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What’s New in Cholangiocarcinoma: Updates From the Annual American Gastrointestinal Cancer Symposium

  • Authors: Lipika Goyal, MD, MPhil; Rachna Shroff, MD, MS
  • CME / ABIM MOC Released: 2/22/2023
  • Valid for credit through: 2/22/2024, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for oncologists, gastroenterologists, pathologists, and other clinicians who treat patients with cholangiocarcinoma.

The goal of this activity is for learners to be better able to discuss the latest clinical data presented at the Annual American Gastrointestinal Cancer Symposium regarding the management of cholangiocarcinoma and to provide recommendations for integrating the data into clinical practice.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Key clinical trial data related to cholangiocarcinoma, including intrahepatic cholangiocarcinoma, reported at the Annual American Gastrointestinal Cancer Symposium
    • Utility of emerging data regarding cholangiocarcinoma, including intrahepatic cholangiocarcinoma, from the Annual American Gastrointestinal Cancer Symposium into the treatment paradigm for patients
  • Demonstrate greater confidence in their ability to
    • Stay abreast of evolving areas of interest for therapies for cholangiocarcinoma, including intrahepatic cholangiocarcinoma, from the Annual American Gastrointestinal Cancer Symposium


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  • Lipika Goyal, MD, MPhil

    Assistant Professor of Medicine
    Director of GI Oncology
    Stanford Cancer Center
    Palo Alto, California


    Lipika Goyal, MD, MPhil, has the following relevant financial relationships:
    Consultant or advisor for: Alentis Therapeutics AG; AstraZeneca Pharmaceuticals LP; Black Diamond Therapeutics; Exelixis, Inc.; Genentech; H3 Biomedicine; Incyte Corporation; Kinnate; Merck; QED Therapeutics; Servier; Sirtex Medical Ltd.; Surface Oncology; Taiho Pharmaceutical Co., Ltd.; TransThera Bio; Tyra Biosciences

  • Rachna Shroff, MD, MS

    Associate Professor of Medicine
    University of Arizona Cancer Center (UACC)
    Interim Chief, Division of Hematology/Oncology
    Associate Director, Clinical Investigations, UACC
    Associate Dean, Clinical and Translational Research, UA-COM
    Tucson, Arizona


    Rachna Shroff, MD, MS, has the following relevant financial relationships:
    Consultant or advisor for: AstraZeneca Pharmaceuticals LP; Helsinn Therapeutics, Inc; Incyte Corporation; Merck; Servier
    Research funding from: Faeth Therapeutics; Merck; NGM Biopharmaceuticals; Novocure; Rafael Pharmaceuticals (now Cornerstone Pharmaceuticals, Inc.)


  • Stephanie Baumhover, PharmD, BCPS

    Medical Education Director, Medscape, LLC


    Stephanie Baumhover, PharmD, BCPS, has no relevant financial relationships.

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  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

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What’s New in Cholangiocarcinoma: Updates From the Annual American Gastrointestinal Cancer Symposium

Authors: Lipika Goyal, MD, MPhil; Rachna Shroff, MD, MSFaculty and Disclosures

CME / ABIM MOC Released: 2/22/2023

Valid for credit through: 2/22/2024, 11:59 PM EST


Activity Transcript

Lipika Goyal, MD, MPhil: Welcome everyone to this program titled "What's New in Cholangiocarcinoma: Updates from the Annual American Gastrointestinal Cancer Symposium​." My name is Lipika Goyal and I am the director of gastrointestinal oncology at the Stanford School of Medicine. It's my pleasure to do this symposium with Dr Rachna Shroff, who is the interim chief of the Division of Hematology and Oncology at the University of Arizona Cancer Center.

We're going to start by talking about the overview of cholangiocarcinoma (CCA), which Dr Shroff is going to offer, and then we're going to talk about all the newest, latest updates from the Gastrointestinal (GI) American Society of Clinical Oncology (ASCO®) Symposium on chemotherapy and immunotherapy regimens in biliary tract cancers (BTCs). After that, I'll be sharing the different updates on targeted therapy in CCA.

Rachna Shroff, MD, MS: Thank you so much, Dr Goyal. It is my pleasure to be here today and to start us off with a little bit of an overview of CCA, a little bit of background and an understanding of the epidemiology and incidence. And when we look at the global incidence of CCA, here in the United States, it's thought of as a rare malignancy, with an incidence of less than 6 per 100,000. But I do think it's important to note that we are seeing an increase in incidence, especially in intrahepatic CCA (iCCA).

