As new mutational targets arise and genetic testing becomes more precise, the field of biliary tract cancer care may soon expand to accommodate a range of tailored treatments, according to Rachna Shroff, MD.

In November 2021, Shroff and colleagues published a paper in 

The Lancet Gastroenterology and Hepatology

detailing current and emerging therapies in advanced biliary tract cancer.1 This publication provided an important foundation for further directions in biliary tract cancer, specifically regarding the efficacy of targeted therapies developed from the heterogeneous genomic landscape of this disease. The authors highlighted promising molecular targets such as FGFR, IDH, MAPK3, MAP2K1, HER2, NTRK, and DNA mismatch repair, and shared encouraging data with potential alternatives to palliative chemotherapy in this population, including the FGFR1-3 inhibitor pemigatinib (Pemazyre), the IDH1 inhibitor ivosidenib (Tibsovo), and immunotherapies.

“This space is changing on a daily basis, and we’re getting new drugs approved quite frequently,” Shroff said. “We went from an era of having no drugs approved to now having 3 drugs approved, and we’re on the cusp of having a couple more.”

®, Shroff discussed her recent publication in the context of additional treatments that have since emerged, the implications of the findings from the phase 3 TOPAZ-1 trial (NCT03875235), and the increasingly crucial role that biomarker testing will play when determining optimal targeted therapies for patients with biliary tract cancers.

Shroff is the interim chief of the Division of Hematology/Oncology, the associate dean of Clinical and Translational Research, and an associate professor of medicine at the University of Arizona College of Medicine – Tucson. She is also chief of the Section of GI Medical Oncology and leader of the GI Clinical Research Team at the University of Arizona Cancer Center, as well as the director of the University of Arizona Cancer Center Clinical Trials Office.

: What is exciting about the paper you coauthored on current and emerging therapies in this field in 2021, and what has changed in the field since its publication?

: What’s exciting about that paper is that it is already outdated. That speaks to the landscape of biliary tract cancers. That paper was impactful in the sense that it focused on the targeted therapy space. In anywhere from 40% to 45% of biliary tract cancers, when properly molecularly profiled, we’re able to find targetable alterations. Comprehensive biomarker testing is important in our patients with newly diagnosed advanced biliary tract cancers.

That paper focused on some of the known targets, such as 

 fusions, which we see in about 10% to 15% of biliary tract cancers, primarily intrahepatic cholangiocarcinomas, 

 mutations, which we see in about 20%, and then a smattering of other rarer, but still targetable mutations, such as 

In all these spaces, there are now drugs that are either FDA approved or in clinical trials that are demonstrating efficacy, including efficacy in refractory patients, those who have already progressed on standard therapies. These treatments are meaningful and impactful, and we need the ability to recognize whether we can offer them to our patients.

How has the field changed since the paper came out? Well, we have a new frontline standard of care [SOC]. What is the most exciting is, for more than a decade, gemcitabine and cisplatin has been our SOC for patients with newly diagnosed biliary tract cancers. [On September 2, 2022], we had an FDA approval come through for gemcitabine/cisplatin plus durvalumab [Imfinzi], based on the TOPAZ-1 study, which was a global study that looked at the addition of immunotherapy to a chemotherapy backbone. [This trial] demonstrated improvement in median overall survival [OS] and, more impressively, a separation of the curves that’s a bit more durable, even at the 18-month and 24-month landmark OS rates.

How have clinicians adapted to all the new chemotherapy, immunotherapy, and targeted therapy options? How do adverse effects (AEs) play a role in the management and treatment of these patients?

Clinicians are recognizing, slowly but surely, the importance of biomarker testing, so we’re doing a better job of sending patients for comprehensive molecular profiling right at the time of diagnosis. We need to continue to educate in this regard, as it’s not being done on every single patient. Having that information up front is key for us to know what to do when and if the patients progress on frontline treatment. That said, with the TOPAZ-1 study out, I’m seeing that most clinicians are integrating immunotherapy into their frontline treatment with the gemcitabine, cisplatin, and durvalumab regimen.

This study was interesting, because after 6 months, the chemotherapy was stopped and the durvalumab was continued as maintenance treatment, which is a bit different than what we do in the United States. That’s a European approach. Historically, our clinicians have been a bit nervous to stop treatment altogether. Now, with durvalumab as an option for continuation beyond 6 months, it makes us start to think about maintenance therapy approaches in this patient population.

Impressively, there was not much added toxicity with the addition of durvalumab. We’re not as worried about the AEs in that group of patients. Now, in the targeted therapy space, there are AEs, especially with FGFR inhibitors, that seem to be class effects. But as we’re using these drugs more, we’re getting smarter about how to be proactive in trying to prevent some of the AEs. As a result, patients are better tolerating these treatments and staying on these treatments during the time in which they’re effective.

Given the efficacy seen with the TOPAZ-1 regimen, how could these results affect precision medicine within biliary tract cancer and molecular profiling for these patients?

