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The Future of MKIs / Questions & Answers

M. Peck-Radosavljevic MD (Austria) / All Faculty

SlotAJ-5 Peck-Radosavljevic, M. + Questions

Chair: M. Peck-Radosavljevic, MD

Faculty: Marcia Simpson Brose, MD; PhD, Bruno Daniele, MD, PhD; Rodolfo Sacco, MD, PhD

Transcription

Markus Peck-Radosavljevic:  Rodolfo, thank you very much, also for making up some time for us.  My task is to give you a brief summary, and I will give you a very brief summary so that we have more time for discussions.

Basically the future is still there and very interesting for multikinase inhibitors, even these days when everybody is talking about immunotherapy, which obviously is something that will be interesting, but even when you look in one of the latest issues of Cell in one of the papers written by James Allison, he makes a strong argument for combining multikinase inhibitor therapy with immunotherapy so even if that is something that will be big in the future I think multikinase inhibitors are here to stay. 

Full transcription

Full transcription

Markus Peck-Radosavljevic:  Rodolfo, thank you very much, also for making up some time for us.  My task is to give you a brief summary, and I will give you a very brief summary so that we have more time for discussions.

Basically the future is still there and very interesting for multikinase inhibitors, even these days when everybody is talking about immunotherapy, which obviously is something that will be interesting, but even when you look in one of the latest issues of Cell in one of the papers written by James Allison, he makes a strong argument for combining multikinase inhibitor therapy with immunotherapy so even if that is something that will be big in the future I think multikinase inhibitors are here to stay.

As for the talks, Bruno showed us mainly that in HCC there is still a massive overuse of TACE, even in disease stage where TACE really should not be used.  This is probably partly due to the fact that there is no reimbursement in some areas of the world, like for example in China, but it is also partly due to the fact that some of our colleagues still don’t really capture the full potential of multikinase inhibitors for this disease. 

Marcia showed us that for second-line treatment in differentiated thyroid cancer we have two drugs and basically the choice for one of these drugs depends not only on the absolute value of progression-free survival, but depends also on the side-effect profile and several other factors which will determine which of these two drugs we will choose, while several questions like, for example, sequencing, have not been addressed adequately so far simply due to the fact that this is a fairly late indication and trials are still on-going.

Rodolfo really showed us that assessing treatment response is very different, depending on which tumour you are looking at.  RECIST is important for clinical trials and for FDA approval; it is not really that important for assessing the response in real-life practice. We tend to use mRECIST for HCC, Choi for GIST and other possibilities have been shown.  One very important message that he is giving is that progression is not equal to treatment failure and that this is something that we in HCC treatment, where we have no second-line treatment, have always been following because we have been treating patients well beyond progression, as long as patients could tolerate it.

However, in other areas we need careful assessment about how long we can really or should really continue with the drugs.

Having said that I would like to open the floor to you.  There are two microphones there and it would be great if you could ask some questions.  Please feel free to go there.  In the meantime if we don’t have any people going there at the moment – or is there somebody?  Please.

?[Hamud Abusin] (Tunisia):  We have the chance to have the benefit scale of ESMO, I don’t know if it has been presented how to improve the rank in the scale of the product presented in this session?  They are ranked between three and four, all the m-kinase that have been presented.

Markus Peck-Radosavljevic:  We are not sure what the question really is about – the ranking of the MKIs in terms of ESMO?

?[Hamud Abusin]:  I am speaking about the clinical benefit.  If we have to defend one of the products, and to improve the rank scale, because most of the studies are comparing the product versus placebo; do we think that comparing product head-to-head or perhaps adjuvant or no adjuvant could improve the rank in the scale of the product?

Markus Peck-Radosavljevic:  For HCC it is very clear because there is nothing you can compare to because it is the only drug.  Perhaps Marcia, you want to say something for thyroid cancer?

Marcia Brose:  In thyroid cancer we would love to do that but this is not lung cancer.  When you have rare cancers that have very few patients and then you add together the fact that patients will benefit by getting both drugs.  Doing head-to-head studies are very unlikely and not necessarily going to be feasible because of the low number of patients.  While we would love to do all those, there are so many more studies that we would love to do to determine which one should go first and things like that.  It will be very difficult to do it and we will have to see whether we can find some other way to determine sequencing, perhaps by doing sequencing studies themselves rather than straight head-to-head.

Bruno Daniele: For HCC there have been several studies comparing sorafenib with other TKI and all show that sorafenib is still better than the others in terms of efficacy and safety.

Markus Peck-Radosavljevic: Here is one question that asks about did any guidelines determine the maximum number of TACE that can be done to the patients, intermediate stage HCC?

This is taken care of.  There is one expert recommendation whose first author is Jean-Luc Raoul, and in this expert recommendation it is two cycles that are recommended. The same is true for the Japanese guideline and the same is true for the Korean guidelines and it is also true for the Austrian guidelines.  There is fairly good consensus that you should give at least two cycles of TACE unless there are a lot of side effects and then at this stage if you have no response you switch to something else.

