Hepatocellular Carcinoma — Ghassan Abou-Alfa, MD, MBA

PROF ABOU-ALFA: Hello everybody. This is Ghassan Abou-Alfa from Memorial Sloan Kettering Cancer Center. It’s a great delight to join in the Research To Practice Year in Review webinar. We all look forward to that, and this year I’m entrusted on giving an update on hepatocellular carcinoma.

So I’ll start by an important paper from last year, 2022, by Dr Maria Reig from the BCLC group in Barcelona. Historically, if you recall, the Barcelona Group has been keen on developing some staging system for liver cancer, but not only staging but also with the applied therapy. And there was a lot of kind of back and forth in regard to that staging system because on the one hand everybody thought that it does very well when it kind of looked at in early-stage disease, that’s why we always say BCLC does very well to the extreme left, in regard to small disease, good liver function; take it out. Small disease, bad liver function; transplant.

And then things become a little bit more kind of unclear when it comes to the intermediate stage, locally advanced disease, as well as metastatic disease. So in this effort Dr Reig for the first time delineated further details in regard to the locally advanced disease.

And as you can see now in the BCLC-B, which is right in the center of the slide in front of you, you’ll see like a tri-fork is coming down, where you can tell that based on the extent of disease, based on the ability to really bring a patient back to transplant, or still apply chemoembolization. But more importantly, yes, in some patients with locally advanced disease maybe systemic therapy will fare better than the local therapy. And it’s nice to see this kind of like multidisciplinary approach evolving and really fitting in very well in the BCLC criteria.

I strongly encourage you to look at that article because it will be very good guidance not only for staging purposes but also for our ability to really find what’s the right therapy for every patient.

From there on it’s going to be a little bit of a potpourri today. I have like collected a lot of information, and it’s actually amazing that we have so much going on in regard to HCC. Usually, historically, 20 years ago, it would be probably 1 or 2 slides, and now look how much we have.

So if anything we’re delighted to see an update on the IMbrave150. This is from Dr A L Cheng and colleagues, and you can see after 1 year still this study is holding very robustly. As you can see the atezolizumab plus bevacizumab still showing an impressive improvement in survival compared to sorafenib.

And at the same time we can see that the progression-free survival again is showing some separation. Not necessarily to the extent we would like it to, but it’s not that big of a deal because as we all know, the impact of the checkpoint inhibitors is mainly driven by overall survival, and especially more into time, and that’s why to see that after 1 year, 12 months, we still have — the analysis is still holding and advantage for the atezolizumab plus bevacizumab is definitely delightful, and we know that this is therapy that works.

While we’re on the IMbrave, yes, there is a 050, or the IMbrave050. This one, as you can see, really dependent on a press release, but it’s an exciting possibility that just was reported at the beginning of the year, and it shows that the Phase III trial looking at atezolizumab plus bevacizumab as an adjuvant therapy for patients with HCC at high risk of recurrence by the size and number of cancerous lesions showed, according to the outcome, even though overall survival was immature at the time of interim, but follow-up in the next analysis will probably be showing us a further update. If anything, these are kind of coming to — when we hear a press release we know it’s going to come to fruition in no time. So we all look very much forward to really see the exact details of that study. And as you can see here in the press release, yes, they are talking to the FDA, they are talking to the EMA, which tells us that hopefully things are going in the right direction.

That’s going to be a great awakening for us to look into the first-time use of checkpoint inhibitors as adjuvant therapy in HCC. It has mechanistically and biologically a very important impact because we are trying to imply here not anymore just trying to kill disease per se but actually we’re trying to set up a stage for the immune microenvironment to really not enhance any further growth or recurrence of the cancer. So we all very much look forward to see the data, and hopefully at our next meeting we’ll be able to tell things.

DR LOVE: So if I could just ask. I know of course we need to see the data, as you say. But just to speculate a little bit, I actually was thinking a little bit about when you presented the BCLC classification you were mentioning that oncologists generally don’t deal that much with the left side, but it looks like they’re going to be very much involved with the left side. Anything that — of course we want to see the data, but anything, any issues that you see right up front that might be informative to medical oncologists? I assume these are not transplant patients, correct?

PROF ABOU-ALFA: Correct.

DR LOVE: So do you think it’s going to change the way localized disease is going to be managed? What are the kinds — do you think oncologists are seeing these patients now? Are there a lot of patients in the adjuvant situation? Assuming this is a positive trial that people want to act on, how do you see it actually getting actualized in practice? Are these cases typically presented in interdisciplinary meetings that oncologists attend? How do you see this being worked into clinical practice, particularly with community-based oncologists?

PROF ABOU-ALFA: Well, the advent of adjuvant therapy, especially in the checkpoint inhibitor setting, can be really perceived from 2 directions. On one hand, from the medical oncologist’s standpoint, exactly as you said, Dr Love, it means that yes, we’re going to have a seat at the table because no doubt that our involvement, our engagement will be very valuable for that purpose.

However, the question is how many patients are those. And that’s really the other part of the discussion because interestingly surgery in certain areas in the world is perceived as being like the go-to reference point in regard to therapy. For example, in Hong Kong this is really what mostly they do. And to be fair, because maybe the disease is cirrhotic because hepatitis B does cause cirrhosis and can lead to HCC, and that’s why there is a quite a bit of robust surgery interventions.

On the other hand, there is always the acclaim for more transplants. And exactly your point is well noted, is this appropriate for people with transplant. No, it’s not, because we don’t like to do checkpoint inhibitors in patients who are transplanted, definitely not a good idea. And please don’t do that because it can really, god forbid, hurt or kill people.

But on the other hand, will this change the perception in regard to surgery versus transplant, i.e. no doubt that getting to a surgical intervention is way faster than waiting for a transplant, and as such with the advent of adjuvant therapy could it be that it would be more inviting for transplant — for surgical intervention. Of course. It all depends on the data.

But you’re right, I can definitely envision already there will be a lot of mobilization in regard to how we understand the disease and how it will be perceived in regard to what are the curative intent that are available and how they will apply ultimately with the advent of adjuvant therapy.

DR LOVE: Yeah, definitely the impact is going to be important. I mean I always — usually when I see press releases I assume it’s not going to be some kind of homerun or really gigantic hazard rate, but it could surprise us. Maybe it will be a very profound effect, even if it’s only progression-free survival. And maybe that will affect how people approach primary therapy.

Any other thoughts about how this is going to play out in clinical practice?

