% of patients with extrahepatic cholangiocarcinoma. For patients with intrahepatic cholangiocarcinoma, approximately 20% of patients have an IDH1/2 substitution.

Tissue-agnostic aberrations also have potential treatment implications, although their prevalence is relatively low. NTRK fusions are found in <1% of individuals with cholangiocarcinoma. Across BTC, the prevalence of MSI-H/dMMR tumors and TMB-H tumors is 1% to 5% and approximately 4%, respectively.

The FDA has approved, and the NCCN has recommended, numerous targeted agents for patients with cholangiocarcinoma following progression on first-line therapy.1 Patients with FGFR2 fusions can receive infigratinib or pemigatinib, both of which are approved by the FDA for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement.8,9 Ivosidenib also is approved by the FDA for patients with locally advanced or metastatic cholangiocarcinoma and a susceptible IDH1 mutation.10 For BRAF V600E mutations, the NCCN recommends the combination of trametinib and dabrafenib.1 With regard to ERBB2 (HER2) amplification, the MyPathway trial showed a 23% ORR with the combination of trastuzumab and pertuzumab in BTC. This combination also is indicated in the NCCN guidelines for patients with BTC and progressive disease. Patients with NTRK fusions can receive larotrectinib and entrectinib, both of which have tissue-agnostic FDA approvals.11,12 Those with MSI-H/dMMR tumors can receive pembrolizumab or dostarlimab,13,14 and those with TMB-H tumors can receive pembrolizumab13; these also are tissue-agnostic approvals. It is important to note that some of these targeted therapies can be considered for primary treatment of unresectable or metastatic BTC.1

Overall, approximately 40% to 50% of patients with intrahepatic cholangiocarcinoma and approximately 15% to 20% of patients with extrahepatic disease have these actionable alterations. As such, it is important to conduct biomarker testing early to identify options for patients who may need treatment in the second line. Furthermore, the NCCN recommends molecular testing for all patients with unresectable or metastatic cholangiocarcinoma.1

Several methods may be used for molecular testing. IHC, FISH, and reverse-transcriptase PCR are easily accessible and useful for testing for single-gene alterations. NGS offers the advantage of allowing us to test for multiple molecular targets and multiple types of alterations. DNA or RNA NGS is appropriate for detecting FGFR gene fusions, but DNA NGS may not detect all types of NTRK gene fusions.15,16 

FGFR2 Mutations

FIGHT-202: Pemigatinib in Previously Treated Cholangiocarcinoma With FGFR2 Fusions

Lipika Goyal, MD:
Pemigatinib is a selective, oral competitive inhibitor of FGFR1-3. FIGHT-202 was an open-label, multicohort, single-arm phase II study of pemigatinib in previously treated patients with locally advanced and/or metastatic cholangiocarcinoma and progression on or after ≥1 prior line of systemic therapy (N = 145).17,18 All patients in this trial were prescreened for FGF/FGFR2 status using DNA NGS. The primary endpoint was ORR in cohort A (FGFR2 fusions), with secondary endpoints including safety and survival in all cohorts, and ORR in cohorts B (other FGF/FGFR alterations) and C (no FGF/FGFR alterations). All patients received pemigatinib 13.5 mg once daily in 3-week cycles until progression, intolerance, or withdrawal from the study.

Pemigatinib in Previously Treated Cholangiocarcinoma (FIGHT-202): Updated Safety and Efficacy Results

Lipika Goyal, MD:
In updated results presented at the 2021 ASCO annual meeting, the ORR for cohort A was 37%, including 4 complete responses (CRs) and 36 partial responses (PRs), with a median DoR of 8.1 months.18 Median PFS was 7.0 months, and median OS was 17.5 months. Of note, median OS with a response to pemigatinib was 30.1 months (vs 13.7 months for nonresponders).

Overall, the safety profile was consistent with earlier analysis with no new safety signals. As expected, the most common treatment-emergent AE was hyperphosphatemia, which affected 58.5% of patients but was limited to grade 1/2. Other common AEs included alopecia (49.7%), diarrhea (46.9%), and fatigue (43.5%). Relatively few grade 3/4 events were reported but did include stomatitis (6.1%), arthralgia (6.1%), and fatigue (5.4%). Additional toxicities included nail changes, ocular disorders, hand–foot syndrome, and gastrointestinal toxicities.

