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Concluding Remarks and Future Perspectives (U-4)

T. Mok (Hong Kong)

SlotU-4 Closing Remarks

Tony Mok looks to the future of ALK, showing that, whatever happened to EGFR, we are actually doing the same thing to the ALK-positive patient and concluding that we have to know the molecular data of each individual patient.

Transcription

Considering the time, I will just move on to the last part of the presentation.  I have tried to put everything close together, in perspective, and see what we can do in the future.

[slide]

You have heard that we have the biomarkers here, like the ALK positive patient, crizotinib, and ceritinib may have a good CNS penetration. 

Full transcription

Full transcription

Considering the time, I will just move on to the last part of the presentation.  I have tried to put everything close together, in perspective, and see what we can do in the future.

[slide]

You have heard that we have the biomarkers here, like the ALK positive patient, crizotinib, and ceritinib may have a good CNS penetration.

[slide]

So now, focusing on this so-called paradigm, of ALK positive patients – what is there for the future?  I want to show you that, whatever happened to EGFR, we are actually doing the same thing to the ALK-positive patient. We look for the ?[plasma] DNA and, certainly in ALK, we are doing the same.

Potential paradigm changes

A part from NGS, there are the paradigm changes of looking into plasma RNA. 

Feasibility of Detecting ALK Fusions with qRT-PCR Assays in Cell-Free Plasma RNA

You might want to ask why to use RNA, and it is because RNA has a longer ?[em…]. They will make the translocation easy to detect in the plasma.  So that is one direction –  and actually, we discussed it in WCLC this year – talking about the extraction of the plasma  RNA and then they used two different methods. 

qRT-PCR Detection of ALK Fusions in NSCLC

One is variant-specific, looking at variant 123, while the other one is L5’-3’ delta, looking at other variants.  They were actually able to pick up about 11 of the 15 cases of with L-positive disease. Basically, this is still very early but, certainly, NGF and even RNA in the plasma, may potentially be a feasible way for us to look for L-positive disease in the blood.

[Slide]

From that in first line, you have already heard many stories from ceritinib.

Alectinib and Ceritnib: First-line Phase III Studies

 These are the two major studies.  One is actually a head-to-head comparison of imatinib versus the crizotinib in a comparison, and the patient was ALK positive defined by ?[IXC].   Then there is the ASCEND 4 study, in treatment naive patients, with ceritinib versus standard chemotherapy. 

The good news is the fact that the alectinib study has already completed accrual, and so has ASCEND 4 and so, in the very near future, most likely within the next two years, we will have this agent being considered as a standard first-line therapy for patients with ALK-positive disease.

There is one question that we need to ask.  We may have this so-called show, a progression-free survival but we always do ?[salvage] a patient after crizotinib.  What kind of improvement in progression-free survival are we looking for, before we change our practice?  I obviously do not have the answer, but this is a worthwhile question for you to ask: what are the differences that you are looking for.

ASCEND 3: efficacy in patients who present with brain metastases

The brain is obviously very important and you have already heard many things about ASCEND 3 in terms of brain metastases.  I just wanted to show you again the fact that the median progression-free survival is about 11 months. 

Should you start the patient with brain metastases at presentation with a second generation, a first [….] agent?  That is actually still debatable, but the ASCEND 4 as well as imatinib will help us to find the answer.

Promising agents

The list is still very long, in the sense that there are so many different agents.  It is difficult to design, at this moment, until we have more data, but certainly there is no shortage of choice of therapy.  There are a few already entering Phase III studies, just started, and so we probably will have some answers in a few years’ time.

[Slide]

In terms of the so-called management of resistance, it is actually more complex. 

Novel combinations in NSCLC

I will not go into great detail but, certainly, looking at the possibility of PDL-1 in ALK-positive [patients] is being investigated.  This is actually a Phase I/II cohort extension study, looking at ALK-positive, EGFR and also cMET positive disease, in combination with a so-called novel agent with nivolumab – and, hopefully, we may get some signal.  Obviously, it is not as easy at this stage, because the two may not be well-combined, but this is certainly one direction we can look for in the future of how to manage resistance.

Summary

Let me just summarise.  In the situation we are in, we have to know the molecular data of each individual patient, and particularly for the patient with ALK positive disease.  We have a number of choices.  In the future, we will be looking to the NGS as well as the plasma RNA, and then we have a long list of new agents being available.  Certainly, the combination of targeted therapy and immunotherapy will certainly be in play of investigation for the future.

1995 – collaboration – 2015

Let me again say one thing: 1995 to 2015.  We have travelled a long way, and we have to travel a long distance but, from my personal experience, I can say that only one thing can make this work, and that is collaboration.  I certainly look forward to future collaboration with all of you. 

Thank you for attending the Symposium

Thank you very much for your time.