PROF ABOU-ALFA: Yeah, no. Actually 2 points here. Number 1, I 100% agree with you, and this is an important message for all of our dear colleagues. Press releases are press releases, they are like media. They are not really a medical report, and we should not depend on those for making conclusions. Because you’re right, we don’t know really what’s there. And there’s intent for that. It’s not like really we’re saying right or wrong, but us as medical physicians we have to make sure we understand and look for data and analyze the data to see what it implies per se.

Now interesting you bring in like how this is going to play a role. Of course it’s got a major role because number 1, it depends on like how much of an impact it has. If it was really a homerun that’s going to really change a lot of things in regard to the perception of therapy. And as such you can envision already that new adjuvant approach will be probably playing a role over here. And as such it becomes really a very much checkpoint inhibitor-driven disease per se.

On the other hand, if it’s really subtle it might kind of probably invite us to say maybe after all this is not really the right approach per se. I think we just have to wait and see. Biologically it does make sense. The immune microenvironment is definitely very much driving this cancer, and I would say it will have implications way beyond that because, for example, in the Western Hemisphere when we resect, our colleagues in surgery will resect the tumor, they will just circle around it, make sure we have a negative margin, and they take it out.

Interestingly, in Japan they don’t do it that way. They will actually cut the whole segment in the liver because they think that this is a segment that’s infected with the tumor. And you can imagine the philosophy of the disease can really be delineated further by what the results are going to be in that regard.

Yeah, go ahead.

DR LOVE: I was just going to say, are there any efforts to actually use neoadjuvant systemic therapy, for example in Japan, to make people resectable?

PROF ABOU-ALFA: Not yet, and we have to really make sure that we pinpoint here a very important differentiation. Making a patient resectable it means we’re not doing it neoadjuvantly, we’re doing conversion therapy, changing nonresectable to resectable. We are way too far from this.

On the other hand, making a tumor — still it’s resectable, but we’re making sure it has less recurrence is what neoadjuvant is, to be fair we will not jump to that next step until we see the adjuvant therapy. So I think after that, and that’s why we said within the impact of IMbrave050, we’ll probably see more and more of the neoadjuvant approaches coming along.

DR LOVE: Okay. Please continue.

PROF ABOU-ALFA: Of course. With this, what is going on? Of course we’re delighted, and we’re proud of the effort that got to the HIMALAYA, which is looking into durvalumab plus tremelimumab versus sorafenib. This study showed improvement in outcome, 16.4 months compared to 13.7 for sorafenib. This study also looked at durvalumab as single agent compared to sorafenib but for noninferiority. Totally different design over here, 16.56 versus 13.7.

The study is positive clinically and statistically. And always, always people ask the question, they say wait a minute, why should I really use treme if durva is already giving me good results per se. Well yes and no, because as we see, the treme is given as only 1 dose, 1 dose only in the patient’s lifetime, that’s quite impressive, because you’re priming the anti-CTLA4 activity to let the durva work better as the anti-PD-L1.

And as you can see, the translation to that is that on the combination of what you call in blue, the STRIDE, which is durva/treme, you can see that about one third of patients were alive at 3 years. We’ve never seen those numbers.

Now the second question that you are asked is wait a minute, are you trying to convince us about this 16.43 months. Already I heard about something called IMbrave150. It was atezo/bev, for 19.2 months. Well, here is an important basic biology, basic science, and basic oncology question. We can’t compare if the demographics are not the same. And if you look very carefully you’ll notice that in the IMbrave150 about 50-plus-percent of the patients were actually hepatitis B, while here in the HIMALAYA it was only about 30%. And we know very well that in all studies, regardless where they are, patients with hepatitis B will fare best in regard to checkpoint inhibitors, followed by hep C, followed by the nonviral. Everybody will benefit, but not to the same magnitude.

What’s important is the study done in the UK recently called the Real-AB study, atezolizumab/bevacizumab study. They found actually median survival for the atezolizumab/bevacizumab was 15.73. Interestingly, if you look at the data the number of patients with hepatitis B were way less than in the IMbrave150. If you were to ask me what’s going on here, I think they’re all okay. I mean atezo/bev, durva/treme are all equal. It all depends. If you were to do the HIMALAYA again in hepatitis B patients only, guess what, you’re going to get a very higher median survival. If you repeat the IMbrave150 in hepatitis B patients it's going to be way lower, et cetera. So I think all of this is just the results are all beneficial therapies and the choices can really be brought in in regard to many other variables.

DR LOVE: What about tolerability and toxicity? Of course you have the issue of the anti-CTLA4, but as you said, it’s only 1 dose. It looks like the incidence of complications is much less than ipi/nivo, for example. How would you indirectly compare, including your own personal experience? You probably have as much experience as anybody with this STRIDE regimen. How would you compare tolerability indirectly, atezo/bev versus durva/treme?

PROF ABOU-ALFA: Well, I would say, Neil, this is a highly tolerable regimen. You recall we spoke about that at the time we presented it back in 2022 at GI ASCO, and a lot of hands-on experience so far, and it’s really a no sweat regimen. Imagine, you give the 2 therapies together, and then you don’t see the patient except once every month for the durvalumab. And thankfully the adverse events have been super minimal. The interventions really that you need for that purpose are really very minimal as well.

So I would say for convenience, practicality, the durva/treme has been really pretty straightforward. And also on top of that, to talk about toxicity, remember we don’t have a concern for any bleeding over here, so the use of any endoscopies to rule out varices is not needed. Actually we didn’t even do it on this study. There was no bleeding reported from that varices study — varices from that trial as well.

So all in all durva/treme is very straightforward. Actually the joke is that we have to convince patients to come every month for their therapy because they’re doing great.

DR LOVE: Awesome. Please continue.

PROF ABOU-ALFA: Great. So to jump on, and this is very important, now we have a bunch of data that jump onto us from the ESMO in Paris last September, among which is the tislelizumab, which is again, one more time, an anti-PD-1 therapy which was looked at as a single agent compared to sorafenib. And as you can see over here, there was noninferiority. It was 15.9 months, for the tislelizumab versus sorafenib 14.1 months.

Interestingly, it shows exactly what already we know, that a single-agent anti-PD-1/anti-PD-L1 will not fare any better or any different from tyrosine kinase inhibitors. And this study proved it 1 more time that this is really correct as well.