The prognosis of this disease remains quite dismal, with a 5-year overall survival (OS) rate of less than 20%. And a lot of that is attributed to the fact that patients are diagnosed at more advanced stages, and even when they have an option for surgical and curative resection, there are high relapse rates.

As I mentioned, CCA is a lump-all phrase that really should be delineated and has historically been delineated anatomically. When we think about the various classifications, it's really based on the order of the bile ducts from which the cancer originates. When we look here graphically at the liver, the intrahepatic bile ducts are really kind of the tree-branching pattern that forms throughout the liver. That is the site of origin for iCCA. When we move to the hilum of the liver, that's where we see the perihilar CCAs, typically from the level of the intrahepatic left and right hepatic ducts, as well as the common hepatic duct. And then, the extrahepatic CCAs are those that originate from the common bile duct that are outside of the liver.

Intrahepatic tumors often are large and mass-forming vs ones that are more perihilar and extrahepatic that look more infiltrating on imaging. And as I mentioned, the rates of iCCA are increasing but the rates of extrahepatic CCA (eCCA) appear to be decreasing, and it was historically the most common tumor when we break down CCA, with 50% to 60% of patients having perihilar vs 20% to 30% with distal or extrahepatic common bile duct CCAs. And only 10% to 20% that arise in the intrahepatic ducts or iCCAs.

As I mentioned, when we think through CCA anatomically iCCAs often being in the smaller ducts as a result tend to be more in the periphery of the liver or more in the center, and typically are mass-forming vs the larger duct types that are more distal and central periductal and infiltrating on radiography.

The risk factors for CCA are somewhat overlapping when we look at intrahepatic and extrahepatic, with issues related to chronic inflammatory processes being the primary risk. But most importantly, when you see the rising global incidence of iCCA, we really think it is linked to lifestyle factors like increasing incidence of type 2 diabetes, cirrhosis, alcoholic liver disease, and cholelithiasis.

In western countries, the annual incidence of CCA in patients that have primary sclerosing cholangitis, a known risk factor, is 0.5% to 1.5%, with a lifetime incidence of 20%. But the truth is, as I tell my patients, the majority of cases, greater than 60%, have no known risk factors. When we look in the eastern part of the world, cirrhosis and hepatitis B infections are really among the primary risk factors, as well as parasitic infections with liver flukes.

We also know as we have started to better understand the molecular complexities of CCA, that there are not only anatomical differences between iCCA, hilar, and eCCAs, but there are also differences in terms of the biomarkers that are noted and associated with these diseases. For instance, in iCCA, we see IDH1 and IDH2 mutations. We see FGFR2 fusions and translocations, BRAF mutations, and then things like BAP1 and ARID1A that are still not a hundred percent targetable but that are emerging as potential targets. This is in stark contrast to our extrahepatic and hilar CCAs, where we see a higher incidence of KRAS mutations, for instance, and HER2 alterations.

Anatomically, BTCs includes the hilar, distal, eCCAs and iCCAs. But historically, ampullary cancer has been included, as well as gallbladder cancer (GBC). The risk factors are also varying across these different diseases, and patients present in different ways. For instance, patients who have eCCA often present with obstructive jaundice just like ampullary cancer, but those with iCCA typically have more vague symptoms like abdominal pain or discomfort, nausea, weight loss, or it can be an incidental finding, and that can often be the case as well in GBC where patients undergo a cholecystectomy and then are incidentally found to have a gallbladder adenocarcinoma.

We also know that how patients do really is based on the stage in which they present. Patients that are potential surgical candidates have a higher chance at not only curative therapy but overall improvements in survival. When we look at some of the data from Surveillance, Epidemiology, and End Results (SEER) that look at stage by stage overall survival (OS), you will see that there is unfortunately a notable stepwise decline and with advancing stages, with stage IV median OS being quite dismal.

Now, as I mentioned, it is really important to understand the molecular landscape of CCA because we now have FDA-approved therapies in a number of clinical trials that are based on potentially actionable genetic alterations that can be identified. When we talk about iCCA and we put together all of the potential alterations, up to 60%, sometimes upwards of 80%, can have actionable genetic alterations. So, it is really important that patients have comprehensive biomarker testing at the time of diagnosis so that we know what tools we have in our toolbox for these patients.

