Prof. Georgio Scagliotti, MD, PhD: Lung Cancer Mutations and the Future of Treatment

Prof. Georgio Scagliotti, MD, PhD discusses the importance of genetics in lung cancer and its various mutations (CMET and ALK pathways) at the 14th Annual World Conference on Lung Cancer 2011 in Amsterdam.

The Group Room at the 14th Annual World Conference on Lung Cancer (WCLC) was made possible, in part, by:

 

VIDEO TRANSCRIPT

Selma R. Schimmel, Founder & CEO, Vital Options International:

This is Selma Schimmel for The Group Room at the 14th World Conference on Lung Cancer, WCLC, organized by the IASLC, the International Association for the Study of Lung Cancer; we are in Amsterdam.  And we’re joined by our good friend, Professor, Doctor Giorgio Scagliotti, who is Director of the Department of Clinical and Biological Sciences at the University of Torino, Italy.  Hello, Professor Scagliotti.

Prof. Giorgio Scagliotti, MD, PhD, Head, Thoracic Onc. Unit, Univ. of Torino, St. Luigi Hospital, Italy:

Hello.

Selma R. Schimmel:

Professor Scagliotti, we understand now that the ability to detect mutations to drive development of lung cancer is really changing the whole landscape of therapies that are available, that go and work in sync with these different mutations.  Would you please explain some of that for us?

Prof. Giorgio Scagliotti:

Well, we are really facing a sort of roundabout because we are truly convinced, and this is something that was already clearly understood in the pre-clinical setting, that any kind of cancer, it’s a sort of genetic disease related to genetic changes in the genome code.  And let me say in a more broad way that cancer is of the genome and in some patients, in some cases, this genome is starting to work less efficiently and when it is working less efficiently it’s accumulating changes and these changes are changes in the sequence of the genome or in other cases there are pieces of the genome that are translocated to another area of the genome.  And this is creating a set of changes that sometimes, in some diseases, and obviously this is different from one tumor type to another, is generic in the critical environment for favoring the progression of the tumor, the expansion of the cancer cells, and those are the ability to proliferate of the cancer cells.  And this is the general concept behind this genomic changes, that we call somatic mutation or translocation.  All these changes are giving some advantages to the cancer cells compared to the normal cells through the program, the normally functioning genome.  This is what I can tell you, so we have these kinds of changes, these changes are accumulating over time, we need a critical number of changes.  This is something that was new already in the past in colon cancer, carcinogen disease, in the pivotal work of Dr. Vogelstein, almost going back to 15-20 years ago told us exactly the sequence of these genomic changes in colorectal cancer, carcinogen disease.  Now we know, we are starting to know, that a set of genomic changes are also in place in lung cancer.  This is mainly true for never-smokers.  That is, by the way, it is an important subgroup of patients with non-small cell lung cancer.  We see a growing proportion of patients that are light smokers or never smokers with lung cancer and this is telling you again, that this subgroup of patients, probably, there are some changes independently from tobacco exposure that are going on because the genome is, in some way, fragile and this is lending to this kind of genomic changes.

I would like, just briefly, address with you how much importance this, for the patients, to push the physician, to push the medical oncologist, to get the full genotype of his or her tumor, especially if you are a never smoker, especially if you are a light smoker.  You have a relatively high chance to have a mutation.

Selma R. Schimmel:

You know, you raise a very good point and I’m glad you raise it because I think that what you just said is a hugely important message for the viewer, the patient who is listening, because they have an opportunity, it perhaps sometimes falls on them to be sure that that tumor tissue is properly analyzed.  And it’s not like with some of the other cancers where you have a limited number of physicians, specialists involved; lung cancer involves you, the medical oncologist, it involves the pulmonologist, it involves the thoracic surgeon, it involves the pathologist… The role of the pathologist in lung cancer must be just exploding.

Prof. Giorgio Scagliotti:

Ya, having this multidisciplinary approach in mind, we should also recognize that in the last 3, 4 years it became everyday more relevant to get enough tissue.  So we need to explain to the patients that probably the medical oncologist or the thoracic surgeon, the respiratory physician, we are asking the patient for a more invasive procedure.  But more invasive procedures are not necessarily, as we’ve said, increasing amount of side effects but this need for a sufficient amount of tissue sometimes is really the key.  Because, first of all, you need to do the histological diagnosis, but at the same time at the time of the histological diagnosis, what we call the molecular pathologist will be able to do additional analysis; additional analysis that, in principle, can lend to a more specific definition, but at the same time having the specific definition and knowing, at least at the moment, most of these genomic changes are related to adenocarcinoma.  We know we can do additional genomic analysis to see, at least, if the tumor is carrying on EGFR mutations, or ALK translocation, or there is a KRAS mutation.  At the moment, we don’t have any drug available for KRAS mutation, but again, medical oncology is a moving field, it’s a sort of evolving field.  What is not available today could be available one year from now; and it could be still of value for the current patients because it could be that one year from now we will get a new drug for KRAS and they can receive it second, third, fourth line disease.