What will be the role of tislelizumab in our kind of regimen? We’re not sure. Actually there’s a certain particularity, and I here disclosed that I was involved and shared efforts of the clinical trial, but nonetheless those variations in regard to the enhancement of the activity did not necessarily fare any different in regard to outcome. I think still we are in the same realm of anti-PD-1/anti-PD-L1, good outcome, but not necessarily different from any other. But it will be nice to see if this will be providing more accessibility to therapy worldwide as we need more interventions that are necessary.

DR LOVE: I’m kind of curious, right now in what situations, if any, will you use first-line single-agent IO, and which agent.

PROF ABOU-ALFA: Yeah. I single-agent IO as a first-line therapy, it’s kind of like — the best I can say is like a certain relative discomfort was doing the tremelimumab in combination with the durvalumab. And as you said already, Neil, the diarrhea has not been an issue at all in regard to the 1 dose of tremelimumab, contrary to what we have seen with ipi. So I would say less of those except if accessibility issue or time is of relative concern. But otherwise durva/treme is a totally appropriate option.

So with this said, this is a very important awakening for us. This is now published, I give great credit to our dear colleague, Dr Katie Kelley, that looked into the combination of cabozantinib, the anti-cMET/anti-AXL/anti-VEGF that we know, plus atezolizumab versus sorafenib. That study, interestingly, was negative. As you can see, it has no improvement in regard to the PFS and no improvement in survival as well.

Now 2 important thoughts about that. Number 1, mechanistically we know very well that the cMET is kind of like a pathway which is almost a little bit to the extreme of the cellular pathway from the cell of the brain to the nucleus. As such, probably the intervention of the cabozantinib in regard to the cell immunity cycle is not necessarily there.

And number 2 is my personal opinion is the primary point being the PFS was not necessarily the right one. This should have been an OS study, not necessarily that, but we’re seeing the results of the OS, which was negative, which goes back to the biology per se. And the reason I say that is because these tumors, they get primed by the immune therapy. It takes a while until they get the effect, and that’s why the OS will kind of like over time will show the effect.

Interestingly, what we heard and learned about the chemotherapeutic intervention with the median survival as being our reference point, yes, it makes sense. You can have all the cells, you kill — it implies that half the patients are alive. That’s totally fine. But interestingly when it comes to checkpoint inhibitors it’s not necessarily that. It actually takes a while until you prime and make sure the effect of the checkpoint inhibitor. And that’s why I kind of jokingly always way we’re using an old dictionary for a new language. And this is really what’s important to remember about the cabozantinib/atezolizumab.

DR LOVE: So I’m not exactly — are you saying this is a negative study?

PROF ABOU-ALFA: Yeah. This was a negative study, and as we know it did not carry any further. And as we can see here, the survival was negative, and the PFS was subtle difference. You can see hazard ratio was 0.63, but not enough to really prove that there was a benefit over here. The one that we were aspiring for got to other combination of the checkpoint inhibitors plus TKIs.

So to carry on, and again, as we said, the potpourri. This is another negative study. This came as a big surprise, the LEAP-002 study. Great credit to our dear colleague Richard Finn for presenting this at the ESMO in Paris last September, a combination of lenvatinib plus pembrolizumab compared to lenvatinib plus placebo, and it was negative. As you can see here, the median survival for pembrolizumab plus lenvatinib was 21.2 months. Shockingly and surprisingly the median survival for lenvatinib plus placebo was 19 months.

Now here there are a lot of thoughts, and to be fair we don’t really have yet all the data because this is still in the setting of an abstract form. There’s way more details to kind of follow, even though it was reported at the meeting that about a quarter of patients in the lenvatinib plus placebo did get as second line checkpoint inhibitors. On the other hand, we know that the FGF might have value in regard to being a driver for the checkpoint inhibitors, and interestingly would it work better in sequence rather than in combination? We’re not sure yet.

And as such, we kind of like always reflect on that study by saying this is the most positive negative study ever because if anything it was a negative study in regard to outcome, but on the other hand it was really showing a quite positive outcome of the lenvatinib as 19.0 months, which is way higher than we’re seeing with other TKIs, including lenvatinib itself.

So this is food for thought. We have to wait until more data comes out so we can understand better what it means per se.

And of course it will probably make us revisit if sequence or combination is really the right way to go. This is like really things that we are really — did not really vet out first. Everyone wants to be in the front seat of the bus. All of those studies do look into combination therapy as first-line therapy, but is it biologically the right thing to do or not? We’re not really sure, so we have to wait for more data in that regard.

This is relatively new, and this is actually looking into the atezolizumab plus bevacizumab versus lenvatinib or sorafenib, that looks at the propensity score matching in a quasi-experimental way to really match the patients that are — with similar characteristics into the treatment per se. And you can see over here clearly that always the outcome of the atezolizumab plus bevacizumab really did not necessarily show an improvement per se because you see lenvatinib stood out most of the time. This is again, one more time, a good opportunity for us to really reflect further on the issue of the sequencing of therapy rather than the combination per se. This is still something that we really don’t have full hands on, but it definitely gives an invitation to carry on to what I just mentioned a second ago.

Now this is one that is in regard to the Child-Pugh score. And over here nice work that, again, I was a senior author on with Dr Khoueiry, looking into cabozantinib in patients with Child-Pugh. And you can see very important here that yes, patients did do well on that therapy, 8.5 months compared to placebo 3.8. And more importantly you can see that the Child-Pugh was not only B7, which usually is kind of like where we think it’s like an A6, as you can see we had an appropriate number of patients with B8 and B9. And if anything, it’s an invitation that after all tyrosine kinase inhibitors probably will fare well in regard to patients with Child-Pugh B.

I think the most robust data still comes from sorafenib. That was studied extensively beforehand as part of an Alliance study, where we showed that actually a dose adjustment of the dosing based on albumin/bilirubin level can be beneficial for adjustment of the therapy. And here cabozantinib is at least suggesting something of that same nature that could be visited further.

This is becoming very important the Child-Pugh B story, and maybe we’re showing cabozantinib data, but of course even our comfort zone in regard to using checkpoint inhibitors in regard to Child-Pugh B is evolving more towards better and better. And I would say I hope that we’ll have at least a safety assessment clinical trial to really show us that yes it’s safe or any adjustment that needs to be done in that regard.

