Dr. Ghassan Abou -Alfa:
Welcome to the ASCO Post Round Table series on updates in hepatobiliary cancer. I'm Ghassan Abou-Alfa from the Memorial Sloan Kettering Cancer Center in New York City. Joining me today are two of my colleagues. Dr. Shroff, please introduce yourself.
Dr. Rachna Shroff:
Hi. I'm Dr. Rachna Shroff from the University of Arizona Cancer Center. Thank you for having me.
Dr. Abou-Alfa:
Well, great seeing you. And Dr. Finn?
Dr. Richard Finn:
Hi there. Richard Finn, a Medical Oncologist at the Geffen School of Medicine at UCLA and the Jonsson Comprehensive Cancer Center. Good to be here.
Dr. Abou-Alfa:
Good to see you as well, Rich. And great to see you both. Today, we'll be discussing recent updates in hepatocellular carcinoma and biliary tract cancers and integrating these new developments into four patient case studies. Our fourth and final installment will focus on the treatment of stage IV intrahepatic cholangiocarcinoma. Dr. Shroff and Dr. Finn, we have a 60-year-old lady with no significant past medical history in evaluation for right upper quadrant pain and right shoulder pain. Imaging shows an evident liver mass with a concern for intrahepatic cholangiocarcinoma. CT scan of the chest and pelvis show evident three liver satellite lesions plus two peritoneal deposits. We have a mass in the liver with three satellite lesions plus two peritoneal deposits. A biopsy of the liver lesion showed clear adenocarcinoma. And the next-generation sequencing (to the credit of our surgeon who did that case), already looked into it and was expedited and showed an FGFR2 fusion. We'll start again with Dr. Shroff. What would you recommend for this patient? We have plenty of options. I'm going to name some for you. But of course, you can help me out if I'm missing anything else. Gemcitabine-cisplatin, gemcitabine-cisplatin-nab-paclitaxel, gemcitabine-cisplatin plus durvalumab or pemigatinib. Your thoughts?
Dr. Shroff:
In this patient with a stage IV proven metastatic cholangiocarcinoma, first of all kudos to them for getting the NGS done so quickly. I’m very impressed. Even though, we have identified a potentially actionable mutation, the standard of care in these patients really remains in having a chemotherapy backbone. Gemcitabine/cisplatin and durvalumab has really just recently been FDA approved with durvalumab based on the TOPAZ-1 data and as Dr. Finn mentioned previously, it is really going to be the new standard of care. This was a study that compared gemcitabine/cisplatin to gemcitabine/cisplatin plus durvalumab. The gemcitabine and cisplatin was continued for 6 months. And after 6 months, the durvalumab was continued as maintenance versus placebo maintenance. And with a hazard ratio of 0.8, there was a statistically significant improvement in median overall survival. To me, the median doesn't seem as impressive as what is the subsequent separation of the curves when you look at the Kaplan-Meier with the tail on the curve as we typically see with immunotherapy. I do think it's important to recognize that it's probably a subset of patients who benefit from the immunotherapy component. I think continued work and understanding biomarkers for identifying that response to immunotherapy is really going to be key. I think it's also important to recognize that the overall response rate and such with gemcitabine/cisplatin plus durvalumab is very similar to what we saw in ABC-02 with gemcitabine/cisplatin alone. It's not like there's a significant improvement in overall response per se. It's really the survival benefit that I think is driving this. In patients such as this where I don't necessarily think there's an urgent need for immediate response, I think gemcitabine/cisplatin plus durvalumab would be my choice. But again, if there's a reason that they could not have immunotherapy, gemcitabine/cisplatin alone of course is an option. And then, there is of course some phase II data to support gemcitabine/cisplatin and nab-paclitaxel as well.
