In an interview with Targeted Oncology, Rachna T. Shroff, MD, MS, FASCO, discussed new systemic therapies that are available or being developed to treat patients with intrahepatic cholangiocarcinoma.
Treatment of intrahepatic cholangiocarcinoma (iCCA) expands each year, with the most recent advance being the addition of immune checkpoint inhibitors to the gemcitabine/cisplatin backbone, according to Rachna T. Shroff, MD, MS, FASCO. Looking forward, there are multiple biomarkers which represent an opportunity for better treatment options.
At The International Liver Cancer Association (ILCA) Annual Meeting in September 2023, Shroff, associate director of Clinical Investigations, University of Arizona Cancer Center, associate Dean, Clinical and Translational Research, chief, Division of Hematology/Oncology, professor of Medicine - (tenured), Clinical and Translational Oncology Program, gave a presentation on the new systemic therapy options that have been introduced or granted FDA approval for iCCA.
In an interview with Targeted Oncology™, Shroff discussed her ILCA presentation, the ICCA landscape, and needs for the future.
TARGETED ONCOLOGY: Can you provide an overview of the presentation you gave during ILCA 2023?
Shroff: I was delighted to present on new systemic therapies for intrahepatic cholangiocarcinoma at the ILCA 2023 meeting. It's an exciting time for intrahepatic cholangiocarcinoma. For the longest time, we had treatment with gemcitabine and cisplatin as our standard of care, a standard dual combination chemotherapy regimen. It was over a decade until we saw progress in terms of taking that and moving the needle forward. My presentation focused on 2 big buckets. One was frontline treatments for newly diagnosed, advanced biliary tract cancers, including intrahepatic cholangiocarcinoma. Chemotherapy plus immunotherapy is a new kind of platform for building on newly diagnosed patients’ therapies, based on TOPAZ-1 [NCT03875235]. That looked at gemcitabine and cisplatin with the addition of durvalumab [Imfinzi], as well as the KEYNOTE-966 [NCT04003636] data, which looked at gemcitabine, cisplatin, and pembrolizumab [Keytruda]. Now, for our newly diagnosed patients, the standard treatment is to give them gemcitabine/cisplatin with the addition of a checkpoint inhibitor. This is being integrated into the National Comprehensive Cancer Network guidelines and is the new base to try to topple or to try to beat.
With these new combinations of gemcitabine/cisplatin plus immunotherapy, the median overall survival is still in the range of 12 to 13 months, so we still have a lot of work to do. But the tail on the curve, meaning that people who had improved survival at the landmark bench points of 18-months survival and 24-months survival is what's really exciting. We’re seeing people, a subset of patients, live longer. We're still trying to understand who those patients are, but to the credit of both the TOPAZ-1 and KEYNOTE-966 data, it does seem that all comers with newly diagnosed intrahepatic cholangiocarcinoma should be getting gemcitabine/cisplatin with durvalumab, and possibly pembrolizumab.
The second bucket that I sort of focused on was targeted therapies because in the space of intrahepatic cholangiocarcinoma, genomic alterations that we see in this disease are molecularly diverse, complex, quite interesting, and potentially targetable. I usually quote about 30% to 40% of patients with intrahepatic cholangiocarcinoma have targetable alterations. The importance of doing comprehensive biomarker testing with next-generation sequencing cannot be underestimated.
The big areas in which we have drugs approved include the IDH1 mutation with the oral IDH1 inhibitor, ivosidenib [Tibsovo], based on the CLARITY data [NCT05174650], as well as oral FGFR inhibitors such as pemigatinib [Pemazyre] and futibatinib [Lytgobi]. These FGFR inhibitors all have accelerated approvals based on single-arm, phase 2 trials that looked at patients with FGFR2 gene fusions and rearrangements, who had progressed on standard therapy and were started on 1of these oral FGFR inhibitors.