One more effort that again I was heavily involved in regard to the cabozantinib and the quality of life. This was reported relatively newly, as well, and you can see that quality of life is dependent on many dimensions, among the most critical ones is mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. It’s the very important 5 components that you can see over here, and thankfully the cabozantinib no doubt that maybe there was a teeny dip in the beginning in regard to the benefit, but ultimately everybody did fare better on this therapy per se.

And this is very important to relay to our patients, that after all any intervention is better than no intervention nowadays because we have seen that besides some side effects that ultimately can be adjusted for or be tolerated will probably be a benefit for the patients, like in the cabozantinib over here.

So again, to go back to the checkpoint inhibitors, and as I said, this is a potpourri of things, but this is an interesting arm of the pembrolizumab, but this time it’s in Asia. And remember in Asia what you have. We have patients with hepatitis B. And over here we can see that there was a clear improvement in outcome. We can see clearly that here the hazard ratio is in favor of the pembrolizumab, and if anything it tells us 1 more time at least that a checkpoint inhibitor in patients with hepatitis B will fare very well compared to the patients without hepatitis B.

Actually there was a different iteration of that same data here. This time it was presented by Professor Qin from Nanjing, but there has been actually looked into this part of the study of pembrolizumab versus placebo in second line. Also it has been looked separately in this trial from Asia.

Now to go back to the discussion that we spoke about a second ago in regard to the ipi, this is, if you recall from the CD40 study, like a very robust clinical trial that really went on in multiple variables. We can see over here that a 5-year follow-up of the nivo 1 mg/kg plus ipi 3 mg/kg given every 3 weeks for 4 doses followed by nivo as single agent every other week is continuing to show that the nivo/ipi — nivo 1, ipi 3 arm, which you can see on top in the light red, is continuing to fare very well. This is of course within the context of being a Phase II study. We cannot conclude more than that. But of course we are all waiting for the Phase III clinical trial that will tell us if really the nivo 1, ipi 3 will remain as an option of therapy which at the moment only has the conditional approval in second line, awaiting — because the CD40 was in second line, waiting for the Phase III clinical trial in first line. So we just have to wait and see.

But again, as Dr Love mentioned, maybe the ipi 3 times 4 has been rather not an easy walk in the park compared to the treme that we have seen without necessarily that much of adverse events.

Quite exciting continued information here. And now we’re really bringing another perspective here in regard to the nivo/ipi, but this time with the cabozantinib onboard as well. So nivo/cabozantinib plus/minus ipi. This data was reported very recently by Dr Thomas Yau and colleagues from the CD40 study. This was in arm — I think called Arm 7 or Arm 9 on this study.

And you can see clearly over here that the nivo/ipi plus the cabo rather fared very well in regard to the progression-free survival. In regard to OS not that much, but again, within the context of Phase III clinical trial at least as an invitation among many others that were seen that looked into a combination of double checkpoint inhibitors plus a TKI, and we will see where this is going to fare ultimately, once hopefully we see the nivo/ipi study results per se.

So as you can see, and not to confuse everybody, this is becoming way too complex of different potpourri of different options for therapy, but I think we have to stick to the data. More in regard to first line the options remain, and to remind everybody the atezo/bev, durva/treme, and sorafenib or lenvatinib as single agent therapy. That’s pretty much it so far.

However, there’s also data on the camrelizumab plus rivoceranib versus sorafenib, a study that was done in China. Again, Professor Qin presented that at ESMO in Paris last September. Positive study. Look at the median survival, 22.1 months compared to 15.2 for sorafenib. Why is that? Because again, one more time, remember, patients have hep B. Actually in that study it was about 70% of the patients were hep B and still with great positive results.

I would not be surprised that this combination will kind of push forward, and we might see even some receptiveness to really consider it in the Western Hemisphere. We just have to wait and see how it settles in regard to the final paper. But that’s quite interesting and very valuable different combination of therapy of an anti-VEGF plus anti-PD-1.

Again, one more time, after we spoke about all of those studies I would like to really revisit one more time the following. After all we were all excited, great results, great data, but who has access. And so in an effort that we did that was an important part of the AORTIC meeting back in Senegal in 2021 we actually interviewed 500 physicians, mostly from Africa, where by the way it has the highest incidence of liver cancer in the world, and guess what? In North and South Africa were the 2 highest GDP, or being Egypt and South Africa, and east/west, where you have some of the second highest GDP, including Nigeria and Ghana, and Tanzania on the east, and then central, which is mostly the central countries, including Chad, Cameroon, and Mali.

As you can see that sadly so far even in the highest GDP 84% of the physicians only have access to sorafenib. That’s it. And as such this is obligation on our part. We are excited. These are very expensive efforts. They are very valuable efforts, but can we really claim one day that we are reaching out to everybody and present those options of therapy. That’s really where the success will be, rather than confining it only to the patient that has access, which ironically will be the limited number of patients compared to what’s really the high preponderance and high incidence of the disease in other parts of Asia, especially in sub-Saharan and also in Egypt and to Southeast Asia per se.

I already spoke about that, but just to bring it in slide format and to reiterate it, after all atezo/bev is still positive study but our real-world data is 15.74 months, not that dissimilar from the 16.43 of the durva/treme, and if anything it becomes more of a convenience for any of you in regard to use one or the other. As Dr Love asked, like yes of course, the atezo/bev is a great positive result, no question that probably 16 months all of them.

But endoscopy is critical. Make sure you do the endoscopy. Don’t really say okay, I don’t think the patient has varices. Please, please make sure you do an endoscopy. And on the other hand the durva/treme does not need an endoscopy, and the convenience of once-a-month therapy.

And lastly I will just bring in a clinical trial only because really again to think the same way we look to the adjuvant therapy and local therapy, yes, can we combine those therapies together? Yes, we can. And this is a clinical trial that we proudly are leading all over the world, EMERALD-3, looking this time into chemoembolization versus chemoembolization plus durva/treme versus chemoembolization versus — plus durva/treme and lenvatinib. TKI, checkpoint inhibitors, and local therapy versus checkpoint inhibitors plus local therapy versus checkpoint inhibitors.

As you can see, we’re obligated to do all of this. This is an important one not because we just like to add things together, because biologically the lymphocyte/neutrophil ratio will be affected so much by the embolization, and no question the immune microenvironment will probably be enhanced to permit probably some value for the use of the checkpoint inhibitors.

So I warned everybody it’s a potpourri of details, but it’s quite exciting there is that much happening in 1 year in HCC, and this is only a snippet of what has been going on, but I pass it back to the chair. Thank you.