Some of the more common actionable genetic alterations with IDH1 being probably the most common one identified in iCCA, anywhere from 10% to 20%. FGFR fusions and translocations are also very important to identify, given the FDA-approved therapies in this space, and this is rarer, this is on the order of 7% to 10% to 15%. There is also a smattering of BRAFV600E mutations, anywhere from 3% to 5%. Again, very important to identify because of the tumor agnostic approvals that are available for BRAFV600E patients.

When we talk about the overview of guidelines and treatments for CCA, there has been general consensus across European Society for Medical Oncology (ESMO), ASCO®, and the National Comprehensive Cancer Network (NCCN) that the first question really is: is the disease resectable? And if it is resectable, proceeding to surgery with curative intent is absolutely the standard of care (SOC). There are some really interesting trials that are looking at neoadjuvant and perioperative approaches for CCA, but at this time, it is surgery first, followed by 6 months of adjuvant chemotherapy with capecitabine really being, based on the BILCAP study data, the standard approach. Here, the median OS was 51.1 months, but the relapse rate remains high at 60%.

Now, if the patient is not resectable, then we're looking at palliative approaches. Really, performance status, where the disease is, extent of disease, and molecular profiling all play a role in helping us decide how to approach these patients.

That being said, median OS in advanced disease still remains right around 1 year, even with some of the newest data that's come out based on TOPAZ with gemcitabine + cisplatin (GC) and durvalumab. Systemic chemotherapy still is the backbone with GC and durvalumab being our SOC. Patients who are not available to receive immunotherapy are still receiving GC, and in the second line setting, 5-FU regimens such as leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX) really set the bar.

If we are able to identify potentially actionable mutations, targeted therapies absolutely have a role in these patients and should be integrated into their treatment approach. Then, of course, we have a number of things ongoing and in development, especially in clinical trial form, with a lot of excitement surrounding immunotherapy and chimeric antigen receptor (CAR) T-cell therapy, and novel combination approaches.

I think it is really important to recognize that it is a new era in the treatment of BTCs and CCA in particular. Immunotherapy now has a firm place in this disease treatment, and we are very excited to see how we can continue to build on the backbone of GC and durvalumab, and/or other immunotherapy approaches.

At GI ASCO this year, targeted therapy absolutely had its limelight, but there were some very interesting and exciting oral abstract presentations that looked at the frontline space, GC and durvalumab being the current king, but for 10 plus years, we've had GC as our backbone. And so, 2 oral abstracts were presented that questioned whether or not GC should remain the SOC or if there are other things that we can build on.

The first study that was presented was SWOG 1815. This was actually a large National Cancer Institute (NCI)-sponsored study that opened across the National Clinical Trials Network (NCTN), which I had the privilege of serving as the national study chair. This was the first randomized phase 3 trial in advanced BTCs in the United States. It was a trial that, in my opinion, proved that we can do large randomized studies in biliary cancers, a "rare tumor" in the United States, and that we can answer these questions in a meaningful way. It was truly a cooperative group effort. It was open across the entire NCTN and accrued 441 patients in rapid time, in 2 years.

The results of the randomized trial of GC/nab-paclitaxel (GAP) compared to GC were presented at GI ASCO. And the study was based on a single-arm phase 22 trial that had previously been done with GAP at MD Anderson Cancer Center in Mayo, Arizona. In that 60-patient study that "safe dosing" of the triplet regimen was identified, and there were signs of promising efficacy with a median OS of 19.2 months. That's what led to the study design for SWOG 1815 as the pivotal comparison against the SOC at the time of GC.

This study had 441 patients who were randomized in a 2:1 fashion to the investigational arm of GAP vs GC. Patients were re-staged every 3 cycles and were continued on therapy until progression or intolerance. And the primary endpoint was median OS with a target hazard ratio of 0.7. This study had enrolled newly diagnosed BTC, so it had CCA and GBC patients, and there were prespecified stratification factors of performance status, disease site, and disease stage.

The primary endpoint of median OS was not met in terms of the fact that the patients had a numerically improved OS of 14 months compared to 12.7 months in the GC arm. But this did not meet statistical significance. Similarly, median progression-free survival (PFS) was numerically improved but not statistically significantly improved. The overall response rate (ORR) of GAP was 31% vs 22% in GC, which again was not statistically significant. And the grade 3 to 5 hematologic toxicities were more noted in the triplet chemotherapy arm, primarily anemia, neutropenia, and thrombocytopenia, compared to GC, though the treatment discontinuation rate between the 2 arms did not differ.