The TOPAZ-1 data are influential because they represent the first change in frontline therapy for patients with biliary tract cancers. The median OS benefit doesn’t necessarily tell the whole story. There is a numerical and statistically significant improvement in median OS. However, as we get to 18 months and 24 months, we see an impressive separation of the curves.

What will be key for us to understand is the 25% of patients who are demonstrating that prolonged, durable benefit. As we start to dig into the biomarkers related to immunotherapy response, we can hopefully better identify which patients are benefiting from the addition of immunotherapy.

Other frontline therapies that we’re currently awaiting results for include the [phase 3] KEYNOTE-966 [NCT04003636] regimen, which looks at gemcitabine, cisplatin, and pembrolizumab [Keytruda]. In that study, gemcitabine is continued with the pembrolizumab. After gemcitabine/cisplatin is given up front for 6 months, you continue one of the chemotherapies and pembrolizumab. It’ll be important to see those results and understand them in the context of TOPAZ-1.

We’re also waiting for the final data from the study that I’m the principal investigator on, [the phase 3] S1815 trial [NCT03768414], with gemcitabine/cisplatin and nab-paclitaxel [Abraxane]. This is a triplet chemotherapy approach, perhaps to be considered in patients who need a quick response or cytoreduction and/or are not candidates for immunotherapy.

There’s a lot in the frontline space that we’ll be learning from soon. Regardless, the TOPAZ-1 regimen should absolutely be our new SOC, and we’re starting to see that integrated.

What has been the importance of targeted therapy in biliary tract cancer in recent years?

Biliary tract cancers have proven themselves to be the poster child for precision oncology. Between intrahepatic and extrahepatic cholangiocarcinomas and gallbladder cancer, about 40% to 45% of patients have targetable alterations for which we have treatments. That’s a sizable chunk of our patients. Identifying what targets they have and recognizing which clinical trials and/or approved therapies are available to them is going to be important in terms of determining the types of tools that we have in our toolbox for these patients.

Excitingly, in the FGFR inhibitor space, we have 2 FDA-approved drugs and probably will have a third 1 soon. But we also have a whole new second generation of FGFR inhibitors that are demonstrating impressive efficacy. We’re learning more about resistance mechanisms, how to circumvent that resistance, and how to potentially sequentially offer FGFR inhibitors to these patients.

Similarly, in the IDH space, with ivosidenib being FDA approved, we have targeted therapy for the 20% of patients who have 

 mutations. Identifying those patients is important. We’re starting to think through resistance and the next generations of these types of drugs. A number of IDH inhibitors are in trials. Hopefully, we will have a multitude of targets and therapies available within just FGFR and IDH.

 amplifications [are another mutation] that we see in about 10% to 15% of gallbladder cancers and extrahepatic cholangiocarcinomas. We have demonstrated, through a number of clinical trials, that there is proof that we can target HER2 using some of the drugs that we’ve historically used in breast cancer and gastric cancer. A number of novel treatments are out there, and many trials are open, looking at several HER2-targeting agents, including those like fam-trastuzumab deruxtecan-nxki [Enhertu], which everyone is excited about in the breast cancer world.

There are rapidly changing trials and availability of these drugs for our patients, which is wonderful for them in terms of opportunities for enrollment on trials and therapeutic options.

How have all these advances affected the use of local therapy in biliary tract cancer?

At the end of the day, 60% to 70% of patients with biliary tract cancer present with advanced disease, so systemic therapy is here to stay—it’s going to be the backbone of our approaches. That being said, in patients who have liver-limited disease and/or potentially operable disease, surgery remains the curative therapy for patients with biliary tract cancer.

As we start to develop new drugs in the advanced space, the obvious question becomes: Can we move some of this into a perioperative approach? Can we use immunotherapy or targeted therapies in a neoadjuvant approach to try to get patients to the operating room after a nice response to treatment? And/or, in the adjuvant setting after surgery, should we be offering patients with 

 fusions FGFR inhibitors? There’s a lot of interest in that space.

Additionally, in patients with localized, liver-limited disease, we’re asking: Should we integrate some of these systemic therapies with more liver-directed approaches such as radiation, stereotactic radiation, radioembolization, and some of the other treatments that we consider with our interventional radiology and radiation oncology colleagues?

The best way to answer questions like that is going to be systematically, through prospective clinical trials. There’s much effort in that space to understand the right patients for those approaches.

What other ongoing clinical trials in biliary tract cancer are you particularly intrigued by?

The most exciting thing about clinical trials right now is that, when I started treating this disease 10 to 12 years ago, there were essentially no clinical trials for our patients with biliary tract cancers, and now our patients have many options, including options based on their molecular profile, their biomarker testing, and the extent of their disease. Many ongoing trials are trying to understand immunotherapy, not just gemcitabine/cisplatin plus immunotherapy but immunotherapy in a perioperative or multi-modality approach, as well as immunotherapy combinations. [We’re asking:] Can we utilize immunotherapy in our refractory patients, for instance?

