Cholangiocarcinoma Awareness Day: Bahary Reviews the Changing Landscape

Nathan Bahary, MD

February 12 is World Cholangiocarcinoma Day, and the biliary tract cancer setting is changing rapidly with a number of promising clinical trials for new treatments and the growing adoption of targeted therapies.

Recent developments in the cholangiocarcinoma space offer opportunities to better tailor effective treatments to patients based on disease subgroups and manage disease to improve the outcomes of surgery and radiotherapy.

“We've really come a long way, in terms of standard chemotherapies, combination chemotherapy, understanding the sequencing of the chemotherapy, and especially with the advent of targeted therapies” Nathan Bahary, MD, PhD, said in an interview with Targeted Oncology^TM.

Bahary, the academic chief of medical oncology and director of cancer research at the Allegheny Health Network Cancer Institute, discussed how the cholangiocarcinoma treatment paradigm has changed and what is on the horizon for treatment and care of patients.

Targeted Oncology^TM: How has the field for cholangiocarcinoma therapy changed in the past 10 to 15 years?

Bahary: About 15 years ago, we first appreciated that chemotherapy had a role in improving survival and quality of life. Prior to that, I think it was a very fatalistic kind of treatment plan for most people. About 10 years ago, cisplatin and gemcitabine in the ABC-02 trial [NCT00262769] improved overall survival [OS].¹

But I think the more interesting thing is in the last 5 years or so when [we gained] insights that cholangiocarcinoma has a very large percentage of patients who could benefit from targeted treatments, and this includes FGFR-translocations, signaling mutations in the IDH gene, BRAF mutations, as well as alterations in ROS1, ALK, and HER2-neu or ERBB2. I've had some wonderful success with patients with immunotherapies, as have others [who have] published on this for patients who have particular subtypes of cholangiocarcinomas, high PD-L1–expressing cancers, high tumor mutational burden [TMB]–expressing cancers, and microsatellite instability [MSI] high cancers.

There's been an entire revolution in trying to do hepatic-directed therapies as well, including hepatic arterial infusion [HAI] pumps, which we've been involved in for a number of years, but also chemo-embolization and radioactive beads, the Yttrium-90 type of treatments that are hepatic-directed. What we've seen is [going from] a more fatalistic kind of treatment paradigm to one with chemotherapy, local, and targeted agents.

What recent or ongoing trials have been the most practice changing in this setting?

Ten years ago, the gemcitabine/cisplatin ABC-02 trial set a new standard for treatment and pushed investigators to keep moving forward. More recently, we've seen similar activity with the combination of nab-paclitaxel with gemcitabine; there are data that showed that this combination had a very similar OS and response rate versus gemcitabine/cisplatin.² Now there's a very large combination trial of gemcitabine, cisplatin, and paclitaxel being headed by Dr Rachna Shroff, SWOG 1815 [NCT03768414]. Their preliminary data look exciting; we're hoping that chemotherapy-wise that this will help set a new standard for all patients, not just targeted subsets of [the patient population].

What’s also interesting is more recent data suggesting that we can sequence therapies. Second-line treatment with fluorouracil [5FU] and oxaliplatin [FOLFOX] has been shown to have some survival benefit in the ABC-06 trial [NCT01926236].³ More recently, the phase 2 NIFTY trial [NCT03524508] showed that liposomal irinotecan and 5FU significantly improved progression-free survival [PFS], and we're waiting on some more mature OS data.⁴ But it's not just the numbers—it's the fact that there are alternative therapies and we can keep moving [forward] for patients.

We've also identified therapies into the adjuvant setting. The BILCAP trial [ECT2005-003318-13] relatively recently showed that capecitabine can improve OS in the adjuvant setting.⁵ The SWOG 0809 study [NCT00789958] from a few years ago suggested a role for chemoradiation for node-positive disease.⁶

After that, there are a number of trials of targeted therapies that have led to pemigatinib [Pemazyre] and infigratinib [Truseltiq] being approved for patients with FGFR2 alterations;^7,8 more recently, data for ivositinib [Tibsovo] for IDH mutations and [larotrectinib (Vitrakvi)] for those with TRK fusion–positive cancers;^9,10 and ERK and MEK combinations for BRAF-mutated and HER2-targeted therapy for patients as well. We’ve been able to take advantage of all of these in our practice here at Allegheny Health Network, for the benefit of all of our patients.