Now, when we looked at the efficacy endpoints looking at the pre-specified stratification factors, there were some interesting signals that emerged such as possible benefit in GBC patients who had better median OS and an ORR of 44% compared to 22%, as well as in locally advanced patients vs metastatic patients in which we saw similar improvements in median OS, PFS, and ORR. I think it's important to point out, however, that these were small numbers and the study was not powered or designed to detect meaningful differences here.

The authors concluded that the GAP treatment did not statistically improve median OS compared to GC, and as such does not change the frontline SOC. There are some interesting exploratory analyses that are ongoing looking at biomarkers and I think that may identify potential other subsets of patients who could benefit from the triplet regimen.

The other oral abstract presentation that was of great interest was the IMbrave151. This was the results presented by Dr [Anthony] El-Khoueiry and colleagues of a phase 2 randomized, double-blind, placebo-controlled study of bevacizumab (bev) in combination with atezolizumab (atezo), and GC, in newly diagnosed advanced BTC patients. The concept here was really based on the fact that VEGF blockade, in addition to anti PD-L1, could lead to a synergistic immune-permissive tumor microenvironment in BTCs.

The study design involved 162 patients with newly diagnosed CCA or GBC who were randomized in a 1:1 fashion to receive GC with atezo, vs GC, atezo, and bev. Patients were re-staged every 3 cycles and continued on until progression with a primary endpoint of PFS. Exploratory endpoints included 6-month PFS and OS rates, as well as key secondary endpoints

When we looked at the patients who were enrolled, the patients were primarily of iCCAs with 57% on the GC/bev/atezo arm being iCCAs.

And when looking at the primary endpoint of PFS, the median PFS of the GC + atezo arm was 7.9 months, and the GC/bev/atezo arm was 8.3 months with a stratified hazard ratio of 0.76. The 6-month PFS rates were 63.1% in the atezo alone, and 78.2% in the GC/bev/atezo arm. Subgroup analyses were done looking at PFS and there was not really clear favoring of GC/bev/atezo with any of the prespecified factors.

The secondary endpoint of ORR was 19% in the GC/bev/atezo arm, and 21% in the GC/atezo alone arm. The OS data was not yet mature for the GC/bev/atezo arm and was 11.4 months for GC with atezolizumab alone. Safety signals were, as one would expect it, with immunotherapy-based approaches with GC/atezo, and there were really no safety signals that came out that were concerning.

The authors concluded that their addition of bev to atezo and GC only modestly improved PFS with a median PFS that was really quite similar in the 2 arms. Objective response rates were also similar, but longer follow-up is really needed for us to better understand the OS data.

Overall, it was a really exciting ASCO GI for CCA with 2 very eagerly anticipated oral abstracts that were presented. While neither of them really changed the SOC, they absolutely answered important questions, and I do think some additional exploratory analyses in both studies will be very informative in terms of how and if we should be integrating these treatment approaches into the journeys for our CCA patients.

Now, it gives me great pleasure to hand it back to Dr Goyal, who will be summarizing targeted therapy approaches in CCA, which is where a lot of drug development and research is focused on and in which a lot of data came out at ASCO GI.

Dr Goyal: Thank you very much Dr Shroff for that excellent overview of CCA and these exciting abstracts that were presented. Now I'm going to be talking about targeted therapy overall in CCA, and then I'll switch to some of the exciting abstracts from the conference.

I'll be starting off with an overview of targeted therapy in BTCs, and then I will discuss 5 abstracts. The first 3 abstracts will be FGFR inhibitors and the interim results of some different interventional trials in FGFR-altered CCA. The next 2 abstracts will be on IDH1-mutant BTC, and another one will be a trial in progress of an FGFR inhibitor.

Let's start with an overview of precision medicine and BTCs. For a long time, we thought about BTCs only by their anatomic subtypes, so intrahepatic carcinoma, extrahepatic CCA, GBC, and primary cancer. Over the last 10 years, with the advent of next-generation sequencing (NGS), we've realized that this disease is a molecularly heterogeneous disease and there are actually multiple molecular subgroups within these anatomic subtypes.

You see FGFR alterations, IDH1 alterations, and a smattering of other ones, and actually among the different anatomic subtypes, the frequencies of these are different. You can see in iCCA IDH1 mutations and FGFR2 alterations in about 15% to 20% of patients each.

Among all the gastrointestinal (GI) cancers, there are more patients with actual alterations with iCCA than any other GI cancer. We also see BRAFV600E mutations, HER2 amplification, NTRK fusions, RET fusions in a small percentage of patients with iCCA.

