Prof Richard Finn – Geffen School of Medicine at UCLA Medical Center, Los Angeles, USA
Prof Viktor Grünwald – Hannover Medical School, Hannover, Germany
Prof Arndt Vogel – Hannover Medical School, Hannover, Germany
Prof René Adam – Hôpital Paul-Brousse, Villejuif, France
RF: Hi, I’m Richard Finn from the Geffen School of Medicine at UCLA and welcome to our ESMO 2017 ecancer programme on difficult to treat tumours. We’ll be talking today about primary liver cancers as well as kidney cancer and I’m joined on the panel today by Dr René Adam from the Hôpital Paul-Brousse, Dr Arndt Vogel from Hannover Medical School and Dr Viktor Grünwald from Hannover Medical School. Why don’t we start today with a brief introduction of the challenges in hepatobiliary malignancies?
RA: I think probably biliary tract malignancies is one of the fields where we should need to make more progress. Indeed, up to now I would say first resection and transplantation are the only curative options and there is still a lot of progress to be done for optimising what chemotherapy is able to provide in such types of cancer, meaning hepatocellular carcinoma or biliary tract cancer. Because by extrapolation of what we see in secondary liver tumours, probably by downsizing such types of tumour it would be possible to go to a more curative option in these patients.
RF: So, Arndt, for patients who can’t be resected, can’t be downstaged, essentially Barcelona stage C advanced liver cancer by stage, what’s the landscape like as it stands today?
AV: At the moment it’s really changing. For a long time we only had local therapies then sorafenib was introduced and we’ve used it now for more than ten years. Now it’s really a time where we have more clinical trials that are reported, not only for systemic therapies but also the comparison of local therapies to systemic therapies which I think is really important because we always thought that local therapies are better than systemic therapies but this is obviously not the case. So for Y90, for example, we just learned that Y90 is not superior to sorafenib for patients with more advanced cancer. This gives us a perspective that we really need to be more careful when we decide whether we use local therapies or systemic therapies and when we use local therapies when is the right time to switch to systemic therapies. In respect to systemic therapies we have now three drugs available, most likely – sorafenib, regorafenib and lenvatinib we have a positive trial. Now also we have to decide which drug should be used first. Then it comes to the decision, not only the effect on overall survival but maybe also on secondary endpoints. So, for example, response rate that you just mentioned – can we use drugs or local therapies for downstaging purposes so that we can do indeed resection, maybe also transplantation. And then that we switch patients from a palliative setting maybe to a curative setting. So this is really important that we also not only consider overall survival but also secondary endpoints to get different treatment algorithms. What also is very important is the perspective of the patient, so side effects, quality of life. Here we had a presentation on quality of life and we compared two TKIs and we saw really differences in terms of how the treatment impacts on the quality of life of these patients. There were differences and we need to learn, to understand them and how we really take this into our decision making, which drug we use first.
RF: So you presented that data and I think you’re referring to the results of the REFLECT study which we saw the primary endpoint at ASCO this year. You alluded to the fact that after ten years of sorafenib being the standard of care in frontline with multiple negative studies at ASCO we saw the results of the first positive study in advanced liver cancer which was comparing lenvatinib to sorafenib for advanced disease, first line treatment. It met its endpoint of non-inferiority and non-inferiority showing that lenvatinib gave a survival of about 13.5 months and sorafenib was about 12.3 months. That was equivalent as far as their effects though secondary endpoints such as time to progression, response rate, PFS, was increased with lenvatinib as compared to sorafenib. The significance of those we’re still trying to find out. But an important endpoint you alluded to was quality of life, can you give us a brief summary of your data?
AV: We used two questionnaires in this study. First of all it was very successful, we got the data for more than 98% of the patients which I think was really remarkable. So the data are very robust and indicate that we can do these quality of life analyses in clinical trials. What we saw is that there is an impact on the quality of life and global health with both treatments, so there’s a decline over time or during treatment. When we look at some of the key domains such as pain, diarrhoea, nutrition, body image we saw a delay in clinically meaningful worsening of symptoms in patients that received lenvatinib compared to those that received sorafenib. Therefore we do see differences and we need to see how we can integrate this in our decisions.