Then there is a question to Marcia, several questions to Marcia, but one is in your clinical practice how do you sequence TKIs in differentiated thyroid cancer?  Sorafenib first and then lenvatinib plus/minus mTOR or first lenvatinib then sorafenib plus/minus mTOR?

Marcia Brose:  In the absence of data to clearly guide me to one or the other, I would say I have done yes and all of the above.  We have a very active clinical trial programme so a lot of the patients that we have treated thus far have been part of the clinical trials.  Many times what happens is that it is determined most of the time by the patient themselves.  We saw the activities, for instance, of lenvatinib in the very aggressive patients, there are times when I have more aggressive patients that I might pick lenvatinib first.  I have patients who have bad trouble with hypertension and I have difficult problems with that; that might be a reason that I would start them on sorafenib first.          

The most important thing is probably that all patients get both, 100% get both.  Now what is not so clear is how we are going to start to incorporate the everolimus data into our practice because it is not clear whether that would add and extend to either lenvatinib or sorafenib before we switch to a completely different agent and we don’t have the data to decide that.  At this point it often has to do with the characteristics of the patient, how well they are tolerating drugs and many other factors that are going into it.

Markus Peck-Radosavljevic: Rodolfo, I have a question to you: in my clinical experience I have problems to convince the radiologist to even give me RECIST scoring on the report.  How do you deal with tumour growth rate?  Is this like a standard result that you will give to everyone or do you really have to convince that they have to put in the extra work?

Rodolfo Sacco:  No, this is a very important question because also in Italy not all radiologists consider mRECIST. I am lucky because we have a department of radiology with Professor Bartolozzi and Dr Bargellini; they are very used to considering modified RECIST.  All these studies I showed they were conducted with them.  I think the radiologists should be used to consider these parameters and also to change their minds to consider other parameters such as volume variation or tumour grow rate, because when using multikinase inhibitors I clearly show that RECIST or EASL criteria often are not so good.

?[Tom Kamismann] (Finland):  Is it possible to use the Choi criteria for other cancers than GIST like HCC?

Markus Peck-Radosavljevic: For HCC Choi does not really work.  We looked at that. I cannot really answer for RCC or thyroid cancer; they haven’t used it. From what I know the Choi criteria uses a very specific feature of GIST for evaluation; that is not a common feature of other tumours, but mRECIST is kind of an adaption of Choi criteria for HCC and I am quite sure you could adapt them as well to other tumours.

There are more questions, most regarding thyroid cancer.

Marcia Brose:  We are the new kid on the block.

Markus Peck-Radosavljevic:  Exactly; do you think quality of life for thyroid cancer patients will be greatly impacted with sorafenib, especially that they tend to live longer with slow progressive disease.

Marcia Brose:  We, in the DECISION trial, did do a quality of life analysis. What was reassuring was that the patients had, not unexpectedly a slight decrement and it was statistically significant in their quality of life, which you would expect when they start dealing with hand-foot skin reaction, etcetera.  However, that small decrement was stable throughout the entire time they were on drug. 

What we do know is that patients do tolerate these agents very well.  Most of them who are working will go back to work full time, etcetera, so yes, they are aware of the side-effects, but after the first few months, once they have learned how to manage them, many of these side effects can, in both lenvatinib and sorafenib, be very well-managed.  It does pose an extra challenge to the education of the physician because we really have, in a way, a different burden of managing side effects than somebody who is perhaps not on a drug quite so often and having really good knowledge, because even the side effects that happen early are different than the ones that happen late.  We even, just recently, published a paper – Francis Worden is the first author on that, that talks about not just which side effects happen, but also the timing of them.

For instance, we don’t worry about diarrhoea because that almost never happens for us in the first six months, but really tends to start up around five or six months and it is a totally different game managing adverse events after six months than before.  It all is going into play but yes, good quality of life throughout.

Markus Peck-Radosavljevic:  One last question for you, Bruno, because you have been left out here.  I would ask you to speculate on one thing, because as you pointed out, we recommend sorafenib after TACE but there is not too much data, especially randomised data, to do that.  What do you think the role of the therapies that are being investigated, like SIRT for example, will be in the decision to do when patients progress with TACE?

Bruno Daniele:  As you said there are no randomised data with SIRT available, so I believe it is an interesting modality of treatment to be investigated, but cannot belong to clinical practice at the moment.  The few data that we have demonstrates that SIRT could achieve the same results as sorafenib, but the strength of evidence of SIRT is much lower than the one we have with sorafenib.

THANK YOU

Markus Peck-Radosavljevic:  Thank you very much. I would like to conclude here. I would like to thank all of you for staying with us and listening. I would like to thank the faculty for the presentations and I would like to thank the sponsor, Bayer, for the symposium.  Thank you very much.