DR LOVE: So can I just ask about that last study. Am I correct in saying it’s durva/treme/lenvatinib in 1 arm?

PROF ABOU-ALFA: Correct.

DR LOVE: And I assume there’s already safety data for that.

PROF ABOU-ALFA: That’s very true. Actually there is already a good read on all of this, and it’s not an issue at all. So we’re happy with that combination, yes.

DR LOVE: It’s just interesting to think about adding lenvatinib into durva/treme. Are there like other trials looking at that triplet?

PROF ABOU-ALFA: Not that I’m aware of, but I know that has been really a visit of the component by many different combinations per se because at the moment you have a Phase II study that looked into the combination in regard to the triplet, and no doubt that we’re going to see more and more of those going on because after all it seems that having a TKI and specifically an anti-VEGF could have a lot of value in regard to the triplet combination.

Biliary Tract Cancers — Richard S Finn, MD

DR FINN: I’m Dr Richard Finn from the Geffen School of Medicine, where I’m a Professor of Medicine in the Division of Hematology/Oncology and direct the Single Transduction and Therapeutics Program at the Jonsson Comprehensive Cancer Center.

I’d like to thank Dr Love and Research To Practice for the opportunity to discuss with you the 2023 Year in Review in biliary cancers. And this has been a very exciting year, and I should say past few years, as we gain more agents to treat this very difficult disease.

So as an overview to my presentation I’ve broken it up into these 3 themes. I want to talk first about immuno-oncology agents. PD-1/PD-L1 agents are now FDA approved, and we have 2 Phase III studies, one of them presented just in the past 2, 3 days at AACR, demonstrating that the use of front-line IO in combination with standard chemotherapy, gemcitabine and cisplatin, improves overall survival, which is obviously a very important endpoint for these patients. And this is after a decade of negative studies unable to build on gem/cis.

Also of interest are newer IO combinations, and one of the first ones we’ve seen data on is the IMbrave151 study. This study builds on the IMbrave150, which established atezolizumab and bevacizumab as the front-line standard of care in advanced hepatocellular carcinoma. And this study evaluated the combination in a randomized Phase II study with gemcitabine and cisplatin that was presented at ASCO GI 2023 by my friend and colleague Dr Anthony El-Khoueiry, and we’ll discuss that.

Now the other big impact in the management of these patients is the development and approval of molecular targeted therapeutics. Like most cancers now biliary tract cancers have been very well molecularly profiled, and we understand that there are many genetic alterations that are potential targets for drug development.

We now have validation of some of these, specifically FGFR2 (fibroblast growth factor receptor 2), a receptor tyrosine kinase just like EGFR, HER2, and others, can be translocated in cholangiocarcinomas, and there are several drugs now FDA approved in the second-line setting for patients who have these alterations.

HER2 amplification has been known to be a potential target in biliary cancers for some time. It tends to track with gallbladder cancer a little more than intrahepatic or extrahepatic cholangiocarcinomas. And we now have data evolving with some of the modern HER2 inhibitors, and we’ll talk about those.

Previous studies with lapatinib, trastuzumab really never yielded high signal of activity. There has been some data, a little older now, with pertuzumab and trastuzumab that looks interesting. But we haven’t seen really a Phase III study with HER2-directed therapy as of yet.

And new data, limited in bile duct cancer, but antibody now against neuregulin fusions, neuregulin being one of the ligands for the HER family and specifically here talking about targeting HER3.

And then we’ve had some updates on chemotherapy. Chemotherapy still, unfortunately, plays a role in this disease. While it’s active, I say unfortunately because this is really an old way of treating cancer and carries certain toxicities. But in second-line cholangiocarcinoma we’ve seen data with nal-iri with FOLFOX, and these were randomized studies versus placebo.

So just by way of background, this is a very heterogeneous group of tumors. It’s heterogeneous anatomically, as well as molecularly. And keep in mind this is really 3 groups of tumors which share that they arise from biliary epithelium, but they do have some different natural histories. We have those tumors which are intrahepatic, within the liver; we have those that are characterized as perihilar, or the so-called Klatskin tumor, which is where the bile ducts leave the liver; then we have extrahepatic, this is the portion of the bile duct that is between the hilum and the ampulla; and then we have gallbladder cancers.

And as we’ve seen with molecular profiling there are several various molecular alterations that track with the anatomical location. And some of these now have been validated for treatment. You can see here that BRAF, there’s now a combination of BRAF and MEK inhibition that’s approved for tumor agnostic indications with BRAF V600 mutations, which occur with a low frequency in these malignancies. FGFR2 translocations, which we’ll talk about a little bit more, occur — you can see more in intrahepatic cholangiocarcinomas, just like IDH1/2 mutations. MSI (microsatellite instability) occurs with some frequency, low, single digit, just like in other tumor types, but already IO works in this disease regardless of MSI status. And you can see HER2 amplification occurs more frequently in gallbladder cancers. And those are the targets that have some validation, but we are certainly open to exploring new and novel approaches.

Now when we talk about advanced disease we should keep in mind these are patients who have extrahepatic spread or metastatic disease to lymph nodes or distant parts or even patients who are not considered resectable. Many of these patients are not resectable for anatomic reasons, but it is important, and this is self-serving as someone in academics, but patients should be evaluated at a center that has high expertise in liver surgery, because the only way to cure this disease is resection, and in the community sometimes there isn’t a high volume of these tumors.

Now in 2010 we saw these results published in The New England Journal of Medicine that looked at gemcitabine and cisplatin versus gemcitabine alone. This study showed an improvement in overall survival, 8.1 months to just under 12 months, an improvement in PFS, and an improvement in objective response rates. This became the standard of care and has not been able to be improved upon for over a decade. Fortunately, in the past year we’ve seen 2 studies that are making progress, and we’re going to review those.

So the first study that was presented and subsequently published in The New England Journal of Medicine last year was the TOPAZ-1 study. This was a global study, but mostly Asian patients, that looked at gem/cis and the PD-L1 inhibitor — or antibody durvalumab versus gem/cis and placebo in just under 700 patients. This study did meet its endpoint of improving overall survival with a 20% decrease in the risk of death and moving medial survival from 11.5 months to 12.8 months. PFS was improved. Objective response rates you see were 27% with durvalumab versus 19% with gem/cis alone. You’ll note that 19% there is a little lower than what we saw in the pivotal gem/cis study where it was around 26%.

