Dr. Rachna Shroff:
Welcome to The ASCO Post Roundtable Series on Immunotherapy Strategies for Hepatobiliary Can-cers. I'm Dr. Rachna Shroff. I'm the Chief of Hematology/Oncology at the University of Arizona Can-cer Center, and I am delighted to have two of my friends and colleagues with us today as well to have this conversation.
Nilo, can you introduce yourself, please?
Dr. Nilo Azad:
Sure. My name's Nilo Azad, and I'm a GI medical oncologist at Johns Hopkins, focusing on early-phase drug development.
Dr. Shroff:
And Anthony.
Dr. Anthony El-Khoueiry:
And hi, I'm Anthony El-Khoueiry, also a GI oncologist at the University of Southern California, USC, in Los Angeles, and I do the same job as Nilo. I do GI and phase I early drug development. Thank you.
Dr. Shroff:
Today, we will be discussing the treatment and management of hepatobiliary cancer with three different patient case studies, and our first installment will focus on advanced unresectable hepa-tocellular carcinoma. So let's start with our case, and then we can jump in and have a conversation about how we approach these patients.
This is a 67-year-old male with a history of fatty liver disease, and he presents with abdominal and back pain. Past medical history includes diabetes, hypertension. He has no history of hepatitis. Labs show mild anemia, but an otherwise normal CBC, chemistries, and LFTs only have a mild elevation in AST and ALT with a normal bilirubin and albumin and a normal PT and PTT.
Alpha-fetoprotein is 47.3 and an MRI of the abdomen and CT of the spine is completed. You can see that there are multiple lesions noted in the liver that appear to have washout when you look at the triple phase, and then there are lesions noted along the spine, including one that's demarcated in the T-spine.
So the patient presents to oncology for further evaluation. The physical exam is within normal lim-its, and the patient has a good performance status with an ECOG PS of 1.
So I'll start with Dr. El-Khoueiry. This patient is sitting in your clinic, and where would you go from here? Do you start with a biopsy? Is there other workup that you think needs to be done to de-termine a diagnosis or to determine the next steps?
Dr. El-Khoueiry:
So obviously we are cued in here that this is likely hepatocellular carcinoma. But if we take it as a new patient presenting in clinic with no history or no evidence of cirrhosis and no chronic hepati-tis, it probably becomes imperative to do a biopsy since the AASLD imaging criteria for the diagno-sis of hepatocellular carcinoma depend on the right clinical context, meaning, patient has to have hepatitis or cirrhosis.
So in this case, which patient doesn't have either, I think a biopsy is important. Even sometimes the radiologist may say, "Well, the liver is a bit nodular, but there's no portal hypertension. It does enhance and wash out." Again, without the right clinical context, the sensitivity and the positive predictive value of these imaging criteria goes down.
We have had cases where there is an assumption that it's HCC and you biopsy and its cholangiocar-cinoma, for example. So point is that in this case, it would be standard of care to do a biopsy.
Dr. Shroff:
And Dr. Azad, I would imagine that you feel similar there, but is there any other workup that you think is necessary outside of a biopsy to determine next steps?
Dr. Azad:
I think that is how we would proceed here as well. Often at the same time, and I might be skipping ahead to how we are going to be thinking about first-line therapy, but we might choose to package that with an endoscopy as well, just to check and make sure that a patient doesn't already have variceal disease when they've got a little bit of this nodularity, but don't have diagnosed cirrhosis yet.
I was curious, Anthony. We discuss all of our new patients in a multidisciplinary liver clinic where we really have specialized liver-based radiologists. Not everywhere has the ability to do that, but we do talk about this patient, whose AFP is less than 50. But if we had a patient who had an AFP of 10,000, but with the same clinical context, those are the times where we sometimes decide to forgo biopsy if the rest of the tumor markers are normal. I'm curious how it's done at USC.
Dr. El-Khoueiry:
It's a great question, Nilo. I actually do worry about that because there have been reports of large tumors being non-HCC and producing AFP in the several thousands. So AFP officially has been re-moved from the diagnostic criteria by AASLD specifically for that reason. So we would still do a bi-opsy, and I've certainly had my fair share of cholangiocarcinomas with very high AFPs.