Dr. Abou-Alfa:
Wonderful. Thank you so much, Dr. Shroff. These are really very important thoughts. And I'm going to go back to Dr. Finn with two questions. Number one, Richard, what Rachna just mentioned is very important about the tail of the curve and we have seen that separation of the curve not only in the TOPAZ-1 study that we're looking at with the gemcitabine/cisplatin plus durvalumab. But for example, we saw that many other or in all of the checkpoints for example durvalumab plus tremelimumab and we see the continued separation even up to 3 years, where now even one-third of the patients are still alive and doing very well on the durvalumab/tremelimumab. My question to you is can you please explain to our colleagues, what is the basic mechanism biologically: why this curve is not good at the median but it happened afterwards? What's the story there?
Dr. Finn:
Well, for one, gemcitabine/cisplatin is an active regimen, right? And then, the question is the general population getting a benefit from the addition of the immunotherapy or is it just a sub-population? I think that the median is separated suggests that there is a broad activity for this regimen, for this population of patients. But clearly, there's a subgroup that gets an extraordinary benefit. And keep in mind, in this study, patients only got the chemotherapy for 8 months. And then, they went on to receive durvalumab alone "as a maintenance type of regimen" that differs from some of the other phase III IO studies that are ongoing. But it suggests, and we see this, as you mentioned in many IO studies, we are raising the tail of the curve. And I think lung cancer is a great example where you saw a single agent IO, PD-1, then you had CTLA4 and that tail of the curve, the long-term survivors keep getting higher, a greater percentage. Hopefully we'll see that in biliary cancer. This is maybe the first step in that direction where we see, now out over 2-3 years or longer, a plateauing of the curve. And there is a group of patients who are having long-term survival and tolerating these drugs very well. And if we go back to our first course in this series in liver cancer, we're seeing that in frontline liver cancer as well with IO combination. We generally don't treat the tail of the curve. We need to treat the individual patient in front of us. But short of a biomarker or a clinical marker to tell us where this patient will lie on the curve, at this point I think a patient like this would get gemcitabine/cisplatin/durvalumab.
Dr. Abou-Alfa:
That's a great thought. Thank you so much, Dr. Finn. And I go back to Dr. Shroff. Because Dr. Shroff, you mentioned something very important. As you and I know, the TOPAZ-1 study limited the therapy of the chemotherapy to 6 months. And we probably both understand this was based on the ABC-02 study, because our colleagues in the UK will limit the chemotherapy to 6 months. And now, we're a little perplexed and I'm sure our colleagues are asking, "Shall I really stop the chemotherapy at the sixth month? Shall I continue the chemotherapy?" Tell us from your practice. Your thoughts?
Dr. Shroff:
I think this speaks to Dr. Finn's point about treating the individual patient sitting in front of you. I think at the end of 6 months, platinum in particular, you're starting to feel the toxicities from cisplatin for 6 months. And there's cumulative fatigue, there's potentially ototoxicity, nephrotoxicity, neurotoxicity. Most of my patients, even in the pre-durvalumab era, I considered either a maintenance approach or giving them a chemotherapy break, assuming we had adequate disease control. In someone like this, it would be a question of, do I continue gemcitabine alone with a durvalumab maintenance or just the durvalumab maintenance? I think historically in the US, our bias has been stopping something altogether makes us all nervous. And so, now that we have an option for maintenance with a durvalumab, perhaps we're going to be a little more comfortable. I think that also speaks to why I think the KEYNOTE-966 study is going to be really interesting since that continues. That's gemcitabine/cisplatin with pembrolizumab, but after 6 months continues gemcitabine with pembrolizumab and I think that will be helpful in helping us tease out this question of what to do with the maintenance component of this.