There were really no new adverse events here. We know durvalumab has some incidence of immune-related adverse events, and chemotherapy is chemotherapy.

I should comment that there was no difference in the duration of these responses, but there is a tail to the curve, and that is often what we see in IO studies, there is a subgroup of patients who get more benefit than others.

What was interesting about this study, and this will be in contrast to KEYNOTE-966, is that they limited chemotherapy to 8 cycles. At that point patients went onto maintenance durvalumab or maintenance placebo. And this is something that has some global heterogeneity, how we manage our patients. Certainly the pivotal gem/cis study did limit at 8 cycles, it’s not clear that more is better, but in this study they did mandate stopping at 8 cycles. And recently we saw an update with 24 months of follow-up, and we see — or with longer follow-up, and at the 24-month benchmark twice as many patients were still alive as compared to those in the control group. And this benefit was regardless if they achieved an objective response or the primary tumor location.

Now we saw the results of KEYNOTE-966, and simultaneously this study was published in The Lancet. And again, a randomized placebo-controlled study, this one quite large, over a thousand patients, larger than what we saw with the durvalumab study. And again, this was gem/cis and placebo, the standard of care, versus gem/cis plus the PD-1 antibody pembrolizumab.

Here, again, we saw an improvement in overall survival, 10.9 months to 12.7 months. That’s a hazard ratio of 0.83. There was a trend towards an improvement in PFS, but this did not reach statistical significance. And in this study both arms had an objective response rate that was similar to what was published initially in The New England Journal of Medicine, but here the duration of response was longer in the pembrolizumab-treated patients with, again, a tail to the curve.

No new adverse events. There were some incidence of immune-related adverse events, and then also chemo side effects.

This study left some options for the investigator to manage their chemotherapy. While cisplatin cycles were limited at 8, again, not uncommon because of dose-limiting neuropathy, and pembro, as done in many pembrolizumab studies, was limited at 35 cycles, but continuing gemcitabine was really up to the clinician. This study, unlike the durvalumab study, TOPAZ, actually had more patients from outside of Asia.

And I think taken together these 2 studies are very similar in their results and probably some nuance between the study populations might explain any differences that might be perceived.

DR LOVE: So could you comment on what we know about or what was presented related to PD-1 and TMB levels in both of these studies? And also comment in terms of from a clinical point of view if you had access to both would it be a coinflip? Or do you have any preference?

DR FINN: So regarding biomarkers, that is still evolving, but PD-1 data has been presented. I’ve not seen TMB data per se. But the PD-1 data does not seem to correlate with outcome, regardless of PD-1 expression. As in other studies, it kind of goes away when you add chemotherapy. And I think that was part of the rationale for these studies, right? The IO story here is not as strong as melanoma, but this idea of combining with chemotherapy does modify the immune microenvironment and was part of the rationale.

Now I have been using durvalumab since the ASCO presentation, probably even since the press release, if I can get it. I think with the data from KEYNOTE-966, which we were significant contributors to, I feel very comfortable with pembrolizumab as well. But I think it’s going to be up to clinicians to decide which drug they’re really more comfortable with. I think the issue of chemotherapy management is something that will affect clinicians personally. If patients are doing well, tolerating chemotherapy, and they’re open to it, I tend to continue it beyond 8 cycles, and not necessarily the cis. Again, that’s up to discussion with the patient. But this is still a very serious disease, and if we can maintain quality of life, and things aren’t broken, I tend not to change that. And that’s not just in this disease.

DR LOVE: Is there a subset that has a high PD-1 level like you see in lung cancer? And what do we know about IO monotherapy, particularly in those patients?

DR FINN: Yeah. I can’t say that IO monotherapy has shown huge signals in this disease. Like in every tumor type with IO you see single-digit response rates, 10% plus or minus, and really there’s no biomarker for those patients. But look, I have patients who came to me with the recommendation of hospice, good performance status, and one patient I’m thinking of has been on nivolumab for 2 years plus doing really well. So there’s a little bit of mystery in IO, but I function for the benefit of our patients, try to give them the benefit of the doubt when we can.

DR LOVE: In an elderly patient who you feel really couldn’t tolerate chemotherapy how do you approach that? Would you ever consider IO alone?

DR FINN: So our next discussion will be on molecular profiling, and I think that is important to be done, because even though most of the molecular approved drugs are approved in second line if someone did have a molecular alteration, FGFR2, didn’t want chemotherapy, then I think we could get those drugs approved. At the same time, single-agent gemcitabine is pretty well tolerated, and I think gem/IO would be an option for patients based on these 2 studies, even though we are not giving them the cis, again giving patients the benefit of the doubt and managing their quality of life.

So continuing our discussion on immuno-oncology agents, atezolizumab, a PD-L1 antibody, has been shown to be synergistic with bevacizumab, improving overall survival in the IMbrave150 study in liver cancer, hepatocellular cancer. This interesting study was a blinded, placebo-controlled, Phase II study which is really a great way to find a true signal for a regimen.

And this study, again, took a gem/cis background, and 1 arm was atezo/gem/cis, and the other arm was atezo/bev plus gem/cis. And I think some of the rationale here is that single-agent PD-L1 and chemotherapy probably has a role, probably when they started this study we didn’t know the results of KEYNOTE-966 and TOPAZ, but forward thinking, and then seeing if there’s any additional benefit with bevacizumab. Primary endpoint was PFS, and there was a small improvement in PFS, 7.9 to 8.3 months. Hazard ratio of 0.76, that was not statistically significant, but again a relatively small study to try to prove that with that delta.

Secondary endpoints were fairly similar as far as objective response rates, although the duration of response was longer with atezo/bev. At the time of follow-up it had not been reached, it wasn’t evaluable, versus just under 6 months with the control arm. And median overall survival was reached in the control arm, of 11.4 months, but again median OS had not been seen yet.

Again, no new safety signals. And I think at this point this study really needs longer follow-up to see how long that duration of response really is and does that translate into what kind of survival delta.

DR LOVE: So I was reading a paper you did on combination immunotherapy, and I’m just curious. We’ve been asking this question for years, but just wondering if there’s anything new on the mechanism of why antiangiogenics seem to potentiate IOs. Any new theories on that?

DR FINN: Yeah. It’s an excellent question. And I think when we say antiangiogenics they come in really 2 different flavors, 3 we would even say; bevacizumab, anti-VEGF, ramucirumab, anti-VEGF receptor domain, and then the TKIs, which are VEGF receptor kinase inhibitors plus other targets.

