Novel Targeted Therapies Under Investigation in Biliary Tract Cancers


Comprehensive insight on novel targeted agents under investigation in the setting of biliary tract cancers.


Milind M. Javle, MD: Inthe final segment of this program, we’re going to talk about targeted therapy. Dr Shroff, the last few years have been exciting, with 4 agents approved: infigratinib, pemigatinib, futibatinib, and ivosidenib. Perhaps there are more to come in the next year or 2. This is quite a staggering trajectory. Could you reflect on the FGFR space? There appears to be some redundancy and overlap in this space. What are you looking forward to? There are exciting clinical trials ongoing with refractory FGFR as well.

Rachna Shroff, MD: We jokingly say that it’s a good problem to have. We have so many options for our FGFR inhibitor, FGFR2-fusion–positive patients. With pemigatinib, futibatinib, and infigratinib, the first generation set a nice bar. Regarding futibatinib, the publication just came out, with an impressive overall response rate of over 40% in patients with FGFR2 fusions and rearrangements. Pemigatinib led the way as the first FDA approval in cholangiocarcinoma, with infigratinib in between. We’ve had a fair amount of experience all 3 of those drugs. They’re available to our patients, and we know how to manage the toxicities.

There are absolutely FGFR class-related toxicities that we’ve learned to manage prophylactically and preemptively, so patients are able to tolerate and be compliant with these medications. The exciting space is the ongoing trials, the second-generation, next-generation FGFR inhibitors that are in clinical trials, including the RLY-4008 and TT-00420. There are a number of them that everyone is looking at.

We want to be able to offer sequential therapies in terms of the FGFR inhibitors. We’ve done a lot of work to better understand the acquired resistance and how to circumvent some of that. Looking at the data that came out at ESMO [European Society for Medical Oncology Congress] for the Relay compound [RLY-4008], its multicohort patients included FGFR-treated as well as FGFR inhibitor–naïve. There was a signal even in the FGFR-treated, in addition to a very impressive overall response rate in FGFR-naïve patients. There’s a lot of interest in seeing these drugs through as more patients go on these trials. Hopefully we can have prospective data on how to sequence patients through the FGFR inhibitors.

Milind M. Javle, MD: I want to remind the audience that ivosidenib was approved based on the ClarIDHy trial, which showed an improvement in progression-free survival. There was a tail in the curve, with 1-year survival in almost 15% of patients, who experienced a benefit in the long term. There are 2 other IDH inhibitors in development and some exciting data in terms of IDH with immunotherapy and CTLA4. Clearly there’s more to come in the IDH space.

There’s a profusion of other therapies—HER2 [human epidermal growth factor receptor 2], trastuzumab, pertuzumab, BRAF inhibition with dabrafenib and trametinib—making NCCN [National Comprehensive Cancer Network] Guidelines. There seem to be some interesting data, Dr Shroff, on TP53 mechanism with MDM2. In the TOPAZ-1 trial data, the NGS [next generation sequencing] showed that a good number, 6% or 8%, had MDM2 amplification. Perhaps that’s an area to explore.

Rachna Shroff, MD: There have been a lot of data all over the place in terms of the frequency of MDM2 amplifications. I was impressed to see that it’s a reasonable percentage in the TOPAZ-1 data, which is even more in line with what we see in BRAF. Targeting MDM2 amplification is going to be an area of great interest, and there are early data. There’s a drug, BI 907828, being studied, and the initial data in multiple solid tumors included some cholangiocarcinomas. The data were presented at ESMO.

We’re seeing more updated data come out that demonstrate that there could be activity in using this compound and targeting MDM2-amplfied cholangiocarcinomas. There are expansions ongoing looking at that compound, specifically in patients with biliary tract cancer. The space will be interesting because when you look at the preclinical data, there are interesting combinatorial approaches with immunotherapy, looking at MDM2 targeting with immunotherapy. Once we understand what the MDM2-targeting space can do, that will be the next layer that we need to add in.

Milind M. Javle, MD: At ESMO we also found out that there were targets that were not mutation based. For instance, CTX-009 was an interesting agent developed in Korea. It’s a VEGF antibody along with DLL4, which is immune resistance mechanism. In a surprising finding, investigators reported that the partial response rate was pretty high in that setting, along with paclitaxel, which is not a commonly used regimen. We look forward to that study.

Nanvuranlat, an agent developed in Japan, is a LAT1 inhibitor. It’s an amino acid transporter. That seems to have a very interesting activity alone, but now it’s being explored with immunotherapy. Dr Shroff, clearly you think there may be a role for DNA-repair inhibitors in this space with some of the data showing an enrichment for BRCA, MDM, etc.

Rachna Shroff, MD: This seems to be a tumor type in which a high percentage of patients have HRD [homologous recombination deficiency]–type of genotypes. It will be important to study this. There are ongoing studies looking at single-agent PARP inhibitors, but there’s also a lot of interest in looking at PARP in combination with immunotherapy and other types. There are ATR inhibitors looking specifically at the ATM patient population. Hopefully, a lot of data will come from looking at that subset of patients.

Milind M. Javle, MD: Dr Shroff and I are excited because pharma is looking at biliary tract cancers. There’s an opportunity for drug approval, which is great because they’re investing in this space.

Transcript edited for clarity.

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