Infigratinib for Advanced Cholangiocarcinoma With FGFR2 Fusion/Rearrangement

Lipika Goyal, MD:
In this open-label, single-arm phase II study, the FGFR2 inhibitor infigratinib was evaluated in patients with advanced cholangiocarcinoma (planned N = 160).19,20

Enrolled patients had advanced cholangiocarcinoma with FGFR gene fusions or rearrangements and progression or intolerance to gemcitabine-based chemotherapy. In this trial, FGFR fusion status was determined from tumor tissue by FISH, quantitative reverse transcriptase PCR, or DNA NGS. Patients were split into 3 cohorts based on which FGFR gene was mutated and previous exposure to selective FGFR inhibitors. All patients received 125 mg of infigratinib orally once a day for 21 days of a 28-day cycle. The primary endpoints were ORR and DoR. Secondary endpoints were PFS, disease control rate (DCR), best overall response, OS, safety, and pharmacokinetics.

Infigratinib in Advanced Cholangiocarcinoma With FGFR2 Fusion/Rearrangement: Efficacy

Lipika Goyal, MD:
At the 2021 ASCO Gastrointestinal Cancers Symposium, Javle and colleagues reported safety and efficacy results from cohort 1 (FGFR fusions and no prior exposure to selective FGFR inhibitors).20

Infigratinib monotherapy resulted in a 23.1% confirmed ORR, of which 1 patient (0.9%) had a CR, 24 patients (22.2%) had a PR, and 66 patients (61.1%) had stable disease. The DCR was 84.3%.

Infigratinib in Advanced Cholangiocarcinoma With FGFR2 Fusion/Rearrangement: Safety

Christine Chio, PharmD, BCOP:
As shown here, hyperphosphatemia, stomatitis, fatigue, alopecia, and dry eye were among the most common AEs.

Eye disorders are a toxicity of special interest for FGFR inhibitors. In this cohort, 16.7% developed central serous retinopathy or retinal pigment epithelial detachment. Changes in calcium phosphate homeostasis also were common, affecting 85.2% of patients.

Monitoring for FGFR Inhibitor AEs

Christine Chio, PharmD, BCOP:
A common AE seen with FGFR inhibitors, as mentioned, is hyperphosphatemia, which is a recognized on-target effect.21 FGFR1 inhibition disrupts a patient’s ability to excrete phosphate in their urine, leading to elevated serum phosphate. This affects approximately 70% to 90% of patients.8.9 The main concern is crystallization which can lead to soft tissue mineralization, cutaneous calcification, vascular calcification, and calciferous crystals in the retina, muscle, and skin. Most patients should follow a low-phosphate diet. Patients receiving FGFR inhibitors must have their phosphate level closely monitored during the entire treatment course. If needed, phosphate-lowering therapy can be used (eg, phosphate binders). Hyperphosphatemia also can be managed by withholding the FGFR inhibitor or via dose reductions, depending on severity.

For individuals with serum phosphate >7 mg/dL who are receiving pemigatinib, the overall management recommendation is to continue the regular dosing, initiate phosphate-lowering therapy, and monitor serum phosphate levels weekly.9 If the initial serum phosphate is >7 to ≤10 mg/dL and does not resolve to <7 mg/dL within 2 weeks of starting phosphate lowering-therapy, pemigatinib should be held. Upon resolution, pemigatinib can be restarted at the same dose level. Reduce the pemigatinib dose if hyperphosphatemia recurs. For more severe hyperphosphatemia (serum phosphate >10 mg/dL) that does not resolve to <7 mg/dL within 1 week of starting phosphate-lowering therapy, pemigatinib should be held. Upon resolution, dosing can be resumed at a lower dose. If serum phosphate >10 mg/dL recurs after 2 dose reductions, permanently discontinue pemigatinib.

For infigratinib, the management recommendation for hyperphosphatemia with a serum phosphate >5.5 to ≤7.5 mg/dL is to continue the regular dosing and initiate a phosphate binder or adjust the dose as appropriate if the patient has already been receiving a phosphate-lowering drug.8 If the serum phosphate is >7.5 mg/dL or there is a 1-time serum phosphate level >9 mg/dL, withhold the drug until resolution to ≤5.5 mg/dL. If the serum phosphate >7.5 mg/dL resolves within 7 days, infigratinib can be restarted at the same dose. However, if the duration of hyperphosphatemia is >7 days or if the patient had a 1-time serum phosphate >9 mg/dL, reduce the infigratinib dose level. For hyperphosphatemia with life-threatening consequences that indicate urgent intervention, infigratinib should be permanently discontinued.