Dr. Abou-Alfa:
I totally agree. And if anything, we're all experimenting with this but, no doubt that I'm feeling the same thing. A little nerved up about stopping the therapy or the triplet of gemcitabine-cisplatin and the durvalumab in a patient who really got at best stable disease. But I might be ready to experiment if a patient really gets a response to stop the chemotherapy and continue only on the durvalumab. Because after all, as we all know, there's a cumulative side effect from the chemotherapy that can really be limiting to patients. And I was so amazed actually, and I'm so happy that on the combination of gemcitabine-cisplatin-durvalumab, I just got the first CR on the therapy. This can happen as well. Without a doubt that it's a great advent in regard to therapy and we're very happy to see it. Back to you, Dr. Finn. Dr. Shroff mentioned and to give her credit, this is her beautiful and amazing work. The triplet combination of gemcitabine-cisplatin-nab-paclitaxel. And respectfully, she said this is in a phase II study. She's also, as we know, the chair of a phase III clinical trial, the SWOG study 1815. Tell us about that triplet. What do we know about it? Use it, don’t use it? Your thoughts?
Dr. Finn:
Dr. Shroff led this study, which was published in JAMA Oncology back in 2019, and which again took the gemcitabine/cisplatin backbone. And there's been efforts over years and years to build on gemcitabine/cisplatin without much success until the TOPAZ study. But this added an active set of toxic nab-paclitaxel to gemcitabine/cisplatin and showed a very provocative disease control rate over 80% with a partial response rate of 45%. Keeping in mind, this is a three-arm phase I/II study, 60 patients, objective response 45%, which clearly is much better than we've seen with gemcitabine/cisplatin historically or for that matter in TOPAZ-1 with the addition of durvalumab. The caveat though is again three-arm phase II studies actually can fool us sometimes and that is why we really are waiting for the phase III SWOG study to tell us how this performs in a well-controlled environment. But certainly, an option for patients, if you need that response, as Dr. Shroff alluded to. Someone who has impending liver failure, is on a cliff and you want to give them a regimen that probably has a good response rate to pull them off that edge. Potentially, that would be a place for this even though we have the phase III data from TOPAZ. But again, we need confirmation of these results.
Dr. Abou-Alfa:
Totally agree. And if anything, Dr. Shroff said it beautifully well. I do remember actually, Rachna, you might recall. I do recall actually our first meeting when you came to us at ASCO and you told us about your concept to which, look where you are today. If anything, we congratulate you. You really were able to bring a concept from a seed all the way to phase III clinical trials. At the same time, I like the way you stated that after all, this is within the context of a phase II study, because you're right. Actually, as you know, I helped contribute a manuscript in that regard, which is publishing in cancer regard to that equipoise. When do we decide and when's the right timing to decide on that therapy? But I like that we are hearing from you that after all, hopefully this study will be positive. Of course, at that time, we're going to cross another bridge, which is of course the triplet of the chemotherapy was nab-paclitaxel and the TOPAZ. But I'm sure we're going to have another event to discuss all of that. But with this said, there's one more question that we need to discuss with our colleagues. If we remember and I agree with you and please: this is an important message from Dr. Shroff, from Dr. Finn, and from myself. Please, please, please make sure that next-generation sequencing on the patient is happening as early as you can. I actually jokingly say while the patient's walking to the clinic, you should already be working on the next-generation sequencing. Now, we have a patient with FGFR2 fusion. We elected to give the gemcitabine-cisplatin-durvalumab. And of course, the question is what about that FGFR2 fusion, which we know is a critical genetic alteration in regard to development of that cancer. What are you going to do about it, Rachna?
Dr. Shroff:
Well, obviously it is wonderful when we are able to find an FGFR2 fusion. We see it in about 10% to 15%. And we know it's an early oncogenic driver. When we identify it, we absolutely know that we have potential drugs and therapies available to us to consider. In this patient who we started on a chemotherapy approach, to me, when and if there is progression, there would be consideration for use of an FGFR inhibitor. We have FDA approval of infigratinib and pemigatinib and we believe pending approval of futibatinib. We will have three FGFR inhibitors available to be considered in the second-line and beyond setting. The data from FIGHT-202, which was the first to lead to FDA approval, which is pemigatinib demonstrates overall response rates in the 35% and perhaps even higher 30% range. Infigratinib is a little bit lower at 23%. And then, for futibatinib, the most updated data is in the 40% range, 45% or so. Again, apples and oranges. I'm not saying one is better than the other. But I think we have three drugs that we could consider in this patient at the time of progression. And I think there absolutely are therapies that need to be, I mean, A, recognized if we can give them, so that's why the NGS at the time of diagnosis is critical. And B, I think the other thing we're trying to determine is, if there is a role for trying to figure out how to sequence these drugs and consider use of all FGFR inhibitors available to these patients?