I also emphasized the fact that there is now a second generation of these drugs that are exciting, like RLY-4008. These are drugs that may potentially work even in patients who have already progressed on FGFR inhibitors, and or may have FGFR alterations outside of fusions and gene rearrangements. The other big area that's really exciting in the targeted therapy space is in patients with HER2 amplifications and alterations, which is a little less common in intrahepatic cholangiocarcinoma. There was some exciting data that came out of ASCO with the monoclonal antibody zanidatamab [ZW25], as well as an oral tyrosine kinase inhibitor tucatinib [Tukysa] in combination with pembrolizumab. Clearly, the potential target and HER2 in intrahepatic cholangiocarcinoma is there as well.
What are some of the novel biomarkers being explored in this space?
Historically, the only things talked about were IDH1 and FGFR2 fusions and rearrangements. But the rare alterations that we are starting to think through, including BRAF V600E mutations, for which we use combination BRAF inhibitors. They've been tremendously based on the ROAR study [NCT02034110]. The HER2 alterations, which are a little less common, but are important to identify, and then more rare things like MDM2 amplifications, which we see in about three to 5% of patients with biliary cancers. Those are relevant because there are now drugs that target the MDM2 p53 axis and seem to have potential in terms of not only cytotoxicity, but also immune microenvironment modulation.
There are also the KRAS inhibitors. Right now, the focus has been KRAS G12C, which is a rare KRAS mutation in biliary cancers. But again, in the big studies that have looked at these drugs, they were targetable in the patients that we identified. We're now starting to see the G12D inhibitors move into the clinic, which is the most common KRAS alteration that we see in biliary tract cancers. That's an exciting space for us, as well as for rare things like NRG1 fusions, which occur in about 1% of biliary cancers, but are important to identify, including NTRK fusions.
Aside from new therapies to target these biomarkers, what are some of the unmet needs for patients with intrahepatic cholangiocarcinoma?
There are so many unmet needs. I would start with the fact that we identify most of these patients at advanced stages. So, early detection or determining if there's a role for screening and or prevention is, of course, a huge area of interest to us. In these patients who have chronic cirrhosis underlying fatty liver disease, we know these are risk factors. Starting to think through how we could find these patients earlier will be important. Additionally, we have the whole concern of when we do find patients at an early stage, and are their approaches in the perioperative space that we can take? There's a lot of good trials being designed in that space as well.
One of the greatest unmet needs is that 40% of patients have alterations, which means about 60% of patients don't necessarily have a targeted therapy that we can think through. So, are there additional targets that are maybe rare that we can identify? Are there newer drugs that we can find in those spaces? And what do we do for all those patients in the refractory setting after gemcitabine-based therapy? We have drugs like FOLFOX, 5-FU-based regimens, but the overall response rates, progression-free survival, and overall survival in the second-line and beyond setting are quite dismal.
We have a lot of work to do in terms of refractory cholangiocarcinoma and thinking through novel drugs. And then of course, the other obvious question is, what can we do to build on the immunotherapy world?
What else is going on in research that you think will be important for the future?
There's a lot of great enthusiasm for how we can make biomarker testing easier, more accessible, and quicker for our patients. That lends itself to the conversation around ctDNA liquid biopsies, the ability to kind of get comprehensive biomarker testing done that is sensitive and specific, as well, and turned around quickly, so we get the [next generation sequencing] results as fast as possible to integrate that into our treatments. There was a great debate at ILCA about tumor biopsy vs liquid biopsy. Again, there's a lot of research going on to understand what the core rates are with liquid biopsies compared with the tumor-based testing. I think that's an important space.
Also, I think a lot of us are committed to making sure that we develop the liquid biopsy space as much as possible, because that's really where we want to be able to detect all of the alterations that we need to be able to detect for cholangiocarcinoma. Then, I think a lot of the other areas of interest are related to these novel targets, and even second-generation targeted therapies for IDH1, FGFR2 fusions and rearrangements, and then things like HER2, as well as some of these rarer things.