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Overview of MKIs in the Treatment of Cancer

Speaker and Chair: Markus Peck-Radosavljevic, MD (Austria)

SlotAJ-1 Introduction

Associate Professor of Medicine
Vice Chair, Department of Gastroenterology & Hepatology
Medizinische Universität Wien
Vienna, Austria

Transcription

Peck-Radosavljevic: Now it is a great honour for me to introduce the distinguished faculty for this satellite symposium.  

Today’s Discussions

Right after a short introduction by myself, Bruno Daniele from Napoli will be talking on the use of MKIs in clinical practice, real-world experience, then Marcia Brose will talk about when to start and sequencing MKIs to maximise patient benefit and then Rodolfo Sacco from Pisa will be talking about assessing treatment effects of MKIs.

Full transcription

Full transcription

Peck-Radosavljevic:  Now it is a great honour for me to introduce the distinguished faculty for this satellite symposium.  

Today’s Discussions

Right after a short introduction by myself, Bruno Daniele from Napoli will be talking on the use of MKIs in clinical practice, real-world experience, then Marcia Brose will talk about when to start and sequencing MKIs to maximise patient benefit and then Rodolfo Sacco from Pisa will be talking about assessing treatment effects of MKIs.

After that I will give you a short wrap-up and we will have, or we should have enough time for questions and answers which you can either hand in to us in written form but there will be also two microphones here on this side where you can come up to and ask us directly.

Signalling Networks Involved in Oncogenesis

I’ll start with a short overview of MKIs in the treatment of cancer. 

Now, here you see one of those fantastic diagrams.  I know we all love them, they are very easy to comprehend and they are even easier to memorise but the reason why I’m showing you this is because these pathways represent potential targets for so-called targeted therapy.

And when you look at that, you realise that of course there is a large number of different pathways, there are some redundancies so there is a lot of potential for some escape pathways and for that reason if you block one pathway, it might work but that is only rarely the case, as you will see.

Oftentimes you will have to block several pathways at the same time and that is where these so-called dirty drugs, the multi-kinase inhibitors that inhibit not just one pathway but usually several pathways come into play and this is the potential reason why these drugs have been shown to be quite effective in a number of different cancer types.

Also of course it’s not only about the tumour cell as it’s shown here but there is also a lot of interaction between the microenvironment and the tumour cell itself and also there, MKIs have a big role to play.

Imatinib in Chronic Myeloid Leukemia

So it all started with imatinib in CML and as you know, imatinib primarily inhibits the Bcr-Abl activity in patients with CML and by doing that it dramatically increased the survival of these patients over chemotherapy where the five-year survival was somewhere around 35% but with imatinib it could be increased to up to 90%.

History of Selected MKIs Approved for Cancer Treatment

That great success story of course stimulated several companies to look at other compounds they had in the pipeline and as you can see over the years quite a number of different compounds were developed for different indications successfully and licensed.

For example, if you go through that list, in 2005 sorafenib was licensed for renal cell carcinoma and then later on two years later also for HCC and even later on for differentiated thyroid cancer and then also regorafenib in 2012 was licensed for colorectal cancer and GIST and is being developed for more indications.

The latest kid on the block here is lenvatinib which was licensed for refractory differentiated thyroid cancer, so you have a number of agents today in clinical use.

MKIs and Other Systemic Therapies Assessed in HCC

Now when we have a closer look at one of those cancers, I start here with HCC because this is the one that I’m most familiar with, you can see that even though you might have agents with very similar activity, it’s not a done deal that those will work, even if they have very similar targets or similar main targets.

Now sorafenib was, as I said, licensed in 2007 and then several other multi-kinase inhibitors with quite similar activity actually failed their Phase III trials; for example, brivanib, sunitinib, linifanib or the combination of erlotinib and sorafenib while lenvatinib is still in clinical development. 

Also in second-line after failure of sorafenib versus placebo where the bar is really not all that high for the improvement in survival, again brivanib failed, everolimus, an mTOR inhibitor, showed a completely negative result.  On ramucirumab, a VEGFR-2 antibody, the verdict is still out.  The trial looked not too bad but did not meet all the endpoints and the second Phase III trial just started to see whether this could work.

Other drugs are still under development; regorafenib in a more unselected approach and tivantinib in c-Met high expressing patients are the ones that are most talked about.

MKIs for the treatment of DTC

Now for the treatment for differentiated thyroid cancer you have two MKIs, sorafenib and lenvatinib that are approved for the treatment of patients and several other MKIs are being studied for the treatment of those patients.

You can see here the list of those drugs and it will be quite interesting to see whether they will be working.

Several MKIs Are Approved for the Treatment of Renal Cell Carcinoma

Now renal cell carcinoma was the first one actually where several drugs have been approved.  As you can see, all of them are targeting VEGFRs one to three, all of them are targeting PDGFR and then they are targeting one or several other targets like RAF, FLT3, Kit or RET, so you do have several MKIs targeting angiogenic pathways.  They are considered standard of care for patients with renal cell carcinoma.

Conclusion: Optimal Treatment of Advanced Disease

So in conclusion here for the optimal treatment of advanced disease, some treatment advances have been made in oncology with a better understanding of oncogenesis, especially with MKIs.

MKIs are the standard of care in several tumour types including HCC, differentiated thyroid cancer and RCC.

However, there are still some questions remaining and those questions will be addressed by the subsequent speakers.

Those questions are; how do we define the appropriate patients for treatment; when is the optimal time to initiate treatment; what is the appropriate treatment sequence and also how do we best assess the treatment effects?