Dr. Shroff:
Yeah, I mean I think we actually have a very similar practice, and biopsy, by and large, in a situation like this would be where we go. And I do think your point about cholangiocarcinoma is well taken, especially in the setting of what could be a mixed HCC/cholangiocarcinoma. Sometimes the imag-ing tells us one thing, and then a biopsy demonstrates an adenocarcinoma as well, so it helps tease out how to approach these patients.
So if you're going to tack on the EGD and things like that, anything else, Dr. El-Khoueiry, that you would do? Let's say the biopsy confirms that we're dealing with a hepatocellular carcinoma. Any other workup necessary before you start to think through how to approach an advanced HCC?
Dr. El-Khoueiry:
Just for the record here, we were told an MRI abdomen and CT spine were done. So to complete staging, I think chest imaging would be appropriate. We know the patient has extrahepatic disease because of the spine lesion, but otherwise, at least on these images, it seems hard to determine the actual tumor burden in the liver.
Now in the setting of extrahepatic disease, it becomes less important, but if we did not have ex-trahepatic disease, you would really want the appropriate quality of imaging and usually it's a mul-tiphase, either MRI or CT, to determine tumor burden in the liver.
Dr. Shroff:
With the biopsy of hepatocellular carcinoma, to your point, knowing that there's extrahepatic dis-ease, Anthony, what would you do? Where would you start with treatment, and what helps you make determinations in that space?
Dr. El-Khoueiry:
We live in a time where we have actually multiple options for these patients. So it's the embar-rassment of riches where we have more than one option and without really scientific guidance on how to choose between the various options.
First, let me start with the two approved options that we have. So we have the combination of ate-zolizumab/bevacizumab, which was shown to be superior to sorafenib, is a commonly used first-line therapy. The other combination, known as the STRIDE regimen, includes one priming dose of the CTLA-4 antibody tremelimumab, along with durvalumab, and then continuation of durvalumab as single agent after that priming dose. That trial, the HIMALAYA trial, had shown the superiority of the tremelimumab/durvalumab combination to sorafenib as well. So both studies had shown an improvement in survival, both had superior response rates. The atezolizumab/bevacizumab study showed a PFS improvement, but the STRIDE regimen, so tremelimumab/durvalumab, did not have a difference in PFS.
What characterizes that, the STRIDE regimen, is a really long-term follow-up out to 36 months and even more, I believe, the latest data, still showing a nice separation of the curves with the tremelimumab/durvalumab being superior to sorafenib. So we have these two approved regimens.
Briefly, I'll mention that we also saw recent data at ASCO 2024 from CheckMate-9DW with the combination of nivolumab and ipilimumab vs sorafenib or lenvatinib (investigator’s choice), and this was a 1:1 randomization. Of note, this is the nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg reg-imen. The two are given together for four cycles and then you continue nivolumab alone.
Well, that's another positive study with a median OS amongst the highest seen around 23 months, and a response rate also. This is probably a record response rate of 36%. Again, giving more support to the idea that PD-1/CTLA-4 combinations are active in HCC. I would say, at a high level, the dif-ference here is that this involves multiple doses of CTLA-4 compared to the tremelimumab/durvalumab combination.
Then lastly, another trial that read out last year, CARES-310, which is the only positive trial that in-volves the combination of an anti–PD-1 with a TKI, which is rivoceranib with camrelizumab. This trial also compared the combination to sorafenib, again with a positive overall survival over 20 months, I think 22 months. Also, a response rate in the high 20s, low 30%, so very similar efficacy, I would say. You know, there are many limitations to doing cross-trial comparisons.
So if we go back to the two approved regimens, to answer your question, this patient really has no contraindication to bevacizumab, so could get atezolizumab/bevacizumab or could get tremelimumab/durvalumab. I think both are appropriate options for this patient.
Dr. Shroff:
Yeah, I think that's a really great description, an embarrassment of riches. I love that because we now have, like you mentioned, four different front-line studies that are positive, almost all being compared to sorafenib, with the exception of the CheckMate data that gave the option of a com-parison to lenvatinib.
Nilo, when you think about things like the landmark OS idea of looking at HIMALAYA with that 36-month OS separation of the curves, you do a lot of work in immunotherapy, how do those types of things factor in? I mean, obviously we have the real-world questions of varices, risks of bleeding, atezolizumab/bevacizumab vs STRIDE, and those are the two regimens we have available to us, but in the future we'll probably have some additional ones. So when you think about multiple doses of anti–CTLA-4, when you think about landmark OS, how do those things play a role in deciding what you do in the clinic?