Selma R. Schimmel:

Well, it’s also the collective data.

Prof. Giorgio Scagliotti:

Yes.

Selma R. Schimmel:

Alright, now let’s talk about, What does it mean that we are investigating CMET inhibition?  In simple English, what is that?

Prof. Giorgio Scagliotti:

CMET is another pathway.  It’s one of the many pathways that are involved, I think, in some way in sub-proliferation, in progression, in the generation of metastatic cancer.  While CMET is not new in the field of preclinical research because we have already plenty of information, we know that there is some genome proliferation.  The number of the copies of the specific gene are increased in 1-7% of all the cases of non-small cell lung cancer.  In the presence of these proliferations is set with a worst prognosis.  But we know, also, that CMET has a role in the generation of the metastatic processes as I said to you before, and we know also that CMET implication could be, and it is, a mechanism of resistance to EGFR TKI’s in those patients that they have an EGFR mutation, they were supposed to erlotinib or gefitinib, and they became, in a second time, resistant to these agents.  In this group of patients, in 20% of the cases, the investigators detected that as a mechanism of resistance a CMET implications.  So there is a good scientific rationale to add to erlotinib or to gefitinib, MET inhibitors.  And we have different MET inhibitors currently in clinical trials.  Some of them are just in the phase two program, others are proceeding in the phase three program.  We know and we are currently evaluating in the context of at least a couple of phase three clinical trials, these agents with the prospective collection of tissues and also investigating several biomarkers including most famously for CMET gene companion assessment.

Selma R. Schimmel:

Every day that a lung cancer patient survives is one day closer to a new possibility.  As these drugs are still in clinical trials, in the not-too-distant future we will be able to see these drugs available to help many, many of these patients.

Prof. Giorgio Scagliotti:

Yes, but to get this next day closer you need to put yourself on a clinical study, that would be the best.

Selma R. Schimmel:

Exactly, and we encourage patients to get that second opinion at academic centers where these trials are going, because it’s really together that there is the paradigm shift in treatment.

Prof. Giorgio Scagliotti:

This is another important message that I would like to give to everyone.  I believe that we need to convince people that they can receive the same standard of care in the community, but when the clinical trial is becoming an option they should consider moving to an academic institution where there are several options and then there are physicians that are doing these kinds of activities all year round.

Selma R. Schimmel:

Professor Scagliotti, we have promising news in the area of maintenance therapy.  First of all, what is maintenance therapy mean?

Prof. Giorgio Scagliotti:

The maintenance is a relatively new approach.  You know that for systemic treatment the guidelines are recommending the use of a platinum agent in combination with another compound that could be for pemetrexed (Alimta) for non squamouns, as I showed in a larger phase three clinical trial almost 5 years ago, or for squamous histology with taxanes (Taxol or Taxotere) or mizoribine or gemcitabine (Gemzar) but chemotherapy is still an option for the vast majority of our patients, front line maintenance or second line.  And after front line, the current standard of care is to stop treatment waiting for progression.  Sometimes this strategy is not working for the patient, it’s not working for the physician because when you are getting a good objective response, in other words you are getting tumor shrinkage that is clinically available at the radiological element, you are making yourself the question, ‘is it time to stop chemotherapy, or not?’  So the reason why maintenance is coming out from this question that I just made and maintenance is the possibility to go ahead with the systemic treatment beyond this four or six cycles, continuing with one single agent; it could be either a biological agent or a cytotoxic agent up to progression.  Now, if you want to extend chemotherapy beyond this four to six cycles you need to have an agent like pemetrexed that is extremely tolerable and safe.

Selma R. Schimmel:

And for our US listeners, they know that as ALIMTA, because that is the generic name you mentioned.

Prof. Giorgio Scagliotti:

And again, the paramount started that has been presented a few weeks ago at ASCO, and the study has been updated with additional data.  At this meeting, it’s showing for the first time that if you are given cisplatin / ALIMTA as an induction treatment and then you are continuing with ALIMTA alone in the maintenance phase you are getting a slowing of your time to progression.  So the progression of the disease is coming later in the course of the disease.  And we are waiting, obviously, until the end of this year, the beginning of 2012 to get also, mature survivor data.  If there will be also normal survival improvement I truly believe, even if we need still to select the most appropriate patient, continuing chemotherapy with a single agent after induction with this blood and pemetrexed, then squamous histology may become an option.

Selma R. Schimmel:

Professor Scagliotti, thank you for making it so much easier for our viewers to understand this complex genomic area and also for taking time out to mention some of the other cancers that we don’t hear so much about.  These patients deserve time and attention too, and we all appreciate that you just acknowledged that.  Professor Giorgio Scagliotti: the Director of the Department of Clinical and Biological Sciences at the University of Torino in Italy.  You always make time for The Group Room.  And thank you so very, very much.

Prof. Giorgio Scagliotti:

Thank you.

END OF VIDEO

 

 

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