The most common alterations that we see that are actionable in eCCA and GBC are HER2 amplification or overexpression, which are seen in about 10% to 20% of these patients. But again, we occasionally see rare targets, such as BRAF mutations, and some of the other fusions. The most important takeaway from this is it's very important to profile tumors in patients who have BTC is because it opens up therapeutic avenues.

While there are a lot of targets in BTC, there are a lot of challenges to deliver in precision medicine in this series of diseases. The first is tissue access. As we know, CCAs are often necrotic and they're often fibrotic, and there's up to a 25% failure rate of doing tissue profiling. In these patients, in terms of solutions, it's important to get core biopsies instead of fine-needle aspirates, so that we have enough DNA quantity and quality to do the profiling.

Second, certainly in tumor DNA, or the DNA that's shed into the blood, these liquid biopsies have also become a promising avenue for profiling these tumors. The third is that this is a rare set of diseases and study recruitment is difficult. Enrolling to these trials is not as easy, but there are a lot of different organizations that are increasing public awareness of these diseases. As long as we can increase awareness among doctors as well, we have a chance to recruit more patients to these trials and get more drugs FDA approved.

Where does targeted therapy fit into this algorithm? People usually get chemotherapy with GC plus or minus durvalumab. And then after that is usually when we use targeted therapies. There's a whole bunch of different inhibitors that we're using for patients with iCCA predominantly, but also for patients with eCCA and GBC.

Now moving on to the exciting abstracts from the GI ASCO Symposium. I'll start with 3 abstracts of interventional trials for FGFR-altered CCA with 3 different FGFR inhibitors.

The first one is for a drug called tinengotinib. This is a phase 2 study of this drug, which is a novel spectrum selective multikinase inhibitor. It has specifically designed to inhibit both primary alterations in FGFR and also some of the resistance mutations that occur. In this multi-center, open-label, phase 2 study, patients were given tinengotinib after they had at least 1 line of therapy for advanced or metastatic FGFR-altered CCA.

Patients who were eligible had advanced or metastatic CCA with an FGFR alteration at 1 prior line. Cohort A1 and A2 were patients who had FGFR2 fusions with CCA who had prior treatment with FGFR inhibitor. Cohort B patients had other FGFR alterations that were not fusions. And cohort C patients had tumors that were FGFR-wild type.

They were all given oral tinengotinib, 10 mg once a day for 28-day cycles. There was certainly activity with this agent in patients who had a prior FGFR inhibitor and had kinase mutations.

How well was this drug tolerated? Fifty-three percent of patients had hypertension. Some of the other side effects are what we see with these tyrosine kinase inhibitors, diarrhea was seen in 31% of patients, stomatitis in 28% of patients, on this palmar-plantar erythrodysesthesia, or hand foot syndrome, in 22% of patients. Overall, one of the notable things is we did not see a lot of ophthalmologic toxicity, which is something that we commonly see with the FGFR inhibitors, nor did we see the hyperphosphatemia.

Tinengotinib resulted in some promising clinical benefit in patients with CCA in a setting of FGFR inhibitor resistance. An ongoing phase 2 study will provide further safety and efficacy data and biomarker evaluations per patients with FGFR-resistant CCA.

The next abstract is for a drug called gunagratinib. This is a highly selective, irreversible, FGFR inhibitor and this was studied in patients with locally advanced or metastatic CCA, harboring an FGFR pathway alteration. And this was a phase 2 dose expansion study. This drug selectively inhibits FGFR 1 through 4 irreversibly by covalent binding. In this study, patients had FGFR2 fusions or rearrangements and they had disease progression after at least one prior line of therapy or were intolerant to prior therapy and they were given this drug orally, 20 mg once a day, until a disease progression or intolerance.

Overall, this study looked at 18 patients and 17 of the 18 patients had evaluable disease. What was the efficacy data for gunagratinib in patients with FGFR2 fusion- or rearrangement-positive CCA? They reported data on 17 patients who had at least 1 tumor assessment. The ORR was 53%. The disease control rate was 94% and the median PFS was 6.3 months.

How well was the drug tolerated? Thirty-five percent of patients had a grade 3 or higher treatment emergent adverse event (AE). The most common AE was hyperphosphatemia. This was seen in 82% of patients. This is a class-specific AE that we see due to the inhibition of FGFR1.

The other side effects or AEs that we saw with this was hepatotoxicity. 35% of patients had an aspartate aminotransferase (AST) elevation. Twenty-three percent of patients had an alanine aminotransferase (ALT) elevation, and 29% of patients had an elevation in the bilirubin. We also saw diarrhea in 23% of patients, and hair loss in 35% of patients. Overall, the study demonstrated preliminary efficacy of this drug and we look forward to the mature data to see both the efficacy and safety profile of this drug.

