Dr. Rachna Shroff:
Welcome to The ASCO Post Roundtable Series on Immunotherapy Strategies for Hepatobiliary Can-cer. I'm Dr. Rachna Shroff, I'm the Chief of the Division of Hematology Oncology at the University of Arizona Cancer Center. And I'm delighted to have two of my good friends and colleagues joining me on this panel for this conversation. Nilo, would you like to introduce yourself, please?
Dr. Nilo Azad:
Absolutely. I'm Nilo Azad. I'm a medical oncologist focusing on GI cancers at Johns Hopkins Universi-ty.
Dr. Shroff:
And Anthony.
Dr. Anthony El-Khoueiry:
Hi, I'm Anthony El-Khoueiry, also GI oncologist at University of Southern California, USC.
Dr. Shroff:
So today, we'll be discussing the treatment and management of hepatobiliary cancers with three different patient case studies. Our second installment will focus on cholangiocarcinoma. I'm going to start with the case, and then we can launch into a conversation. This is obviously Drs. Azad and El-Khoueiry's and mine's area of expertise, so I'm sure there will be some great conversation.
This is a 70-year-old female with no major medical history, who presents after an acute episode of nausea, vomiting, and abdominal pain. She had presented to the emergency room for workup, and an MRI was performed that showed a large liver mass and multiple satellite nodules. Other labs were within normal limits with the exception of some mild electrolyte abnormalities. And a CA 19-9 was drawn that was elevated at 473.
So this is just one slice of the imaging that was performed, and you can see a large mass in the liver that is notable on this slice at least. A biopsy of this liver mass is performed, and it shows a moder-ately differentiated adenocarcinoma that is CK7-positive, CK20-negative, negative for HepPar1, and the patient presents to oncology for further management. On exam, physical exam is within normal limits, and the patient has an excellent performance status of 0.
So in terms of workup, now that you have a biopsy and some MRI imaging, Dr. Azad, what would you do next in terms of a workup and what you need to get started on treatment?
Dr. Azad:
So the imaging features that we see for this patient are classic for cholangiocarcinoma. And so with the biopsy that we have, as well as with the elevated tumor marker, I would be very comfortable calling this patient a patient with cholangiocarcinoma. And my next step in my diagnostic and ther-apeutic workup would be to send for NGS testing, which would include microsatellite instability, but that's only present in about 1% of cholangiocarcinoma patients. But also would be looking at multiple other potential driver mutations and actionable mutations that we see with a high pre-ponderance in intrahepatic cholangiocarcinoma, compared to most GI cancers.
Dr. Shroff:
So Dr. El-Khoueiry, I don't know about you, but I get a fair number of patients that are referred to me, and they've had a full... I mean, I agree with you Dr. Azad, these are classic imaging features of a cholangiocarcinoma. You have a biopsy that says adenocarcinoma, but I have a lot of patients who get sent to me sometimes that have undergone an EGD, and a colonoscopy, and a PET, and all of these things as they do almost like a carcinoma of unknown primary workup. What are your thoughts on the need for those types of things, to Dr. Azad's point, with now our knowledge of what the classic imaging features are for a cholangiocarcinoma? Do you do those additional steps as well, or what's your take?
Dr. El-Khoueiry:
Oh, that's a great question. The short answer is we don't. So if the imaging criteria are consistent, the biopsy is consistent with cholangiocarcinoma. With modern imaging, whether it's MRI or CT scan, it's unlikely you would miss another primary elsewhere. So if the clinical and histologic data are supportive of cholangio, this is where it ends. But incidentally, as you alluded to, this is the classic old unknown primary. I think this accounted for the majority of unknown primaries in the past. So these extensive workups which tend to delay care and frustrate patients, and get them a bit lost are not really always necessary.
Dr. Shroff:
Yeah. So when Dr. Azad, you mentioned doing next-generation sequencing. Just out of curiosity, is that tissue, liquid? What's your typical approach here with an intrahepatic?
Dr. Azad:
That's such a great question. And so for intrahepatic, or frankly for any cholangiocarcinoma, if you have enough tissue, tissue-based testing is going to give you your highest degree of positive results, in terms of having sufficient quality of tissue and DNA and RNA to do the testing. But there are mul-tiple components of the testing that we should talk about. So first of all, one of the major things that we are looking for when we sequence patients is looking for an FGFR2 fusion... that's present in about 5% to 10% of intrahepatic cholangiocarcinomas. And fusions can be detected both on DNA and RNA-based testing, and sometimes they will only be detected on RNA-based testing. So it's very important with cholangiocarcinoma, that you are selecting a testing company or vendor that is do-ing both DNA and RNA-based tissue testing. There are multiple vendors that are doing that, and many of them are the usual suspects that we think about, but that's an important thing to be look-ing for.