Dr. Azad:
There's been such an evolution in how HCC has been treated over the course of the last decade. And I think it's been a really exciting series of trials, but also in ways where we can really tailor multiple positive regimens based on individual patient features. So now we have HCC is a patient population that can be very challenging. You can have very healthy HCC patients and you can have patients that have had many medical comorbidities. So now we've got regimens that we can really choose from that I think will allow us to more tailor regimens that still have activity.
I think 4 years ago, 3 years ago, we were really focused on the atezolizumab/bevacizumab combina-tion and then the STRIDE and the long-term follow-up. And I think this is the beauty of immuno-therapy is the tail of the curve because that's where we're trying to get patients. Median survivals that shift by a couple of months doesn't have that impact in terms of really altering the course and trajectory of patients' lives the way that the tail of the curves with these long follow-ups with sepa-rations do.
But I have to say that the new CheckMate study is really compelling, and I know that it's not an ap-proved indication yet, but multiple different features that really have meaningful clinical impact. It does have this high ipilimumab dose, which I think we're going to have to watch in the larger seg-ments of real-world patients that are getting treated with the 3-mg CTLA-4 dose. But between the response rates, the survival being where we've not seen it before, both in terms of median and that tail, I'm really excited by that data.
Dr. Shroff:
Yeah, I completely agree. I think it'll be interesting to see how that data evolves.
Moving on to this patient, this patient actually did not have a recent EGD and was started on STRIDE and at 3 months, the AFP had decreased to 12.4, imaging showed a nice response in the liver and spine and no new areas of involvement. Tolerability-wise, the patient had a grade 1 der-matitis on his trunk that was managed with some topical steroids and then continued on therapy for about 12 months and subsequently had progression.
So I'm just going to ask one final question because this is, of course, again a real-world scenario that I think we deal with. The patient continues to have a good performance status, remained Child-Pugh A, and what do you do next in the post-IO world? Obviously not clear data on what to do in the post-STRIDE world, but Anthony, what's your typical approach here?
Dr. El-Khoueiry:
The short answer, that outside of a clinical trial, which would still be my favorite approach in sec-ond line and beyond at this point, we actually go to one of the TKIs, and there are different schools of thoughts. Some folks like to kind of reset the clock and start with one of the first-line TKIs like lenvatinib or sorafenib. Others like to go to a more second-line TKI, like cabozantinib or regoraf-enib. It really does not matter. There's real-world evidence evolving that all of these have some activity in the second line and beyond.
You know, we're starting to see data come out for second-line studies post-IO. One of them that I presented at this ASCO 2024, which was the combination of pembrolizumab/regorafenib post-IO and there were two cohorts, one post–atezolizumab/bevacizumab cohort and one other cohort, which is post–any IO including single agent, and really the message from the trial at this point is that we did not see activity beyond what you would expect with a single-agent TKI in this trial. So at this point, outside of this study, continuation of anti–PD-1 therapy after the first line should only be done in the context of a clinical trial. Otherwise, we would switch to a TKI.
What's unknown and the big question mark here is are we going to start doing what we do in other diseases like pancreas? If we didn't use FOLFIRINOX in the first line, we'll use it in second. So if the patient had tremelimumab/durvalumab, are we going to use atezolizumab/bevacizumab in the sec-ond line? I know we tend to do this in oncology. My only caution again is we need the data for these types of approaches. So for now it would be TKI for me.
Dr. Shroff:
Great. Well, thank you. So just to kind of summarize what our key clinical takeaways are and where we stand currently, there are two options that are FDA-approved for hepatocellular carcinoma pa-tients with advanced disease and with Child-Pugh A cirrhosis. That includes the atezolizumabbevaci-zumab combination, as well as the STRIDE regimen, tremelimumab and durvalumab. But as Drs. El-Khoueiry and Azad mentioned, this is an evolving space with potentially other therapies coming down the pike.
The choice of regimen currently depends on comorbidities, safety, patient preference, and second line therapies in the post–bevacizumab/atezolizumab and STRIDE world are not clearly delineated. We do not have, like Dr. El-Khoueiry mentioned, clear evidence though, again, that's starting to evolve, but TKIs do remain options, especially as we gather more real-world evidence.
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.