The third abstract of an FGFR inhibitor is for erdafitinib, which we know is approved by the FDA for the treatment of urothelial cancer, who patients with FGFR2 or 3 alterations. This was a phase 2 open-label, single-arm study in patients with CCA who had FGFR alterations. And in this poster, the interim results of this ongoing study were reported. The key eligibility here were patients had prespecified FGFR1 through 4 alterations, including mutations or fusions, and they had to have received at least 1 line of prior therapy.

In this study, they looked at 35 patients with FGFR alterations. The vast majority of them had FGFR2 fusions. The response rate was 60% overall with a duration of response of 5.55 months. In terms of how well tolerated was this drug, 71% of patients had a grade 3 or greater treatment-related AE, and the rate of serious treatment-related AEs was 26%. The most common AE was hyperphosphatemia, 83%. Again, a class-specific AE that's expected with this drug. Diarrhea was seen in 80% of patients, stomatitis in 74% of patients, and dry mouth in 54% of patients. Overall, encouraging efficacy activity.

Finally, I'll discuss 2 abstracts that were of interest at the GI ASCO Symposium related to BTCs. The first one is on IDH1-mutant BTC, and the second is an FGFR2- and 3-altered CCA. So, first, the IDH1, this was a real-world study looking at over 1000 patients with BTC that underwent somatic genomic sequencing.

They found that 143 patients (12.7%) had an IDH1 mutation. The most common co-occurring alterations were in ARID1A, seen in 22% of patients, PBR1, seen in 21% of patients, and BAP1, seen in 13.3% of patients. These patients did not have a high tumor mutational burden. The median was 2.6 mutations per megabase. The main thing this study was looking at is: how do these patients do on chemotherapy and on IDH1 inhibitors? The median line of therapy in these patients was 2, and the median OS was 23.8 months.

Overall, this retrospective study showed that patients with IDH1-mutant BTC exhibit a similar PFS to first-line cytotoxic chemotherapy compared to historical unselected populations and they had favorable outcomes to second-line IDH1 inhibition.

The last abstract is this trials in progress poster on the drug KIN3248. This is a next-generation selective, irreversible, small molecule pan-FGFR inhibitor, strict redesigned to inhibit primary FGFR oncogenic alterations as well as secondary kinase domain mutations associated with disease progression. Preclinically, indeed, this drug does show activity both against primary drivers in FGFR2 and 3, and also, the secondary FGFR2 resistance mutations.

In this study, there's going to be a part A and a part B. It's currently enrolling globally. In part A, it's going to include patients who have FGFR inhibitor-naive or pretreated CCA, taking all comers. And then, in part B, 3 cohorts, the first with patients with CCA with FGFR2 alterations, the second, urothelial cancer with FGFR2 or 3 alterations, the third cohort, patients with other solid tumors that have FGFR2 or 3 alterations.

In conclusion, molecular profiling is now the SOC in patients with CCA, with multiple targeted therapies currently approved by the FDA and/or recommended by the NCCN. We are encouraged that, at this Congress, there are data on multiple FGFR inhibitors that are in development, both in the FGFR inhibitor-naive space and the FGFR inhibitor-pretreated space. We're seeing activity in both, and we look forward to the mature data from these trials.

We're also encouraged to see real-world data showing favorable outcomes with using IDH inhibitors in the second line in patients with IDH1-mutant BTCs; overall additional biomarkers and drugs are needed so that we can match patients with optimal targeted therapies.

Thank you very much everyone for joining this program. It was really exciting to see the data that Dr Shroff presented on the SWOG 1815 study that showed that, overall, that while GAP did not show an OS benefit over GC in patients with advanced BTC, there was a signal in patients with GBC and those who had locally advanced disease, and this can be further explored in upcoming studies.

Also, we appreciated her analysis of the IMbrave 151 study of GC, bev, and atezo, compared to the triplet combination of GC and bev. The data suggested that combining atezo with bev and chemotherapy may provide clinical benefit in a subset of patients and further ongoing follow-up is warranted.

Overall, we are excited that there's a lot of development in targeted therapies in CCA, the FGFR inhibitor space, the IDH1 inhibitor space. It's really important that we encourage all of our patients to have molecular profiling and open up avenues for therapies for them, because we're certainly seeing benefit from these drugs. Thank you very much for joining this program.

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