With intrahepatic cholangiocarcinoma, usually we do a better job of having sufficient quality tissue, not all the time. And if we don't, then that's where I really move forward with blood-based tissue to supplement that testing if the tissue isn't giving us what we need in terms of quality. With peri-hilar, that's not this case, but with perihilar cholangiocarcinoma, tissue can be very difficult to come by. Often, it's just brushings from an ERCP. And so at that time, if I know that that's all we're going to have, I often will at the same time, I won't even wait for the tissue-based testing to come back. I'll send blood at the same time, because so many times we end up not having both. There are some insurance ramifications, and so that's just something to make sure that you're talking about with your patient. And then sometimes we just have to facilitate that at the tail end.
Dr. Shroff:
Okay. So you have the NGS cooking, Dr. Azad, where do you start in terms of treatment? You've de-cided this is a cholangiocarcinoma, how do you proceed?
Dr. Azad:
We may not have the same embarrassment of riches of four different regimens that we have in HCC, but we now do have two approved regimens for patients in the first line that have unresec-table cholangiocarcinoma. And because of the satellite lesions that this patient has, we would deem this patient to be considered unresectable at the outset. And so the two regimens that we have include the TOPAZ-1 regimen, which is gemcitabine/cisplatin plus durvalumab, that's given for 6 months, and then the patients move on to durvalumab maintenance therapy if their disease re-mains stable.
On the other hand, the other option that we have presented at AACR last year by Dr. Kelly, is the gemcitabine, cisplatin, pembrolizumab study. And that KEYNOTE trial was also 6 months of therapy with the triplet, but the difference in that study was at the time of maintenance, patients could continue on gemcitabine and the pembrolizumab. We are not supposed to do cross-trial compari-sons, but the two regimens look very similar in terms of the benefit that they likely provide, and both are completely appropriate first-line regimens.
Dr. Shroff:
Dr. El-Khoueiry, I think we just recently, a couple months ago, saw updated 3-year OS data on TO-PAZ. And I think the obvious question—and I'll be the first to admit, I was in the beginning, a little dubious. I'm like, "Does this work in all biliary cancers? Does this work based on... Does mutational status impact? Does region, is it Asia vs non-Asia?" Can you kind of take us through what some of the subsequent work, which has been primarily from the TOPAZ data, but KEYNOTE has also started to dig into it? Does any of the exploratory analyses, because they're not powered to look at these things. But do any of the exploratory analyses point you towards one regimen or another, or make you dubious about using IO in certain patients? I mean, what has been your general take?
Dr. El-Khoueiry:
So I agree with you, it's been a pleasant surprise to see this sustained benefit with long follow-up, and really to also see that the benefit seems to be across all subgroups. So my read of all these ex-ploratory analyses is that we've not been able to identify... It's hard to come up with predictive markers in general. But the question is, were we going to identify a group that doesn't benefit at all, or where we would be even worried? And that didn't seem to pan out. So whether it's etiology, whether it's region, whether it's age, I don't see anything in these exploratory analyses that would actually tell me that I should not be using the addition of anti–PD-1 or PD-L1 therapy with gem-citabine-cisplatin. So that's my short answer to this, unless Dr. Azad has anything else to add, a nu-ance that I forgot?
Dr. Azad:
No, not at all. I mean, I think the TOPAZ team has also presented comutations. And again, because these are subsets of subsets, the power of each individual mutation group wasn't high, but it still again looked consistent across the different mutations that can happen as well. And so I think that was also very satisfying.