RF: That brings us to an important topic in liver cancer because, especially with the non-inferiority study, we’re trying to figure out which subgroups might do better with one drug or the other. I presented an interesting biomarker analysis from that study and our hypothesis generating study looking at serum biomarkers. We identified a few things that are prognostic, actually, for both lenvatinib and sorafenib. We also showed how these molecules differently modify the pathways. While both sorafenib and lenvatinib modified VEGF markers, only lenvatinib affected the FGF family. That might be an important differentiator between the two as we evolve into more data. You also alluded to the fact that the only other drug that has positive data is regorafenib in the second line setting, still the only drug that has shown activity in that setting, unlike the first line setting which we were just discussing. Again at this meeting in an attempt to identify who may or may not benefit from regorafenib, which was compared against placebo in the RESORCE study and showed an improvement in survival of about three months. Certain proteins were identified in an exploratory analysis that showed some patients might do better than others. Interestingly, again, angiopoietin-1, an angiogenesis marker, popped up among other proteins as well. It all became relative; the conclusion from that abstract at the meeting was not that there’s any group that did not benefit but maybe there are degrees of benefit. There’s a lot of activity going on in this area, local regional, systemic treatment, but in many ways kidney cancer is a model for us. We’re maybe ten years behind because now we have a sequence of two TKIs that looks effective; now we have two options, potentially, in the first line setting once, presumably, if lenvatinib gets regulatory approval we’ll have two multi-kinase TKIs in the frontline setting. How does the kidney cancer field manage this and what was new at ESMO to help clarify the many questions in kidney cancer?
VG: It’s a wonderful question because what happened during the past eleven years is that we’ve got now in Europe eleven different agents on the market, so one each year. This kind of tells you the story if you have effective treatment on how the landscape may evolve, so you still have a couple of those ahead of you. What I think that we have seen at ESMO this year is really a game-changer. We have entered the field of combinations; I think that started with lenvatinib/everolimus a couple of years ago when Bob Motzer presented the data and we have seen for the first time really impressive response data. So since then that really succeeded and nowadays we have different combinations. We work on combinations, IOIO combinations. This is probably the biggest message from this year’s ESMO because patients that have been exposed to a CTLA4 and PD-1 inhibitor really lived longer compared to sunitinib which is the standard TKI in first line. So that is the first time it happened, really. It’s not only OR improvement it’s also OS improvement by a hazard ratio of 0.61. So this is really something that is new to the kidney community because we were lacking evidence of providing OS benefit in first line. The question would be is that the end of the story and I think that’s not the case so we would like to combine TKIs, the old stuff with the new stuff, with the immunotherapy. That’s what’s ongoing and we have seen some phase I/phase II data that supports the ongoing phase III trials that are already launched and ongoing in RCC. One of the combinations is lenvatinib and PD-1 inhibition.
RF: Right, so last year at ESMO there was very exciting data about that combination.
VG: Today it enlarged in its size. So now we have a safe dosage for the combination; now we have thirty patients to look at and the overall response rate is 63% so that’s very good, isn’t it?
RF: Very good.
VG: So we kind of doubled it, compared to sunitinib or regular TKI in first line. So one way to look at this is the magnitude of response, the other way is to look into those patients that don’t benefit from treatment and you barely find those in this combination. So usually we have 20-25% of patients immediate failure to a TKI and here it has been just 5%. So this tells you how effective these kinds of combinations can be and that is why we currently pursue phase III clinical studies in the first line setting with these kinds of combinations.
RF: Wow, that’s very exciting, that high response rate. I think now with lenvatinib showing activity in front line liver cancer I know that there’s already interest in looking at that combination in HCC as well. René, you hear us talk in oncology about these new combinations, new drugs, surgeons, interventions, they play a pivotal role in the management of liver cancer. What do you think when you hear this or do you see a role for integrating some of these into earlier stage?