As mentioned, another important concern with FGFR inhibitors is ocular toxicity. Dry eye is the most common disorder, but more serious retinal toxicity occurs in approximately 10% of patients.8,9,22 This can include retinal detachment and central serous retinopathy, so it is very important to instruct patients to report any vision changes right away (eg, blurred vision, visual floaters, halos, and flashes). All patients prescribed a FGFR inhibitor should have a comprehensive eye exam at baseline and periodically during therapy.

Ophthalmic toxicity can require dose interruption or discontinuation of treatment.8,9 For patients with asymptomatic retinal pigment epithelial detachment (RPED) that is stable, pemigatinib dose can be continued.9 However, if the RPED is symptomatic or worsening, the drug should be withheld. A dose reduction can be implemented if asymptomatic RPED improves, but if symptoms persist or worsen, permanent discontinuation should be considered. Patients with RPED who are receiving infigratinib may continue on their current dose if RPED resolves within 14 days.8 If resolution does not occur within 14 days, infigratinib should be withheld until resolution then resumed at the same or a lower dose.

Dermatologic toxicities are another common concern of FGFR inhibitors.23 Patients can develop nail changes starting at approximately 6 months, including discoloration, breakage, paronychia, and even separation of the nail from the nail bed, called onycholysis, which can be very painful. Patients are advised to trim their distal nails. They can apply iodine solution under the nails. If there is concern for infection, the use of antibiotics may be appropriate.

Primary palmar–plantar erythrodysesthesia, or hand–foot syndrome, is quite common with FGFR inhibitors. It is often seen later in the course after several months on FGFR inhibitors because this is a cumulative toxicity. We typically advise patients to apply thick emollient cream to their hands and feet and to avoid activities that may cause friction and pressure on their hands and feet.

Other issues associated with FGFR inhibitors include dry skin and alopecia. Of interest, although patients can lose hair on their head, they may have growth of their eyelashes.

Lastly, FGFR inhibition may cause gastrointestinal toxicities such as diarrhea, mucositis, dysgeusia, nausea, and dry mouth.

Lipika Goyal, MD:
Hyperphosphatemia is very common because, as you said, it is an on-target effect of the FGFR inhibitors blocking FGFR1. In cholangiocarcinoma, however, the goal is to inhibit FGFR2, so the hyperphosphatemia is considered an “off-tumor” effect. For many patients, hyperphosphatemia is just a laboratory abnormality, and they have no symptoms. Generally, my practice is, if a patient’s serum phosphate level is greater than approximately 7 mg/dL, I continue them on the FGFR inhibitor but start sevelamer or another phosphate binder. For more severe hyperphosphatemia with serum phosphate greater than 9 mg/dL, I will hold the FGFR inhibitor and resume at the next lower dose when serum phosphate level is less than 7 mg/dL.

What other interventions do you recommend for patients receiving FGFR inhibitors, in addition to starting the phosphate binders?

Caroline Kuhlman, NP:
We encourage patients to stick to a low-phosphate diet and provide a worksheet that includes foods to avoid while they are taking the medication. Because of the likelihood of developing hyperphosphatemia, we give our patients a prescription for a phosphate-binding agent when they start taking the FGFR inhibitor, because sometimes there are difficulties with insurance approval. We also encourage hydration to help ensure that their bowels function normally, which will aid in this process of phosphate excretion.  

FOENIX-CCA2: Phase II Study of FGFR Inhibitor Futibatinib in Intrahepatic Cholangiocarcinoma With FGFR2 Aberrations

Lipika Goyal, MD:
Other FGFR inhibitors are being investigated in cholangiocarcinoma. Futibatinib is a potent, selective FGFR1-4 inhibitor that binds covalently and irreversibly to a cysteine in the FGFR kinase domain.24 Preclinical data indicates that futibatinib can overcome resistance mutations that occur in the FGFR2 kinase that arise with ATP-competitive FGFR inhibitors (eg, erdafitinib, pemigatinib, infigratinib). A phase I dose-expansion study (in multiple solid tumors) showed a 25% ORR in patients with FGFR2-positive intrahepatic cholangiocarcinoma and responses in patients with FGFR inhibitor resistance.25,26