What newer treatments have become standard-of-care for your practice?

[I use] the standard chemotherapy combinations that we talked about, and if a patient is young and healthy, and not eligible for the SWOG 1815 trial, we've used the triplet of gemcitabine, paclitaxel, and cisplatin. All patients deserve next-generation sequencing [NGS] as well as an immuno-oncology profile up front. What I mean by that is to look at the TMB from the NGS as well as determining if their tumors have a high PD-L1 score. In those patients, I would go right to using combinations with immunotherapies.

There are new trials looking at directed therapies. About 40% of cholangiocarcinomas have a targeted therapy.¹¹ Pemigatinib and infigratinib are first to be approved for FGFR-altered tumors and they've been approved in the second-line setting.^7,8 [Patients can receive] first-line chemotherapy and a second-line targeted agent.

The lung cancer space, as well as lymphomas and leukemias, has demonstrated for us that a targeted therapy up front often has a survival advantage. There are some very interesting first-line trials with [targeted therapies in cholangiocarcinoma]. For patients with FGFR2 fusions or rearrangements, there’s the FIGHT-302 trial [NCT03656536], which is looking at pemigatinib versus cisplatin and gemcitabine in patients with unresectable or metastatic cholangiocarcinoma. Infigratinib has the PROOF 302 studies [NCT04197986] also looking at first-line treatment versus gemcitabine and cisplatin. There are also the FOENIX-CCA3 trials [NCT04093362] of futibatinib [TAS-120] versus gemcitabine and cisplatin as first-line treatment.

I think it's really exciting. The targeted therapies, which were unknown just a few years ago or underappreciated—even if we knew about them through theoretical reasons—are now being tested in the first-line setting. I'm very excited for that because they're much better tolerated. Additionally, people can have wonderful responses to them and have an excellent quality of life when they respond to it.

What other biomarkers and targets for treatment are showing promise in trials in this space?

Along with the FGFR-directed therapies, we've participated in a second-line sorafenib [Nexavar] trial. There are other similar studies with regorafinib [Stivarga] as well. These are multi-tyrosine kinase inhibitors [TKIs] that show some stability of disease. They have very interesting PFS outcomes, and those should be tested going forward to offer patients some sort of help in the third-line or so settings.

But I think we are trying to figure out where immunotherapies will play a role in biliary tumors. We absolutely know that the subsets of patients with high PD-L1 and have a high TMB seem to respond very well to immunotherapies. I personally have had patients who are very excited when we find this out up front. I have given them single- or double-agent immune-directed therapies and they've had near complete responses. And these have been maintained for years, which is just incredible.

But the question is, can you use immunotherapies, either in combination or with chemotherapy, for patients with other intrahepatic cholangiocarcinomas. There is a phase 2 trial [NCT02834013] going on of nivolumab [Opdivo] and ipilimumab [Yervoy]. The TOPAZ-1 study [NCT03875235] of gemcitabine and cisplatin, plus or minus durvalumab [Imfinzi], which is an inhibitor of the PD-1/PD-L1 axis, showed promise with a 2-month OS benefit.¹² We are just awaiting the final results of that trial. When they come out, we can look at the subgroup analysis and so on, but it’s a very exciting time of trying to combine these immunotherapies which have a much more favorable toxicity profile, and more importantly, they have that nice tail on the [Kaplan-Meier] curve where if you take a look at patients who do respond, they often have a response that continues for a long duration of time. The ultimate goal is to see patients have excellent responses for a prolonged duration of time.

There have been combination trials also with liver-directed therapy. We've participated in these, and I know a number of surgical oncologist groups that are very much involved and very excited about these trials with HAI and trans-arterial chemoembolization.

More and more, I've had patients that are referred here for liver transplant. That is a subset of patients who don't have extra-hepatic disease, whose disease has been controlled for a period of time with chemotherapies, with directed therapies, or targeted therapies as well, and have gone on to an extensive evaluation with only hepatic limited disease. A number of those patients have undergone transplant, and they've done extremely well in the long term. It opens up a whole new horizon of trying to help patients who have hepatic-limited disease.

