OCTalks: targeting FGFR2 in advanced cholangiocarcinoma

Hello and welcome to this episode of OC Talks. The podcast series brought to you by Oncology Central. I’m Rachel Jenkins, senior editor of Oncology Central, and today I am joined by Professor Arnt Vogel, a senior consultant and professor of gastrointestinal oncology in the Department of Gastroenterology, Hepatology and Endocrinology at Hanover Medical School. Aunt and I are going to discuss cholangiocarcinoma the challenges of the field and any promising avenues for the therapy. Aunt to start us off, please, could you give us a brief overview of cholangiocarcinoma as a disease and kind of the current treatment landscape?

Arndt Vogel

Yes, of course. First of all, thank you very much for inviting me. It’s a pleasure to be here. There, in respect to cholangiocarcinoma, I think usually we are talking about biliary tract cancer which actually comprises 3 different tumour types. It’s intra particular carcinoma, extrahepatic, cholangiocarcinoma and also gallbladder cancer. And because it is a very rare cancer, they’re usually grouped together. As binary truck cancer and then. All clinical trials we have performed so far, which were basically using chemotherapy. We did not really make a difference and all patients were basically included into the trials and in terms of efficacy of the chemotherapy we’re using to treat these patients with advanced disease. They were never really significant differences. Between the three, two more times in respect to the treatment, I think in general we can distinguish potentially curative treatment and palliative treatment. Of course we are trying to apply curative treatment, which is usually surgery. Unfortunately, however, because of the tumour location or extrahepatic metastasis, we cannot really apply surgery to all of our patients and many of our patients are basically diagnosed in a very advanced stage and. Once surgery is now option anymore, we would apply chemotherapy. Overall, there’s one established first line, chemotherapy, gemcitabine and cisplatin, based on a phase three study published 10 years ago. And then there was not much else we could do for our patients. I mean, in, in the second line setting, we tended to use really Tekken based or oxaliplatin based. Combinations without any evidence. And very recently the ABC 06 study was published, providing evidence that for Fox might be an option compared to best active tumour control for patients with who basically failed. Jump higher and cisplatin first time chemotherapy. Overall, however, the prognosis is very poor and the median overall survival is only around one year currently.

Rachel Jenkins

So in terms of the hurdles in the way of advancing treatment and developing that second line therapy, what would you say are the major challenges that need to be tackled?

Arndt Vogel

Yeah. So we I think we tried in the past on different chemotherapies and they’re nice meta analysis providing what we can expect from chemotherapy. But I think overall we have to acknowledge that these valid tract cancers are basically not very sensitive to chemotherapy and therefore. I mean, we’ve made some progress in systemic therapy in the past and specifically IMMUNOTEC. Therapy basically was introduced. Unfortunately, just one checkpoint inhibitor is most likely not be sufficient to to really achieve a good tumour control in Antonio carcinoma. So here we also need additional strategies to to introduce immunotherapy and bilateral tract cancer. So at the moment it’s not really an option in. Daily clinical practise and the other progress or advantage we have made in the. Past is basically. The better understanding of the genetic alteration which actually lead to cholangiocarcinoma and very interestingly, despite it’s a rare tumour and it’s a very heterogeneous tumour, it appears that around 40 to 50% of patients have genetic alterations that would allow targeted. Molecular therapies and among these genetic alterations, I mean these, they are usually very rare. The most frequent ones occurring in around 15% of patient. RTF 2 fusions IDH 1 mutations and then we also have some patients that are MSI have Mira mutations or contractions so there are a couple of genetic evaluation that allow basically targeted therapies. The hurdle here is that in contrast to chemotherapy which we will apply to all patients. We are really aiming here for a very selected subgroup of patients of a rare cancer, indicating that it’s really difficult to perform these phase three studies to get basically approval by FDA and EMA and to use this drug in in our daily clinical. 1.

Rachel Jenkins

The potential biomarkers that you just mentioned are you involved with or aware of any ongoing clinical trials regarding FRF 2 fusions?

Arndt Vogel

Yes. So for all these biomarkers I mentioned before we for a couple of them, we have at least phase two data and we actually already have one completed phase three study. Which is for IDH 1 mutations and here it was inept and IDH 1 inhibitor has shown a thickety in these patients in the second line setting and you will see whether and how these drug is basically introduced into into into the clinic. At the moment there’s no approval by FDA or Imam in respect to the FL. Confusion. It’s kind of interesting that even if you do not really have a lot of patience, there are a lot of companies that are basically interested in these population of patients. And because there are a couple of FGFR inhibitors. Around which have shown efficacy in in early phase two studies and I personally was it was in the 522 study which looked at the efficacy of people guards in in patients with FGF 2 iterations. It was basically a three phase two study looking at patients without genetic alterations in the FFA. Between patients with mutations in the FFR receptor and also patients with FGFR 2 fusion and very interestingly with Amigas, and if we were able to achieve a very high disease. Control rate of more than 80% in partial response and some complete responses in around 36% of patients, indicating that pimi gardening and FGFR inhibition can be highly effective in at least in the second line setting of cholangiocarcinoma. And this is also one of the differences. What I mentioned before, I mean in the past we basically looked at all the different groups, extra cancer in respect to the genetic adoration. It appears that these FFL 2 Fusion and idea mutations we can specifically find them in intrahepatic cholangio carcinoma, so it’s a it’s a subgroup that genetically defined subgroup of patients with intraarticular.

Rachel Jenkins

To close us off, how do you hope that the future of cholangiocarcinoma will evolve, focusing mainly on the next 5 to 10 years?

Arndt Vogel

Yeah. So I think we have now seen with all these FFR 2 inhibitors efficacy in patients with F2 fusions, these trials have been specifically done in the second line setting and interestingly, at least three of them and in figurative are all now. Developed in in in the first line setting in phase three studies which are all ongoing, so these are really big studies with hundreds of patients. And I’m I’m convinced that this will be a challenge to to fully recruit. These these studies, but I think we have now really introduced the way that in in cholangiocarcinoma we will look at the genetic alteration and this is I think the really the the next step within the next one to five years and where we will perform these clinical trials both phase two and phase three studies in these genetically defined. Groups and. I think 1 next step could be the introduction of immunotherapy. So we have here seen the first interesting guides for dual checkpoint inhibition or checkpoint inhibition in combination with chemotherapy. And then could envision that also the combination of targeted therapies with immunotherapies could be quite effective. So I think there are a couple of ways how we will proceed in in the next years and I could imagine that just chemotherapy is probably will not really evolve much further. I do not really see any promising combination at the moment. And for the targeted therapies, I think we do have a couple of targets that are available and I truly hope that we will have more drugs available to also target more frequent alterations such as K, Ras and NRAS for example. And we have seen the first K Ras inhibitors, but for for many of these. Iterations. You already have props available, such as the B reputations for EXA. But which there was quite successful trials, not only in Melanoma but also in colon cancer. And we also have interesting data for combinations in with Newton. So in respect to these druggable alterations, I think we will certainly make more progress. In the next year.

Rachel Jenkins

Great. Well, thank you so much for joining me on the podcast. And it was really interesting to hear all about cholangiocarcinoma and the kind of the potential of FRF 2 inhibitors. So thank you very much.

Arndt Vogel

Sure.

Rachel Jenkins

Thank you to anyone listening to this podcast. If you’d like to hear more, you can find them in the podcast section of our website at www.oncologyhyphencentral.com.