Dr. Abou-Alfa:
Thanks so much, Dr. Shroff. Actually, you bring two important points. Number one is, yes to the best of our understanding the gemcitabine-cisplatin plus durvalumab in TOPAZ-1 study was really the mover and shaker, because it really pushed all the targeted therapies to the second-line where already they are approved anyway. And it has weakened a little bit, the potential for the complete accrual of the first-line studies that is looking into pemigatinib and infigratinib and others. However, we'll see maybe patients who are not eligible for the checkpoint inhibitors because of autoimmune disease or what have we. They might still be eligible. Time will tell. But I think at least, they have a robust presence in regard to second-line therapy. But Dr. Shroff, you bring up a very important point, which I would like to ask Dr. Finn about. No doubt that patients get resistance to those therapies. And in other words, you give pemigatinib after a while you might lose the response. And the question is, what's going on there? Shall we try another anti-FGFR therapy? If we were on pemigatinib, we'll go to infigratinib? How do you practice that?
Dr. Finn:
This is a challenging space. I mean, the good news for this patient is they do have an actual mutation and there are others to be looked for. IDH, for example, BRAF, where we have other targeted regimens, because otherwise the patient's looking at additional chemotherapy. And in this patient who's progressing on an FGFR inhibitor, again, we're faced with the idea of going back to chemotherapy FOLFOX or potentially nab= liposomal irinotecan and 5-FU, things that probably have some activity but certainly carry other toxicities. And the question is, can we take further advantage of this FGFR alteration? And there is evolving data that some of the FGFR inhibitors could have activity in sequence. I think certainly as newer drugs are approved and going through development in a relatively small population of patients, it is not unreasonable to offer a patient another FGFR inhibitor in hopes that we could get at least some stable disease. I'm not saying we'll get a robust response, but at least some period of stable disease. These drugs do have side effects, right? Even though they are targeted agents and not chemotherapy. There are things that can become troublesome for patients. The skin and nail changes, for example, can be uncomfortable for patients. Watching phosphate and things like that.
Dr. Abou-Alfa:
I totally agree and thanks so much for your input in that regard. And if anything, you're bringing up a very important point, which we know there's plenty of data already available in regard to the resistance to the anti-FGFR. And we know that yes, certain alterations in regard to some of the alterations, invite variations or variants that we are not sure yet if the therapy will benefit or not. And interestingly, what we really don't understand yet is whether this is happening by random or is it really a pre-planned seed in regard to how things evolve from one alteration to the other? Ironically, science tells us, as Einstein said, "God doesn't play dice with nature." And maybe, they are deterministic, but this is yet to be proven. You see, ultimately, interestingly, can we alter the different therapies? And ironically, can we go back to let's say pemigatinib at some point in time that's yet to be told and really see where this might take us. With this said, however, this is a great, great discussion. And at least, for our colleagues who are listening to us this time, we have definitely very firm answers for you. First-line therapy for biliary tract cancer is no question gemcitabine plus cisplatin plus durvalumab. Please, please next-generation sequencing, as you heard from all three of us should be done promptly and as early as possible. The duration of the gemcitabine plus cisplatin in case of response on the gemcitabine-cisplatin-durvalumab could be limited to 6 months. And we leave it up to your assessment here as we heard sometimes with the response, now we might stop the chemotherapy. And number four, targeted therapy is so far allotted in second and third-line treatment. And of course, it is a very valuable therapy and that's why the NGS should be happening as soon as possible. This brings us to the end of this case. Please see the other segments for further discussion about the latest data in hepatobiliary cancer or visit ascopost.com.