RA: Of course I would give you a point of view of a surgeon and I would say when we are speaking about combinations it’s true that in many cancers combinations of drugs are optimising what we are giving to the patient in terms of medical treatment. But there is another combination that we are speaking less on, it’s the combination of a good chemotherapy with a good surgery. We have now, I would say, many examples. If I take you an example in biliary tract cancer, the Mayo Clinic protocol combining radiochemotherapy, explorative laparotomy, transplantation, has significantly improved from 30% to 70% the five year survival of those patients. If you take the model of the colorectal metastatic cancer it’s the same. Combining drugs with targeted therapy, combining these optimising treatments with surgery is able to provide the patient, I would say, a significant benefit in survival, if not a possibility of cure in some very selected patients. So my comment on all this is that we should combine all our efforts, all the drugs, all the different treatments in a way to fight against what is a big enemy which is cancer in general. Putting it all together in a very good team spirit would optimise the treatment of the patient.
RF: And these are difficult to treat diseases. We just had some adjuvant data with kidney cancer for the first time, is that correct? With sunitinib, was that right?
VG: Yes, indeed. There are three large studies nowadays and two of them are negative and one is positive. So we’re still in the process of sorting out what’s the net benefit for the patient. So that would be a completely different new session that we would open if we start into that discussion.
RF: And in regards to biliary tract cancer, again highlighting the challenges, in our session yesterday in the oral non-colorectal session there was a presentation of adjuvant GEMOX after resection for biliary tract cancer. Could you comment on that?
AV: Yes, we have now two trials that have been reported this year, one was the PRODIGE trial from France and that was surprising they used GEMOX versus observation. They observed a PFS benefit of 12 months, overall survival benefit of 25 months but still the data were not significant.
RF: Statistically significant.
AV: Statistically, but maybe not only statistically. They concluded that they would not recommend GEMOX as adjuvant treatment for biliary cancer. But when we look also at the BILCAP data and they used just 5FU, Xeloda, as adjuvant therapy, they also observed an improvement in PFS and overall survival. Again, the overall survival benefit was not statistically significant, it was clinically meaningful. So we have now two negative trials but in both trials we have a survival benefit of 15-24 months which is clinically meaningful. We now have to make the decision whether we should. I think we at least need to discuss the data with our patients. Personally I would recommend adjuvant therapy in my patients, maybe not with GEMOX but with Xeloda. I think it’s very important that we continue with the ACTICA trial which compares gem/cis versus now Xeloda. We really need this data which is clear with these statistically negative trials.
RF: Yes, it’s hard for me to see that gem/cis, gem/ox…
AV: Where’s the difference?
RF: It’s all chemotherapy. I think the thing that has made a big impact in kidney cancer and also in HCC is probably a better understanding of biology and certainly biliary cancer is one where there are clinical subgroups that might benefit better from these interventions or a biomarker subgroup. We’re continuing to work and try hard and there’s obviously a lot of work to be done. Any last closing comments, René?
RA: All these show, in my view, the great collaboration that we may do against cancer. In the past only medical oncologists were involved in the treatment of cancer. Today what we are seeing is that molecular biologists are involved, pathologists, medical oncologists, surgeons, radiologists. This is illustrative of the need of a real expert team around all the treatment of cancer patients in a way to improve the results. For me, it’s probably the best achievement in recent years.
RF: A lot of us in liver cancer, like I said, look at kidney cancer as a paradigm of success or great progress. What would you tell us in the liver cancer field, some advice?
VG: What we have seen in renal is that tumour response is meta. If you would like to succeed with therapy you’re not aiming to provide a four or six or eight week benefit in progression free survival. Once you’re beyond that point and you really deliver something to the patient that is meaningful, this is the best advice I can give you because then it will be away from this discussion is it significant, clinically relevant and so on. Because what is important is what really is the net benefit for the patient. The priority of our patients is they want to stay alive and we have to acknowledge that and we have to work on this. René did a wonderful example that multidisciplinary teams are necessary, it’s not only the drug.
RF: Yes, that’s great. I hope all of you found this interesting, this snapshot discussion from ESMO 2017 on advances and challenges in difficult to treat tumours. Thank you very much.