There are more studies going on in Europe, for example, trying to understand how we can better improve adjuvant therapy. Can we do better than the SOC, which is currently capecitabine? [The phase 3] ACTICCA-1 study [NCT02170090] is looking at gemcitabine and cisplatin vs capecitabine, and we’re all anxiously awaiting the readout on it.

We’re also doing a better job of creating niches. We’re looking at studies specifically in gallbladder cancer. The [phase 2/3] OPT-IN study [NCT04559139] is looking at incidentally found gallbladder cancer and the role of a perioperative chemotherapy approach there. As we start to better fine-tune these trials to specific subsets of patients, we’ll be able to better identify who should be receiving what types of therapies.

The most exciting thing is that there is a significant amount of interest from industry and drug development experts in terms of developing novel therapies for these patients. We have proven that [patients] are interested in enrolling in clinical trials, that those clinical trials enroll quickly, and that these patients have targetable and meaningful alterations that we should be focusing on and trying to develop drugs for.

What main message regarding biliary tract cancer treatment would you like to emphasize for treating physicians?

This is, by far, the most exciting time to be involved in drug development in treating these patients. We went from having gemcitabine/cisplatin and nothing else to having a multitude of treatments available, and a number of clinical trials and engaged clinicians, researchers, scientists, and advocates who are all focused on trying to develop new therapies for these patients.

[The focus has also shifted toward] developing patient-centric trials, trials that patients are interested in enrolling on and that are meaningful to them. The Cholangiocarcinoma Foundation and the advocacy that they have done has been tremendously effective in biliary tract cancer. The reason we now have FDA approved drugs is from all the work that they have done to activate, energize, and synergize patients, advocates, researchers, scientists, and clinicians, along with industry and the FDA.

If I were to predict the next few years, I imagine we will have even more drugs FDA approved, and we will possibly even identify newer targets that we’re not even thinking of right now.

Kam AE, Masood A, Shroff RT. Current and emerging therapies for advanced biliary tract cancers. 

 2021;6(11):956-969. doi:10.1016/S2468-1253(21)00171-0

Articles

As new mutational targets arise and genetic testing becomes more precise, the field of biliary tract cancer care may soon expand to accommodate a range of tailored treatments.

Targeted Therapy Generates Early Excitement in Biliary Tract Cancer

Chemoimmunotherapy combinations, along with therapies targeting 

 mutations, are ushering in a new era of treatment for biliary tract cancers, according to Do-Youn Oh, MD, PhD.

The longtime standard of care (SOC) for this collection of diseases was gemcitabine plus cisplatin, after the chemotherapy combination demonstrated efficacy in the phase 3 ABC-02 trial (NCT00262769). A new combination, durvalumab (Imfinzi) plus gemcitabine and cisplatin, has emerged, displaying a 24-month overall survival (OS) rate of 24.9% in the phase 3 TOPAZ-1 trial (NCT03875235).

FDA approval of durvalumab in combination with gemcitabine and cisplatin in adult patients with locally advanced or metastatic biliary tract cancers

“The main message of the TOPAZ-1 study is that the combination of immunotherapy, in this case, durvalumab, a PD-L1 inhibitor, on top of the current SOC of gemcitabine/cisplatin cytotoxic chemotherapy, improved the OS compared to the cytotoxic [chemotherapy regimen alone],” Oh said.

, Oh discussed how the incidence of biliary tract cancers differs around the world, why the subdivisions of this rare disease are important to be aware of when designing clinical trials, and how the TOPAZ-1 regimen and other agents, such as ivosidenib (Tibsovo), have set the stage for advances in immunotherapy and targeted therapy for this population. Oh is a professor in the Department of Medical Oncology at the Seoul National University College of Medicine.

: Could you speak to the geographic diversity of risk factors for biliary tract cancer and the resulting impact on the incidence of this disease around the world?

: From a global point of view, the incidence of biliary tract cancer is relatively low compared with other solid tumor types such as lung cancer, breast cancer, gastric cancer, [and others]. However, the incidence of biliary tract cancer is higher in Asian countries compared with the Western countries. The incidence is quite high in southern China, some areas of Thailand, and South Korea. For example, in South Korea, the annual incidence of new cases of biliary tract cancer is 10 to 12 patients per 100,000 [people in the] population, which is quite high compared with the incidence in the United States, Europe, and other countries.

What is the best path toward drug development, given some historical challenges in this area?

The prognosis of biliary tract cancer, especially in advanced stages, is not good. The main reason is that it’s a relatively rare cancer, so [not much research is] presented to sponsoring companies in the drug development field. That’s the main reason [why we have not developed] many good treatment regimens.

Based on [findings from] the ABC-02 trial, [which were presented in 2010,] the global first-line SOC for advanced-stage biliary tract cancer is the combination of gemcitabine and cisplatin. That regimen has not been changed in over a decade, because we hadn’t had a successful phase 3 global study to [improve upon the]gemcitabine and cisplatin combination [until TOPAZ-1].