What should community oncologists know about this disease?

I think [community oncologists] are the mainstay of our treatment paradigms for all our patients. Many of their patients come to us where we can discuss options, as the front line of treatment is often with our community colleagues.

Many community oncologists have remained right on the cutting edge of the science, obtaining enough of a biopsy in order to be able to do NGS and immune oncology profiling. However, we want them to not only understand how we can treat patients who have unresectable disease or metastatic disease, but also that they can begin to partner with us either for local therapies, targeted therapies, and/or chemotherapies to transform patients who were previously unresectable to a resectable state because, in the end, surgery is the curative option.

So, combined with progressive local treatments, I think we're increasingly evolving from a one-size-fits-all to a true multidisciplinary paradigm. It’s incredibly important that as they begin treating and evaluating such patients, they can help by referring them to a tertiary center where we may have trials open that might be of benefit, or that we can discuss their cases in a multidisciplinary fashion with our surgical oncology, transplant oncology and interventional radiology colleagues. We can offer a treatment plan for them, and let them return to the communities where they can receive their treatment.

Unfortunately, not everybody can be cured, but we can almost always help a patient achieve other goals of care. It’s important to integrate palliative care earlier for [patients], whether they're getting treated or not, or having [adverse events] from treatment. I've seen a huge uptake of that in our community oncologists, and it's wonderful to see.

What areas of research you are involved in do you think are important?

We're very much integrated with our surgical, transplant oncologists, and interventional radiologists in our multidisciplinary team. We have opened a variety of trials looking at targeted therapies along with local therapies. We've been an early adopter of HAI pump therapy and using combinations of therapies to try to facilitate patients to resection, or even transplant. It’s very important for us to integrate with our oncology colleagues.

We are also participating in investigator-initiated trials such as from the University of Michigan including the BilT-04 trial [NCT04203160] of devimistat [CPI 613], which is a mitochondrial-directed compound. The preliminary data in the first few patients are quite promising in combination with chemotherapy. I am excited about the SWOG [1815] trial, which is looking at the triplet combination with gemcitabine, cisplatin, and paclitaxel. I think that these are all important trials that community oncologists can also involve themselves in.

_References

_{1. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281. doi:10.1056/NEJMoa0908721}

_{2. Zhang J, Lin Y, Sun XJ, et al. Biomarker assessment of the CBCSG006 trial: a randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer. Ann Oncol. 2018;29(8):1741-1747. doi:10.1093/annonc/mdy209}

_{3. Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22(5):690-701. doi:10.1016/S1470-2045(21)00027-9}

_{4. Yoo C, Kim KP, Jeong JH, et al. Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study. Lancet Oncol. 2021;22(11):1560-1572. doi:10.1016/S1470-2045(21)00486-1}

_{5. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study [published correction appears in Lancet Oncol. 2019 Apr 2;:]. Lancet Oncol. 2019;20(5):663-673. doi:10.1016/S1470-2045(18)30915-X}

_{6. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015;33(24):2617-2622. doi:10.1200/JCO.2014.60.2219}

_{7. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. FDA. Published April 17, 2020. Accessed February 7, 2022. https://bit.ly/3us3uRQ}

_{8. FDA grants accelerated approval to infigratinib for metastatic cholangiocarcinoma. FDA. Published May 28, 2021. Accessed February 7, 2022. https://bit.ly/3HAzN4K}

_{9. FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma. FDA. Published August 25, 2021. Accessed February 7, 2022. https://bit.ly/3B2MGSw}

_{10. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Published November 26, 2018. Accessed February 7, 2022. https://bit.ly/3osQwj2}

_{11. Chun YS, Javle M. Systemic and adjuvant therapies for intrahepatic cholangiocarcinoma. Cancer Control. 2017;24(3):1073274817729241. doi:10.1177/1073274817729241}

_{12. Oh D, He AR, Qin S, Chen L, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. J Clin Oncol. 2022 40:4_suppl, 378-378. 10.1200/JCO.2022.40.4 suppl.378}