Subsequently, the global phase II FOENIX-CCA2 study was initiated to evaluate futibatinib in patients with intrahepatic cholangiocarcinoma and FGFR2 fusions or rearrangements, prior treatment with gemcitabine plus platinum chemotherapy, disease progression, and no prior FGFR inhibitor (N = 103).27 In this study, local testing for FGFR2 fusion/rearrangement status was performed using NGS, FISH, or tumor tissue/circulating tumor DNA testing. Patients received oral futibatinib 20 mg/day in 21-day cycles until progression, intolerance, or withdrawal from the study. The primary endpoint was ORR.

At a median follow-up of 17 months, the overall DCR was 82.5%, with an ORR of 41.7% (1 CR and 42 PRs) and stable disease in an additional 42 patients (40.7%). Of note, 72% of responders remained in response for >6 months, with 14% remaining in response for >1 year. The median PFS was 9 months, with a 12-month PFS rate of 40%. With the caveat that these are early results, the median OS at this time is 21.7 months, with a 12-month OS rate of 72%. Safety appears similar to other FGFR inhibitors, in that the most common AEs were hyperphosphatemia, alopecia, dry mouth, diarrhea, dry skin, fatigue, and hand–foot syndrome, mostly grade 1/2. That said, 57% of patients experienced grade ≥3 AEs.

A big current question in cholangiocarcinoma treatment is determining why an FGFR inhibitor or other targeted therapy stops working—why did the drug fail the patient, and what treatment do we prescribe next?

The most work on resistance in this setting has been done in patients with FGFR2 fusion–positive cholangiocarcinoma who receive ATP-competitive FGFR inhibitors.28 In our clinic, we use serial tumor biopsy and serial assessment of circulating tumor DNA. Sequencing the tumor DNA at the time of progression helps elucidate the mechanisms of resistance to FGFR inhibitors.

We have seen that many patients develop mutations in the target itself (ie, the kinase domain of the FGF receptor). Next-generation inhibitors such as futibatinib, which has FDA breakthrough therapy designation for the treatment of patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR2 gene rearrangements (including gene fusions), may be of benefit. There have been anecdotal reports that futibatinib can overcome resistance to ATP-competitive FGFR inhibitors and thereby prolong the benefit of FGFR inhibition, and I am optimistic this will be seen in clinical trials of next-generation inhibitors, as well.29


ClarIDHy: Ivosidenib vs Placebo in Previously Treated Cholangiocarcinoma With IDH1 Mutation

Lipika Goyal, MD:
Ivosidenib is approved by the FDA for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated and have a susceptible IDH1 mutation.10

The ClarIDHy study was an international, double-blind, randomized phase III trial enrolling 187 patients with previously treated cholangiocarcinoma.30,31 This study enrolled adults with a tumor harboring an IDH1 mutation (confirmed by NGS on paraffin-embedded tissue), 1-2 previous systemic therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomized 2:1 to receive the IDH1 inhibitor ivosidenib (n = 126) or placebo (n = 61). Stratification was based on the number of previous therapies. Ivosidenib was given orally at 500 mg daily in 28-day (±2 days) cycles. Patients in the placebo group were permitted to cross over at radiographic disease progression. The primary endpoint was PFS by independent review committee (IRC), and key secondary endpoints were PFS by local review, OS, ORR, safety, quality of life, and pharmacokinetics/pharmacodynamics.

Ivosidenib vs Placebo in IDH1+ Cholangiocarcinoma (ClarIDHy): PFS and OS

Lipika Goyal, MD:
Median PFS was 2.7 months for ivosidenib and 1.4 months for placebo (HR: 0.37; P <.0001), meeting the primary endpoint. The 12‑month PFS rate by IRC was 22% for ivosidenib, while patients in the placebo group had disease progression by 6 months. The final median OS was 10.3 months for ivosidenib vs 7.5 months for placebo, with a 12-month OS rate of 43% for ivosidenib vs 36% for placebo (HR: 0.79; P = .093). The difference was not significant for unadjusted HR, which did not account for patient crossover. It is important to note, however, that when the effect from patient crossover was factored in using rank-preserving structural failure time, the difference in median OS was statistically significant (HR: 0.49; P <.0001).