What is the optimal design for clinical trials for patients with biliary tract cancer?

Biliary tract cancer is a heterogeneous group [of diseases that are defined] based on the primary location, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.

According to the primary site of origin [of the disease], the molecular profiles of tumors are a bit different [from each other]. It’s always challenging when we design clinical trials [to decide] whether we include all types of biliary tract cancer together, or exclude [certain types].

You presented the primary findings of the TOPAZ-1 trial at the 2021 ASCO Gastrointestinal (GI) Cancers Symposium. Since then, we’ve seen subgroup analyses presented at the 2022 ESMO World Congress on GI Cancer, showing a benefit with the immunotherapy regimen regardless of primary tumor location. How do you see these results affecting precision medicine and molecular profiling in this population?

At the original primary analysis, the OS benefit [elicited by] adding durvalumab to gemcitabine and cisplatin had an HR of 0.80. The benefit of durvalumab was observed regardless of the primary tumor origin. [Patients with] intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer all benefitted, even though there were some differences. For example, in gallbladder cancer, the HR was a bit high compared with the other 2 tumor types. In the TOPAZ-1 study, we did not include ampullar of vater cancer, just the 3 other subtypes. Now, we can say that when adding durvalumab to gemcitabine/cisplatin chemotherapy, all the patients [with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer] benefit, regardless of primary tumor origin.

After the primary analysis, we did a longer follow-up of the TOPAZ-1 population. At the 2022 ESMO Congress, we reported the updated efficacy analysis. [In total,] 6.5 months of follow-up were added from the primary analysis. The median follow-up duration was 23.4 months [for the durvalumab arm].

With the longer follow-up, the HR for OS was 0.76. With this longer follow-up, we can say that the durvalumab benefit is consistently and clinically meaningfully observed in patients with biliary tract cancer, compared with gemcitabine/cisplatin alone.

Could you speak to the role that targeted therapy has taken on in recent years in biliary tract cancer?

[Beyond the] success with immunotherapy in the TOPAZ-1 trial, recently, we have seen some success with targeted therapy in biliary tract cancer, which is good news.

The first success of targeted therapy in biliary tract cancer has been the targeting of the 

 mutation. A portion of patients with biliary tract cancer patient have 

 mutations. Now, we have a drug targeting mutant 

. We have positive data with ivosidenib in the second- and third-line setting for biliary tract cancer. We have seen success targeting the 

Another important success is targeting the 

 fusion or translocation. Several FGFR inhibitors have already been approved, such as pemigatinib [Pemazyre] and infigratinib [Truseltiq]. Those 

 fusions or rearrangements are interesting and important therapeutic targets.

Nowadays, I’m happy to see the progress of ongoing clinical trials using interesting targeted agents in the biliary tract cancer field. One example is targeting 

 [mutations]. Like breast cancer or gastric cancer, some patients with biliary tract cancer harbor 

 mutation and protein expression. Targeting 

 is another promising therapeutic strategy in biliary tract cancer. 

What does the FDA approval of durvalumab in combination with gemcitabine and cisplatin mean for patients and providers?

Based on the success of the TOPAZ-1 trial, the [National Comprehensive Cancer Network] guidelines adopted the durvalumab plus gemcitabine/cisplatin combination regimen as the category 1 preferred regimen in the first line for advanced biliary tract cancer. On September 2, the FDA approved durvalumab plus gemcitabine and cisplatin in biliary tract cancers.

This is quite good news for our biliary tract cancer patients. So far, the first-line SOC for advanced biliary tract cancer has been gemcitabine and cisplatin. Globally, that has been the SOC for over a decade, without changing. But at this time, we can say that the new SOC in the first line for advanced biliary tract cancer is durvalumab plus gemcitabine and cisplatin.

I expect other regulatory authorities besides the FDA might also approve this durvalumab [regimen] in biliary tract cancer. I hope to see those approvals soon.

What research in biliary tract cancer is ongoing at Seoul National University?

At our site, we have many clinical trials targeting biliary tract cancer, and new compounds [are being investigated in] phase 1 studies. Now, I’m exploring the role of immunotherapy in the first-line setting, [plus] the second- and later-line settings, in combination with other targeted agents. A new and interesting targeted agent has been also tested in a formal phase 1 study, which included a biliary tract cancer cohort.

Oh D, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. 

FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. News release. FDA. September 2, 2022. Accessed September 28, 2022. 

Chemoimmunotherapy combinations, along with therapies targeting IDH1, FGFR2, and HER2 mutations, are ushering in a new era of treatment for biliary tract cancers.

Durvalumab/Chemo Combination and Other Novel Treatments Arise in Biliary Tract Cancers 

The varied landscape of biliary tract cancer has long stalled therapeutic developments, but disease subdivisions may provide insight into the best avenues for effective treatments and individualized care, according to Flavio G. Rocha, MD, FACS, FSSO. In particular, Rocha highlighted that treatment with durvalumab (Imfinzi) plus gemcitabine and cisplatin has the potential for further study beyond the findings from the phase 3 TOPAZ-1 trial (NCT03875235).

