Targeted Therapy Generates Early Excitement in Biliary Tract Cancer

Sep 30, 2022
Supplements And Featured PublicationsMilestones in Medicine: Treatment Developments in Biliary Tract CancersVolume 1Issue 1

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.

Rachna Shroff, MD

Rachna Shroff, MD

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 Hepatologydetailing 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.”

In an interview with OncLive®, 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.

OncLive®: 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?

Shroff: 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 FGFR2 fusions, which we see in about 10% to 15% of biliary tract cancers, primarily intrahepatic cholangiocarcinomas, IDH mutations, which we see in about 20%, and then a smattering of other rarer, but still targetable mutations, such as BRAF V600E and HER2amplifications.

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 IDH 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.

HER2 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 FGFR2 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.

Reference

  1. Kam AE, Masood A, Shroff RT. Current and emerging therapies for advanced biliary tract cancers. Lancet Gastroenterol Hepatol. 2021;6(11):956-969. doi:10.1016/S2468-1253(21)00171-0
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