Dr. Shroff:
Great. Well, so this patient, we were obviously awaiting NGS data, but was started on gemcitabine, cisplatin, and durvalumab. But in the meanwhile, the NGS data comes back, and this was a mi-crosatellite stable tumor, low tumor mutation burden, p53 mutation, and a HER2 3+ on IHC. The CA 19-9, while the patient is on front-line therapy with gemcitabine/cisplatin/durvalumab decreas-es to 257, and the imaging shows response in the larger liver mass and stable satellite nodules, no other areas of progression. So like Dr. Azad mentioned, after completion of 6 months of gemcita-bine/cisplatin plus durvalumab, the patient was then put on maintenance durvalumab. But unfor-tunately, after 4 months on maintenance durvalumab, all the lesions demonstrated growth, and the patient continues to have no extrahepatic disease. Good performance status with a PS of 1, and labs are acceptable with the exception of a slightly decreased GFR, with an elevation of creatinine of 1.13.
So Dr. Azad, where do you go next? Is there a chemo, targeted therapy, liver-directed approach? What would you do with the information that you have at hand?
Dr. Azad:
So luckily for our patient, we have a few different options, and I would be intrigued by the target-ed therapy option with HER2. So the data that has been looked at in terms of HER2-based therapy comes from both looking at combination HER2-targeted therapy and the trastuzumab/pertuzumab phase II study that was a single-arm study, but that resulted in NCCN level approval for patients to do HER2-targeted therapy. There have now been multiple HER2-targeted drugs that have been tested in this space too. Broadly, what we are seeing across these different studies is that patients that are HER2 3+ positive or amplified by FISH, are patients that potentially benefit from this ther-apy. And it's also interesting that this patient has intrahepatic cholangiocarcinoma and is HER2-positive. We tend to see a very high number of HER2-positive patients in gallbladder cancer, so it's a really important subset to be looking at in gallbladder cancer as well.
But second-line therapies that are also approved include FOLFOX, based on the ABC-06 study that randomized patients to FOLFOX vs best supportive care. There is also a study that has looked at lip-osomal irinotecan and 5-FU as a approach for... There was a randomized study in the second-line as well, which also showed potential activity, and is a reasonable regimen. So this patient has chemo-therapy options as well as HER2-targeted therapy. And then I also want to mention that because the patient was on maintenance durvalumab at the time of progression, it always remains an op-tion for patients to go back to the gemcitabine-cisplatin component as well. So for this patient, un-der my care, likely my next step would be to move towards HER2-targeted therapy. Also to give a different side effect profile, so the patient could have a bit of a break from chemotherapy side ef-fects, and then launch back into some of these other options if there weren't a clinical trial. I want to endorse what Dr. El-Khoueiry said earlier about always looking for clinical trials.
Dr. Shroff:
Anthony, we also just recently had a tumor agnostic approval for an ADC approach to HER2-targeting therapy. Do you mind telling us a little bit on your take the PanTumor DESTINY data, and whether that could be considered for somebody with HER2-positive disease in biliary cancers?
Dr. El-Khoueiry:
Oh, absolutely. It really expands the options of anti-HER2 therapy, right? So I think the way I think of it from a practical perspective, these are all small data sets, right? We're not talking about phase III level 1 evidence here. But generally what I would do in these situations, because HER2 tends to be a driver when it's 3+ or FISH amplified, is start with a direct anti-HER2 therapy that includes ei-ther the combos like trastuzumab, pertuzumab, or zanidatamab, which is a bispecific targeting two HER2 epitopes, and then potentially go to an ADC approach or vice versa. So the availability of the ADC data expands our options of targeting HER2, I think, in more than one line. That's how I think of it from a practical perspective.
Dr. Shroff:
Yeah, I think that's a great take. So just like you mentioned, clinical trials are always our choice. So this patient actually enrolled on the HERIZON-BTC-01 study, which is with zanidatamab, and had a fantastic response that actually remained on study for greater than 10 months. And then we moved on, and she's currently on FOLFOX.
So just when we think about the key clinical takeaways for an advanced cholangiocarcinoma in the setting of advanced biliary tract cancers, gemcitabine and cisplatin with an immunotherapy, either durvalumab or pembrolizumab is the standard of care, and is approved for these patients.
Like mentioned by Drs. El-Khoueiry and Azad, the comprehensive profiling part of this molecular profiling with next-generation sequencing should be done at the time of diagnosis because integra-tion of targeted therapy is now vital to the management of these patients with multiple FDA-approved drugs. For instance, in the HER2 targeting space, we do have drugs available now. And there are some things that are an NCCN Guidelines and some things that are FDA approved, and actually a couple more coming soon.
So this brings us to the end of this case. Please see the other segments for further discussion about the latest research in hepatobiliary cancer, or visit ascopost.com. Thank you to both of my panelists.