And the data doesn’t seem to be exactly the same. When we look at ramucirumab, the VEGF receptor inhibitor, really not a lot of synergy with IO. However, pairing VEGF with bevacizumab or biosimilars seems to somehow modify the vasculature, which we know that’s it’s mechanism, but by modifying the vasculature modifies the immune microenvironment and causes a more inflamed environment, more T-cell infiltration. And this all comes from normalizing the vasculature.

Something — now let’s be honest, when we developed VEGF inhibitors I don’t think were high on the radar. The VEGF receptor kinase inhibitors are a little magical, I like to say. They certainly hit VEGF receptor, but they also hit a lot of other targets, and even all the VEGF-TKIs have different profiles. If we look at cabozantinib and IO, not such a robust readout. Len/pembro looks active; did not meet its endpoints in liver cancer, but in renal cancer looks very active.

So part of it probably has to do with changing the microenvironment, but I don’t think with the TKIs it's all explained by the VEGF receptor component, which raises an important question. Is VEGF/IO, patients who respond to that, the same as the group that responds to VEGF receptor/IO? And is there a role for sequencing?

DR LOVE: All right. Please continue.

DR FINN: So we will transition now to the molecular targeted therapeutics. There’s been a lot of interest in targeting VEGF receptors — I’m sorry, the FGF receptors (fibroblast growth factor receptors), and the FGFs have been around for a long time, and it’s taken us some time to figure out how best to target them and in what diseases.

Initially the approval of infigratinib in this disease was based on single-arm Phase II data that showed objective response rates in the 30% range. That was followed by pemigatinib, which was evaluated in this study, the FIGHT-202 study, which is a selective FGFR receptor inhibitor against 1, 2, and 3. And initially these studies looked at various FGFR alterations, mutations, translocations, no alteration. And as it turns out it’s not the mutated patients, a mutation in the kinase domain like in EGFR in lung cancer, but the alteration here is a translocation, where FGFR2, the gene gets moved next to another gene, creating a protein that is abnormal, and these tumors have dependency.

In all these studies these drugs have been looked at generally after gem/cis and sometimes after second-line agents as well.

This drug is dosed 13.5 mg daily, 2 weeks on, 1 week off. This was an open-label, single-arm study in previously treated patients, with the primary endpoint of objective response rate, and this was initially published by my friend and colleague in this program Dr Abou-Alfa from Sloan Kettering. And we recently had longer-term follow-up. And quite striking, objective response rate with the novel agent of 36%, with a fairly long duration of response, just over 9 months, and in second line an overall survival of 17.5 months. Think about that. The survival in second line is longer than the historical survival in front line, and even the front-line survival, at least in the general population that we see with gem/cis/IO.

Now these drugs are not toxicity free. They can have challenges for patients, because of an on-target effect in the kidney we can see hyperphosphatemia, and often patients need prophylaxis for that and be watched closely. There’s also GI toxicity and dermatologic toxicity, such as alopecia and some unique nail changes that can be quite disruptive for patients.

Recently, and again building on this idea of the activity of these drugs in second line, this analysis by Arndt Vogel looked at the progression-free survival on a patient’s front-line regimen and compared it to their PFS on second line, somewhat of an internal control for patients. And again they showed that the PFS in second line was longer than the PFS in front line.

Now these drugs are approved second line. I don’t think it’s impossible to get them front line, but right now with the coming of IO I think for most patients these drugs will be second-line agents. There have been efforts to do front-line studies, but it’s a fairly rare alteration in, let’s be honest, a relatively uncommon disease. Interesting, there tends to be a trend for this alteration in intrahepatic cholangiocarcinomas and also a higher frequency, it appears, in younger women.

Now the newest FGFR inhibitor is futibatinib. This drug is a very selective inhibitor of FGFR1 through 4 but also is irreversible. And again, not all TKIs are the same, and by being irreversible it has a very potent kinase profile against some of the acquired mutations that are felt to be important in resistance to these drugs.

This drug is dosed at 20 mg daily. It got FDA approval this year based on the FOENIX-CCA2 study, which was published in The New England Journal of Medicine, and this was, again, a large, single-arm, Phase II study with FGFR fusion patients. Here the objective response rate is 42%, long median duration of response, and PFS of 9 months. And recently we saw an updated mature OS of 20 months, again second line. And the side effect profile here is really representative of the class.

I should mention another drug that is evolving in this space is one from Relay Therapeutics that again is showing very promising results. And one thing that is not answered for us yet is there a role for sequencing these drugs. There is some thought that perhaps futibatinib may have activity after progression on one of the first-generation FGFR inhibitors, but really this is yet to be proven in larger cohorts. But as we’ve seen even with HER2 in breast cancer, just because you have 1 drug that works for the target it doesn’t mean there won’t be new drugs in the future, and hopefully improving outcomes for patients.

DR LOVE: I’m just curious if you’ve ever heard of a device called TAR-200 used in bladder cancer. It actually is a way to deliver drugs into the bladder locally. They actually use it with chemo. But the other thing they’re looking at, because bladder cancer of course has FGFR also, is intra-bladder high-dose FGFR. It was erdafitinib. Any thought about that kind of strategy in biliary tract, a local antimetabolic? I was like really surprised they were even looking at it. But any — would that make any sense in terms of maybe higher dose and less toxicity?

DR FINN: Yeah. I mean it depends on the tumor type. Obviously bladder lends itself because it’s accessible through the urethra, but there have been approaches like that in biliary cancer for intraluminal tumors, going through an ERCP. There was initially an interest in photodynamic therapy. So I guess we’ll have to see how it plays out in bladder cancer.

I mean it brings me to an important problem for these patients, which is infection. Many of these patients get into problems because of obstruction and infection. That is a leading complication and cause of morbidity and mortality for these patients. And that is a unique aspect of this tumor type, and perhaps if we could get better at managing that through the scope in some way then I think that would probably improve things for our patients.

DR LOVE: Interesting. Please continue.

DR FINN: Yeah. So along the idea of molecular targeted therapy — and we touched on HER2, which has been a life-changing target for so many women with breast cancer, and now gastric cancer and potentially other malignancies. We’ve known it’s been altered in biliary tract cancers for a long time. Most of these amplification events occur in gallbladder cancer. And there’s been early studies with trastuzumab single agent, lapatinib, more recently we saw pertuzumab and trastuzumab, and generally these are single-arm Phase II studies that show a signal, but nothing’s really been grabbed by the horns, so to speak, and brought to well-done Phase III studies. And it’s hard when we’re dealing with relatively rare malignancies and relatively uncommon alterations.