“It has been an exciting time in cholangiocarcinoma with all the new molecular information and all the new drug development,” said Rocha, who is an associate professor of surgery in the Division of Surgical Oncology and the Hedinger Chair and division head of surgery in the Division of Surgical Oncology in the School of Medicine at Oregon Health & Science University, in an interview with 

In the interview, Rocha discussed the types of biliary tract cancer and what has been learned about them, explained the effects of systemic therapy on surgery, and relayed remaining questions pertaining to the efficacy of immunotherapy.

: Please provide some insight on the epidemiology and pathogenesis of biliary tract cancer.

: [To clarify,] biliary tract cancer is a conglomerate of several disease entities. What they have in common is that they grow along the biliary tract epithelium that starts in the liver and goes from the microscopic ducts [flowing] down into the larger channels, [such as] the hepatic ducts and the common bile ducts. There is an offshoot of that to the gallbladder, which is usually lumped into biliary tract cancers. [The tract also] moves down into the head of the pancreas and out to the small bowel. [Biliary tract cancer] is a collection of different diseases.

When thinking about how to [differentiate] biliary tract cancer, cholangiocarcinoma and gallbladder cancer are the 2 main divisions. Then, within cholangiocarcinoma, there is also a subdivision into intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. We put them all together because [cholangiocarcinoma] is a relatively rare disease here, in the United States, with around 4000 to 8000 cases. However, [this disease] is much more prevalent in other countries—especially Asia, where we think epidemiology may [be a contributing factor]. In Asia, we know there is an association with parasitic infections. [For example], liver flukes cause inflammation in the bile [ducts] in patients with cholangiocarcinoma.

Gallbladder cancer is interesting because some areas are known to be endemic with it. We see a much higher incidence in countries like Chile and India. In the United States, we see certain populations that have a higher incidence of gallbladder cancer, for example, in our Native American community. Some genetic and environmental factors contribute to the development [of this disease].

What we’re seeing as a trend in the United States, however, is that in general, the onset of liver disease, whether from hepatitis or from metabolic syndrome, is predisposing patients to develop more intrahepatic cholangiocarcinoma than extrahepatic cholangiocarcinoma. The incidence used to be higher for the extrahepatic component than for intrahepatic disease. We [continue to learn] a bit more about the disease process and how it may develop.

How have the many subdivisions of this disease have influenced drug development?

The patterns of biology are different. For example, gallbladder cancer tends to present either asymptomatically or very late with symptoms, but it tends to spread early, so we see a higher proportion of patients present with metastatic stage IV disease. We also see in some ways, but to a lesser degree [than extrahepatic disease], the intrahepatic component, because those patients present with a liver mass that may or may not be symptomatic. They may present with a solitary mass or multiple masses at 1 time. Extrahepatic cholangiocarcinoma may present a bit earlier, because when the bile ducts get obstructed, people can develop jaundice, and it’s hard to ignore jaundice or cholangitis, which is an infection of the bile ducts.

The way the patterns of the disease grow is the way they present. This certainly presents challenges for drug development and treatment. As a surgeon, it also presents a challenge with what operation should be done, whether it is a liver resection [alone], a pancreas resection [alone, or] some combination.

We’ve also learned that these differences in biology are probably due to the genetic components [of these diseases]. We’re learning that cholangiocarcinoma has a rich mutational landscape. The profiles are different between these tumors. For example, [although we see] a higher proportion of 

-[mutated] cancers in gallbladder and extrahepatic disease, we don’t often see 

 being the driver of intrahepatic cholangiocarcinoma. We do see an increased incidence of actionable mutations in intrahepatic cholangiocarcinoma, with certain mutations like 

 fusions. That’s where much of the drug development has been focused.

How have you seen systemic therapy affecting surgery, and how may this therapeutic approach continue to make an impact in the future?

A trend in general in most gastrointestinal cancers is that many new treatments and novel therapies are typically targeted at the advanced disease population where there are no other treatments available. As a surgeon, I would love to see that treatment paradigm moved up to convert patients who were not initially thought to be surgical candidates because they have locally advanced disease, and that can be potentially down staged.

This is what we’re seeing, for example, with the new triplet regimen, gemcitabine, cisplatin, and nab-paclitaxel [Abraxane], which was being investigated in the stage IV setting. We recently took that to a neoadjuvant approach to see if we could convert patients from what we termed to have oncological high-risk disease and [instead] get them to surgery.

[We want to achieve the] same with the molecular markers. We were operating on patients when they had a liver mass without a diagnosis, [but now] we are increasingly asking for that piece of tissue to do the [molecular] profiling to see whether we can recognize some actionable mutations. The [mutations] that come to mind are those like microsatellite instability [MSI], because that’s an entity that we can now treat with immunotherapy [and see] fantastic results. [It makes me think] back to some of the cases I’ve had recently where we’ve treated large liver masses in patients with MSI-high disease or Lynch syndrome, [and they] have had almost a complete response [CR] to just the drug therapy alone. [A CR without surgery] would be the home run.