Ivosidenib vs Placebo in IDH1+ Cholangiocarcinoma (ClarIDHy): Safety

Christine Chio, PharmD, BCOP:
The most common treatment-emergent AEs in the total ivosidenib group were nausea (38%), diarrhea (33%), fatigue (29%), and vomiting (20%). The most common grade ≥3 toxicities were ascites (ivosidenib: 9%; placebo: 7%) and anemia (ivosidenib: 7%; placebo: 0%). Overall, ivosidenib was well tolerated by patients and was associated with a slight reduction in discontinuation due to treatment-emergent AEs vs placebo (ivosidenib: 7%; placebo: 8%). However, treatment-emergent AEs leading to dose reduction (4% vs 0%) and interruptions (30% vs 19%) were more common for ivosidenib vs placebo.

Of importance, ivosidenib may lead to QT prolongation, so monitoring with EKGs should be performed in all patients.10,31 For patients with congenital long QTc syndrome or those concurrently receiving medications known to cause QTc interval prolongation, more frequent monitoring of electrocardiogram and electrolytes may be required.

Ivosidenib is also approved by the FDA in acute myeloid leukemia, where differentiation syndrome is a known and serious AE.10 However, to date, this has not been a concern in patients with cholangiocarcinoma.

Overall, this is a very well tolerated medication.

Lipika Goyal, MD:
My clinical experience also has been that ivosidenib is well tolerated. The main caveat, as you mentioned, is the QT prolongation. We try to avoid QTc-prolonging nausea medications such ondansetron if alternatives are available and effective. In patients with biliary obstruction as a complication of cholangiocarcinoma that require fluroquinolones such as ciprofloxacin and levofloxacin, we closely monitor QT.

Overall, treatment with ivosidenib resulted in statistically significant improvement in PFS in patients with previously treated cholangiocarcinoma with IDH1 mutation. I think IDH1 is an important target in cholangiocarcinoma that highlights the importance of knowing targets across gastrointestinal malignancies to improve patient care and outcomes.


Dabrafenib + Trametinib for BRAF V600E–Mutated BTC: Tumor Size Change and Response Duration

Lipika Goyal, MD:
BRAF mutations are found in approximately 5% of patients intrahepatic cholangiocarcinoma.32 For BRAF V600E mutations, the NCCN recommends the combination of trametinib, a MEK inhibitor, and dabrafenib, a BRAF inhibitor.1 ROAR is an ongoing phase II trial of dabrafenib and trametinib in patients with various rare cancers with BRAF V600E mutations (NCT02034110).

In interim results from the cohort with BTC, the ORR (primary endpoint) was 47% by IRC (51% by investigator).33 The most common any grade AEs were pyrexia (60%), nausea (42%), vomiting (33%), fatigue (33%), and diarrhea (30%). The most common grade ≥3 AE was increased γ-glutamyltransferase in 5 patients. In total, 40% had serious AEs; 9 patients had treatment-related serious AEs, including pyrexia in 8 patients. No treatment-related deaths were reported.


MyPathway: Trastuzumab + Pertuzumab for HER2-Positive BTC

Lipika Goyal, MD:
MyPathway is a large, ongoing, nonrandomized, multibasket phase IIa study of 6 different targeted therapy regimens in patients with advanced solid tumors and potentially actionable molecular alterations (NCT02091141). The current report suggests efficacy of trastuzumab plus pertuzumab in patients with BTC and HER2 amplification, overexpression, or both (n = 39).34 In this group, the ORR was 23%.

In the 14 patients with cholangiocarcinoma, 2 patients responded (both with extrahepatic disease), and the DCR was 50%. Median PFS was 2.6 months for intrahepatic vs 6.8 months for extrahepatic disease, and median OS was 3.9 months and 8.0 months, respectively. These data are interesting, but the caveat is that these subgroups are too small to draw meaningful conclusions about the difference in benefit between patients with intrahepatic versus extrahepatic cholangiocarcinoma.

Tissue-Agnostic Biomarkers

Actionable Tissue-Agnostic Biomarkers

Lipika Goyal, MD:
Tissue-agnostic treatment is based on genomic markers regardless of histology. Genomic alterations used as tissue-agnostic biomarkers are likely to predict response to therapy and are seen across various tumor types.35 The 3 primary tissue-agnostic biomarkers identified to date are:

  • MSI-H/dMMR: this indicates defective cell repair and the inability to repair DNA errors
  • TMB-H: high tumor mutational burden (TMB) correlates with response to immunotherapy
  • NTRK: Alterations in NTRK are associated with multiple tumor types, including lung cancer, sarcoma, head and neck squamous cell carcinoma, thyroid cancer, and central nervous system cancers

We will discuss each of these in further detail.