With that being said, because of a large unmet need there are newer drugs being moved into the HER2 amplified gallbladder/biliary tract space. Zanidatamab is a HER2 bispecific antibody. So this is actually a HER2-directed therapy against 2 different epitopes on HER2, nonoverlapping epitopes, somewhat like the pertuzumab/trastuzumab approach. In this cohort about 87 patients, a very provocative objective response rate, 41%. Long duration of response. And again this is in second line. And these patients were amplified or IHC 2 and 3+.

No new safety signals with this molecule, which is being looked at in other diseases, infusion reactions and some GI toxicity.

The other drug that has now moved its way into the biliary tract space is trastuzumab deruxtecan. And to be honest, T-DM1 has also been looked at in this space. Deruxtecan is actually a very interesting molecule now being looked at in a number of malignancies, and I would say almost regardless of HER2 expression level; initially approved in amplified breast cancer, now in HER2-low breast cancer, and also playing a role in gastric cancer. And so it was quite rational to look at this drug in HER2-amplified BTC (biliary tract tumors).

And here, building on what they know from other malignancies, relatively small, 32 patients, 22 which were truly HER2 positive and 8 that were characterized as HER2 low, and in the HER2 positive cohort objective response rate of 36%, very comparable, I think, to other HER2-targeted drugs. HER2 low 12.5%, 8 patients, very hard to know what that means. PFS here you see longer in the HER2-amplified patients.

And again, no new treatment-emergent adverse events. We know this drug can cause bone marrow suppression, as well as rare occurrences of interstitial lung disease. Or not rare but uncommon.

So we’ll have to wait and see how these drugs move ahead in clinical development.

DR LOVE: So the bispecific zani is very interesting. The only other bispecific I can think about that sounds like that is, I don’t know if you’re familiar with amivantamab in lung cancer’s exon 20, where it has 2 different — it sounds like this. The other bispecifics all have an immune, I think it’s CD3, tag on it.

DR FINN: Correct.

DR LOVE: But the obvious question is in terms of the zani what do you see in breast cancer?

DR FINN: Yeah. I mean I can’t say I’m familiar so much with the breast cancer data with this molecule, but it’s building on this idea of dual HER2 targeting, which we have precedent for, in again the pertuzumab/trastuzumab story, and there’s reason to think it could have activity in breast cancer. Obviously that space has gotten very crowded in the HER2 area, and things have been shuffled quite a bit with the antibody-drug conjugates, which I think are in general a very exciting new approach for many malignancies. So we’ll have to wait and see where this approach goes.

DR LOVE: All right. Please continue.

DR FINN: Yeah. So the last molecule I want to discuss is one that is quite interesting, seribantumab, is an antibody to HER3. And HER3 has been known about for a long time, part of the EGFR or HER1 family, and we have cetuximab and panitumumab for HER1. We just discussed a number of molecules against HER2. And HER3 has been a little bit more difficult to pin down as where it might have a role. HER3 is very important in HER2 signaling, and part of the mechanism of action of pertuzumab is to block the heterodimers of HER2 and HER3.

This drug is given IV every 3 weeks. And interestingly it competes with one of the ligands for HER3, neuregulin. And it’s been observed scientifically that there are fusions in neuregulin, very rare, 0.2% of solid tumors, and that these fusions might be the driver in targeting HER3. And this occurs more frequently in non-small cell lung cancer. This study did include 2 patients with cholangiocarcinomas, but we have not seen any robust activity in that space. Again, they need to build up on the numbers. And again, how do you build up numbers when an alteration is generally fairly rare? But it does occur. And that’s part of the challenge with developing targeted drugs in a targeted population.

With that being said, very provocative data in lung cancer, where 36% of patients responded with a fairly long duration of response. The median had not been reached. The overall objective response rate in this study was about 33%.

So we’ll have to see how this evolves. Again, a potential target, though obviously rare, but highlights the fact that molecular profiling is important for our patients.

So in closing, going back to good old chemotherapy, nal-iri (liposomal irinotecan) is a relatively new drug in our oncology space. We did see very interesting data presented by my friend and colleague Zev Wainberg at ASCO GI this year with this drug in pancreatic cancer that looked very promising as a new option for patients, actually better than FOLFIRINOX.

But here in this second-line, open-label study in cholangiocarcinoma we have nal-iri plus 5-FU and leucovorin versus 5-FU and leucovorin alone after gem/cis. Primary endpoint was progression-free survival by blinded independent review, and this was more than doubled, 1.7 to 4.2 months. Hazard ratio of 0.61. Very promising. A response rate of 19% versus 2% with 5-FU/leucovorin alone, which seems like it’s close to placebo as far as activity, and median overall survival was also improved, with a hazard ratio of 0.68.

And again, the whole issue with chemotherapy in this disease is managing quality of life and the cytotoxic side effects. But certainly an important option for patients who don’t have a molecular alteration, right? Patients are going to get IO/gem/cis and at progression if they have an alteration they’ll go to one of our targeted therapies or to a clinical trial looking at a specific alteration, or they will come to chemotherapy, which would be options of FOLFOX or this nal-iri regimen from the NIFTY study.

So in closing, again, thank you very much for joining me. Front-line gem/cis and IO is now the standard of case based on 2 Phase III studies using either durvalumab or pembrolizumab. Molecular profiling must be done for our patients, hopefully early in their course, just to have that information handy, because it can always take time, because we have FDA-approved agents for FGFR2 alterations. We didn’t discuss but IDH mutations have approvals, and BRAF mutations all have full FDA approval. There’s early signals of new HER2-directed therapy. Some of these do have NCCN listing and can be options for patients. And for patients without genomic alterations second-line chemotherapy may be appropriate, either FOLFOX or nal-iri.

The other thing that also, it reminds me, that has NCCN listing is actually pembrolizumab and lenvatinib in second line. And again, this is prior to IO being used front line. And again, that’s based on a single-arm Phase II study that shows some activity.

But a lot has changed in this disease recently. We had a long drought, just like in hepatocellular carcinoma. Ten-plus years of no progress, and now that the ball is rolling hopefully our progress will continue, and this will be very important for our patients to keep this momentum going.