What is known so far about the durability of benefit with immunotherapy?

The most recent data we have is from the TOPAZ-1 trial, which looked at an unselected patient population with advanced biliary tract cancer that was treated with gemcitabine, cisplatin, and durvalumab. TOPAZ-1 was a positive trial [for the triplet] compared with chemotherapy alone.

However, we don’t have good information on the subsets [of patients]. One subset analysis might be favoring patients in Asia, one may be favoring locally advanced disease, and one may be favoring intrahepatic cholangiocarcinoma. However, we don’t know the details yet.

The important part of this is [to determine] the durability [of these benefits]. In TOPAZ-1, durvalumab was given as a combination therapy, but also as a maintenance regimen, whereas the control arm only had the chemotherapy alone and was stopped at 6 months. The next important questions to ask are: What should the duration of therapy be? Should we give it preoperatively or postoperatively? What subsets of patients are likely to benefit the most? The MSI-high population certainly benefits, but in these unselected patients, who are most likely to benefit from this treatment?

What ongoing or planned research are you excited to see explored at Oregon Health & Science University?

Here, at Oregon Health & Science University, we certainly have a keen interest in biliary tract cancer. We take a multidisciplinary approach and have ongoing protocols for neoadjuvant chemotherapy.

As a follow-up to the TOPAZ-1 study, which was presented at [the 2022 ASCO Annual Meeting,] we are going to be part of the [phase 2] OPTIC trial [NCT05514912], which is in development, and is looking at a similar population of patients with resectable intrahepatic cholangiocarcinoma. Those patients will be profiled, and those who have a 

 fusion will be treated with an FGF2-targeted agent, followed by a resection. Those who do not have an actionable 

 mutation will then be treated with what will hopefully be the new standard, which is gemcitabine, cisplatin, and nab-paclitaxel.

In addition to that, we also offer hepatic arterial infusion therapy, which is a device that is implanted and delivers chemotherapy straight to the liver. We have seen some success with that approach in intrahepatic cholangiocarcinoma with bulky or multifocal tumors because the chemotherapy is directed straight to the liver, which is the area of the tumor and typically the area of recurrence following resection.

What facets of multidisciplinary biliary tract cancer treatment would you like to emphasize to fellow surgeons or medical oncologists?

Let’s work together. Let’s try to bring some of these treatments perhaps earlier in the treatment sequencing. [We should also work] with our interventional radiology colleagues. We give many therapies locoregionally.

The ultimate goal is [determining whether] we [can] provide the optimal treatment sequencing as all these treatment modalities come into play. We’re learning that perhaps the molecular landscape may also be different between early-stage and late-stage disease. We may need to tailor our approaches based on patient factors, liver factors, and tumor factors.

Flavio G. Rocha, MD, FACS, FSSO, discusses the types of biliary tract cancer and what has been learned about them, explains the effects of systemic therapy on surgery, and relays remaining questions pertaining to the efficacy of immunotherapy.

Immunotherapy and Targeted Therapy Approaches Drive Advances in Biliary Tract Cancer

The addition of durvalumab (Imfinzi) to gemcitabine and cisplatin elicited a modest yet durable survival benefit in biliary tract cancer, according to Mark Yarchoan, MD, who added that the development of additional treatments in this disease are dependent on innovations with immunotherapy.

the FDA approved durvalumab in combination with gemcitabine and cisplatin in adult patients with locally advanced or metastatic biliary tract cancers

 The approval was supported by findings from the phase 3 TOPAZ-1 trial (NCT03875235), where the triplet improved median overall survival (OS) at 12.8 months (95% CI, 11.1-14.0) compared with 11.5 months (95% CI, 10.1-12.5) with chemotherapy alone (HR, 0.80; 95% CI, 0.66-0.97; 

“[Gemcitabine, cisplatin, and durvalumab] will become a new standard of care [SOC] option for many patients with advanced-stage disease,” Yarchoan said in an interview with 

In the interview, Yarchoan, an associate professor of oncology and co-leader of the Liver Cancer Multidisciplinary Clinic at Johns Hopkins Medicine, laid out the evolution of drug development in biliary tract cancer, discussed the findings from the TOPAZ-1 trial, and shared the positive future direction of immunotherapy in this disease.

: Could you provide some background on the historical outcomes of biliary tract cancer?

: Biliary tract cancer is unfortunately a treatment-resistant tumor type. It’s an aggressive cancer. The median survival for patients with advanced-stage disease is about a year. Unfortunately, most patients with earlier-stage disease often relapse shortly after surgery. This is a cancer that needs a lot of help and new therapies.

What are some of the challenges of drug development for biliary tract cancer, and do some of those challenges stem from heterogeneity of the disease? 

