FGFR Inhibition: A Novel Therapeutic Strategy - Episode 2
Rachna Shroff, MD, MS:So, Dr Kim, in terms of the current approach to cholangiocarcinoma, we have baseline knowledge of some therapeutic options that are available as well as a lot of emerging data for novel therapeutics. Can you discuss a little bit about cholangiocarcinoma, who these patients are, how they present, and what role FGFR [fibroblast growth factor receptor] inhibitors as well as other targeted therapies could play in addition to chemotherapy?
Richard Kim, MD:Sure. The cholangiocarcinoma can be divided into 3 different categories. One’s intrahepatic, the second is extrahepatic, and third is gallbladder. And extrahepatic is comprised of distal and perihilar tumors. And the symptoms that you present as a patient differ depending on the locations of the tumor. For example, if you have a distal you may present with painless jaundice. If an intrahepatic cholangiocarcinoma, you may really have no symptoms except for maybe some abdominal discomfort. And gallbladder, you may have some pain as well after eating or that kind of symptom. So the symptoms that present in cholangiocarcinoma do vary. At this time the only way to cure the disease is by surgery. So if you see a patient with that diagnosis, obviously we do the work-up to see what we could do in terms of the surgical resectability. Therefore, the multidisciplinary approach is very important, so we present the case. If they are not a candidate for a surgical resection, then that’s where we go into more of a palliative approach.
At this time the only data that we have are in the first-line setting. It is using gemcitabine/cisplatin, that’s based on the ABC-02 study that shows overall survival benefit compared to gemcitabine alone. Currently that’s the only standard that’s out there. Afterward, really everything else is sort of experimental and on a trial basis. So that’s the area where it’s a highly unmet need. And this is where the FGFR comes into play. This is a fusion that occurs in 15% to 20%, and that is an oncogenic driver in this cholangiocarcinoma patient population. So if you’re able to target those fusions in 15%, 20% of the patients, those patients may benefit from those drugs.
Rachna Shroff, MD, MS:Yes. And it’s also important, like you said, that even with gemcitabine and cisplatin, the majority of our patients present with advanced disease, 60% to 70% of them we can’t offer that curative surgery. And even with the use of gemcitabine and cisplatin we’re still looking at median survivals that are less than a year. So these types of targeted therapies are definitely a new hope.
Richard Kim, MD:Sure. So Dr Shroff, you mentioned [gemcitabine/cisplatin] being a first-line therapy, but you also did a trial using triplets, [gemcitabine/cisplatin]/Abraxane, which had a provocative phase II study. Can you explain the phase II data that’s been published I believe inJAMA Oncology, and ongoing phase III data showing that we’re making progress in the first-line setting?
Rachna Shroff, MD, MS:Yes. We did a single-arm phase II study at MD Anderson Cancer Center in Arizona that was 60 patients with either locally advanced or metastatic biliary tract cancer. So cholangiocarcinoma as well as gallbladder cancer. And in those patients we gave them gemcitabine, cisplatin, and nab-paclitaxel, which was an FDA approved drug for pancreatic cancer. We know that stroma and stromal barriers play a role in chemoresistance in biliary cancers as well, and so that was the thought process.
In that study, we found that we have to use a slightly lower dose than the kind of FDA approved doses, but with that dose regimenday 1 and day 8 of a 21-day cycle—patients actually tolerated the triplet surprisingly well. And the median PFS [progression-free survival] was 11.8 months, which for historical control comparison [gemcitabine/cisplatin] gives us a median PFS of about 8 months. And what was really striking was the median overall survival, which was 19.2 months, and a response rate of about 45%. So because the data were intriguing, obviously a single arm study is not the way to know if that’s what works. And so we started a phase III study, SWOG 1815, which is a randomized study of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin, with a primary endpoint of overall survival.
Richard Kim, MD:There are other backbone chemotherapies such as FOLFIRINOX [fluorouracil/irinotecan/oxaliplatin] that have been studied in the group in France. They had a randomized phase II against [gemcitabine/cisplatin]. That data’s not out there, so if that shows a better survival benefit compared with [gemcitabine/cisplatin], it may be another backbone that we may be able to use.
In terms of the usual survival in a patient with cholangiocarcinoma, as you mentioned, the first-line setting is about 11 to 12 months. In the second-line setting, at this time in terms of your standard management, in your practice, what do you do in second-line typically?
Rachna Shroff, MD, MS:So right now, just like you mentioned, there is no standard of care. The ABC group is working on changing that with some of their ongoing studies. But currently I would say the majority of practitioners use 5FU [fluorouracil]-based chemotherapies. I like to use FOLFIRI [folinic acid/fluorouracil/irinotecan] just to give patients a break from platinum chemotherapy, or FOLFOX [folinic acid/fluorouracil/oxaliplatin/irinotecan] as an option. But obviously if we have something that we can target and something that we can go after, the first choice is always clinical trials. Because over time we recognized that about 30% to 40% of our cholangiocarcinoma patients in particular have targetable alterations for which hopefully we have drugs and clinical trials that we can put them on.
Transcript edited for clarity.