Phase II KEYNOTE-158: Pembrolizumab in MSI-H/dMMR and TMB-H Noncolorectal Cancers

Lipika Goyal, MD:
Pembrolizumab is a PD-1 inhibitor that was approved in 2017 for adult and pediatric patients with unresectable or metastatic MSI-H/dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.13 In 2020, the pembrolizumab indication was expanded to include unresectable or metastatic TMB-H (≥10 mutations/megabase) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

These FDA approvals were based on the ongoing multicohort phase II KEYNOTE‑158 trial, which is evaluating pembrolizumab in an estimated 1595 patients with advanced solid tumors who had progressed on standard therapy (NCT02628067). Patients are given pembrolizumab 200 mg every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or consent withdrawal. The main efficacy endpoints were ORR and DoR.

As shown here, pembrolizumab significantly decreased tumor size in the majority of patients in a population with MSI-H/dMMR tumors across all tumor types in all cohorts. The ORR was 34.3%, and 77.6% had a DoR >24 months.36 The ORR in 22 patients in the cholangiocarcinoma cohort in this preliminary analysis was 40.9%. In a prospective analysis of patients evaluable for TMB, the ORR for those with TMB-H tumors (n = 102) was 29% compared with 6% for those without TMB-H tumors.37 This analysis excluded cohort K, which enrolled patients with any noncolorectal solid tumor not included in other cohorts.

More recently, updated efficacy data at a median follow-up of 37.5 months were presented for patients enrolled in KEYNOTE-158 cohort K, which included patients with MSI-H noncolorectal solid tumors. In this patient population, the ORR was 30.8%, with 70% having continued responses at 3 years.38

Phase I GARNET: Dostarlimab in Nonendometrial Tumors, Cohort F

Dostarlimab is another PD-1 inhibitor indicated for the treatment of patients with dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment with a platinum-containing regimen.14

Dostarlimab was approved by the FDA based on the results of the ongoing multicohort, open-label phase I GARNET study, which enrolled 740 participants (NCT02715284). In this trial, participants were screened for MSI-H/dMMR status based on IHC, PCR, or NGS in a local laboratory, and eligibility was determined by IHC. Patients are given 500 mg IV dostarlimab every 3 weeks for 4 cycles, then 100 mg IV dostarlimab every 6 weeks until progressive disease or discontinuation. The primary endpoints are ORR and DoR.

These are the results for cohort F, which enrolled patients (n = 173) with nonendometrial dMMR tumors or POLE-mutated cancers, including mainly gastrointestinal tumors.39 Patients eligible for this cohort had no satisfactory alternative treatments available after disease progression post systemic therapy. At a median follow-up of 16.7 months, the response rate in 106 evaluable patients in cohort F was 38.7%, with a DCR of 63%. The median DoR was not reached in this cohort. The initial approval for dostarlimab was for endometrial cancer, but results from cohort F confirm this agent’s antitumor activity across multiple tumor types. 

Activity of TRK Inhibitors in TRK Fusion–Positive Cancers

Two TRK tyrosine kinase inhibitors, entrectinib and larotrectinib, are approved for adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, have metastatic disease or are likely to have severe morbidity from surgical resection, and have progressed on treatment or have no satisfactory alternative option.11,12

Larotrectinib and entrectinib both have been shown to have activity across a range of tumor types.40,41 Although NTRK fusions occur rarely in most solid tumor types (<5% frequency; <1% in cholangiocarcinoma42), it is important to test for this alteration, as larotrectinib and entrectinib can be effective against NTRK fusion–positive malignancies and provide a viable treatment modality for patients who may have otherwise been lacking therapeutic options.

As shown here, in these pooled analyses of both entrectinib and larotrectinib in cholangiocarcinoma and other solid tumors, response rates were high (61% and 79%, respectively).40,41


Lipika Goyal, MD:
There are many new therapies for cholangiocarcinoma, and there is much more hope for this disease. We look forward to more drug development in this space and anticipate that emerging therapies will improve patient outcomes. 

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