One of the challenges is one we share with many other cancers, which is that this is a rare cancer, and patients are geographically split apart all over the country, which, in the past, has made it difficult to accrue a large number of patients to large, randomized phase 3 trials. Until recently, most of the drugs we had for biliary tract cancer had been borrowed from other more common tumor types.

That being said, [patients with biliary tract cancer have] recently been the beneficiaries of the development of tumor-agnostic drug approvals. In the past couple of years, there have been tumor-agnostic approvals of pembrolizumab [Keytruda], NTRK inhibitors, and BRAF inhibitors, most recently with trametinib [Mekinist] plus dabrafenib [Tafinlar]. These drugs are clearly active in cholangiocarcinoma. There are always patients with cholangiocarcinoma in these tumor-agnostic trials, and they tend to respond. That has been incredibly helpful for our field.

What was the significance of the TOPAZ-1 trial, and what were some key efficacy and safety findings?

[The TOPAZ-1 trial showed that] the combination of gemcitabine, cisplatin, and durvalumab was superior to gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. This was a global study.

The added benefit of durvalumab was relatively modest, even though TOPAZ-1 was a positive study. The median OS was prolonged by only about one month, but progression-free survival [PFS] and response rates were also prolonged with the addition of durvalumab.

The combination was well tolerated, and immune-related adverse effects were infrequent with durvalumab, so [safety will likely not hinder the] adoption [of this combination].

[However], there are patients who I wouldn’t offer the combination to. We have data from a phase 2 trial [NCT02392637] showing that gemcitabine, cisplatin, and nab-paclitaxel [Abraxane] is a highly active triplet, and that combination is currently [being investigated] in a phase 3 study [NCT03768414] vs gemcitabine plus cisplatin. Even without phase 3 data, [this combination is] something we’ve adopted [at Johns Hopkins] for patients with locally advanced disease or borderline resectable disease, where the primary goal is tumor reduction. It’s something that I would use, even though we only have phase 2 data, for patients who need a response, patients with extensive symptomatic disease [who need quick tumor debulking].

There’s also an ongoing phase 3 study of gemcitabine plus cisplatin and pembrolizumab, [the KEYNOTE-966 trial (NCT04003636)], that should read out soon. That study is similar to the TOPAZ-1 study, but there is a key difference in the design. In the [TOPAZ-1] study, patients received 6 months of gemcitabine plus cisplatin and then continued with durvalumab monotherapy. In the ongoing [KEYNOTE-966] study, patients are receiving gemcitabine, cisplatin, and pembrolizumab, and then continuing gemcitabine as a maintenance therapy with or without pembrolizumab.

If both studies are positive, that will suggest that immune checkpoint inhibitors are truly a new SOC in the frontline. If the KEYNOTE-966 study is negative, [then it may be possible that] the TOPAZ-1 study was positive because it did not include a maintenance therapy, as it was randomized against placebo in the maintenance setting. The KEYNOTE-966 study is going to be important for determining how helpful checkpoint inhibitors are in the frontline.

How durable is the benefit with immunotherapy in this population? Are there any particular genetic signatures that responders have that may inform patient selection for this treatment?

The excitement of immunotherapy has always been that the responses are deep and durable, much more so than other treatment modalities. In the TOPAZ-1 study with durvalumab, we saw that separation between the [OS] curves increases over time, and there appears to be a tail at the end of the follow-up period where the patients [who received durvalumab] appear to be doing significantly better. That’s why many of us would adopt this as a SOC in the frontline setting, even if the median OS is not much different between the durvalumab-containing arm and the placebo arm.

In terms of biomarkers, the contribution of durvalumab appeared to be relatively similar across anatomic subsets of biliary tract cancer. [It appeared to have a benefit] in both PD-L1–positive and PD-L1­–negative patients, so we wouldn’t use PD-L1 to select patients.

TOPAZ-1 was an all-comers study that included patients across different molecular subtypes, and it included patients with or without mismatch repair deficiency. We’re all eagerly awaiting a subgroup analysis that will look at the benefit of durvalumab across the different molecular subsets of cholangiocarcinoma.

This is a heterogeneous disease. We have patients with 

 fusions who are completely clinically and pathologically different from patients with 

 mutations who tend to have more extrahepatic disease. It will be interesting to see if durvalumab appears to provide a benefit across the major molecular subsets of this cancer.

How does the FDA approval of durvalumab in this population affect patients and providers?

I suspect that [the TOPAZ-1 regimen] will be widely adopted in clinical practice, because TOPAZ-1 was a randomized phase 3 study that clearly showed OS, PFS, and overall response rate [ORR] benefit without much toxicity.

It’s a positive study, but even if durvalumab becomes widely adopted, it’s important to remember that our outcomes still lag behind many other tumor types. The ORR was only 26.7% with the triplet, and the benefit over gemcitabine plus cisplatin was quite modest. [We should not] become complacent. We need to do better for these patients, and I hope that even if this [triplet] is widely adopted, we continue to look at new frontline regimens that do even better.

How have the positive data from the TOPAZ-1 trial informed further research with immunotherapy in this disease?

Cholangiocarcinoma is generally an immune-resistant tumor type. The response rates with PD-1 or PD-L1 monotherapy in the largest studies that have been done have generally ranged from about 5% to 10%. Unfortunately, even though there is activity, it is modest with these agents.

We need a better understanding of mechanisms of resistance to immunotherapy in cholangiocarcinoma and new rational strategies to make these tumors more amenable to immunotherapy. That’s where my research is focused as a laboratory-based translational researcher. We’re excited about exploring novel strategies that could eventually move into the frontline setting to make these tumors respond better.

What biliary tract cancer research at Johns Hopkins would you like to call attention to?

I’m honored to be part of a clinical study run through the Cancer Therapy Evaluation Program, which is part of the National Cancer Institute, for which we’re a lead site. My colleague, Nilofer Saba Azad, MD, [of Johns Hopkins Medicine], is the overall principal investigator, and my friend and colleague Gregory B. Lesinski, MPH, PhD, [of Winship Cancer Institute of Emory University], is an important laboratory partner for this study, which is looking at a novel immunotherapy combination of atezolizumab [Tecentriq] plus a CD27 agonist plus a MEK inhibitor.

We previously enrolled a randomized study of a PD-L1 inhibitor with or without the MEK inhibitor cobimetinib [Cotellic]. This was technically a positive study for the doublet, as there was a modest PFS benefit with the dual therapy vs single-agent therapy. However, the activity was not enough to get overly excited about, as the response rate was in the single digits for the doublet.

In our lab research, we focused on trying to understand why the doublet didn’t work, because it looked promising in mouse studies. We found that MEK inhibitors have a complicated immune effect. They make the tumors more amenable to immunotherapy, but they also have a negative effect of dampening T-cell activation, and that is both a good thing and a bad thing for immunotherapy. We found that adding an immune-activating agent like a CD27 inhibitor could overcome the detrimental effects of MEK inhibitors in T-cell activation. This is a totally novel strategy that we’re testing now in a phase 2 clinical trial, and we look forward to seeing if there’s activity for the triplet.

We want to better understand the immune microenvironment in cholangiocarcinoma. My colleague, Marina Baretti, MD, [of Johns Hopkins Medicine], is leading a perioperative study investigating gemcitabine, cisplatin, and pembrolizumab, seeking to understand the mechanisms of response and immune resistance to the current strategy of triplet therapy in this cancer.

Finally, many of us are working to understand how different DNA mutations in cholangiocarcinoma affect the tumor immune microenvironment. How do 

 fusions or rearrangements affect the microenvironment? How do 

 mutations affect the tumor microenvironment? If we can understand the immune microenvironment in these biologically distinct groups of cholangiocarcinoma, then we can develop more personalized treatments and combination strategies. This is something that is ongoing.

FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. News release. FDA. September 2, 2022. Accessed September 14, 2022. 

Mark Yarchoan, MD, lays out the evolution of drug development in biliary tract cancer, discusses the findings from the TOPAZ-1 trial, and shares the positive future direction of immunotherapy in this disease. 

Durvalumab/Chemo Triplet Signifies Novel Advances in Treatment of Biliary Tract Cancer 

Mark Yarchoan, MD, associate professor of Oncology, Johns Hopkins Medicine, discusses the addition of durvalumab (Imfinzi) to gemcitabine and cisplatin in biliary tract cancer.

The phase 3 TOPAZ-1 trial (NCT03875235) evaluated durvalumab or placebo in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer.

The addition of durvalumab to gemcitabine and cisplatin displayed superiority vs gemcitabine and cisplatin alone, Yarchoan says. Despite TOPAZ-1 being a positive study, the added benefit of durvalumab was modest, with the median overall survival prolonged by about 1 month in the experimental arm vs the placebo arm, Yarchoan explains. Response rates and progression-free survival were also improved with the addition of durvalumab vs placebo, and the triplet could become a standard-of-care option for patients with advanced biliary tract cancer, Yarchoan adds.

Though the durvalumab-based combination was well tolerated, it may not be the optimal therapy for all patients with advanced disease, Yarchoan adds. The addition of nab-paclitaxel (Abraxane) to gemcitabine and cisplatin showed promising results in a phase 2 trial (NCT02392637), and the triplet will now be investigated in a randomized phase 3 study (NCT03768414), Yarchoan explains. Nab-paclitaxel, gemcitabine, and cisplatin could also have a role in patients who have locally advanced or borderline resectable disease, Yarchoan concludes.

Videos

Mark Yarchoan, MD, discusses the addition of durvalumab (Imfinzi) to gemcitabine and cisplatin in biliary tract cancer.


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Dr. Yarchoan on Gemcitabine and Cisplatin Combination Therapy Biliary Tract Cancer