Mark G. Kris, MD; Giorgio V. Scagliotti, MD


June 12, 2012

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Mark G. Kris, MD: Hello, I am Mark Kris, Chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center in New York. This is Medscape Oncology Insights on lung cancer.

Today we will look at some of the important studies on lung cancer that are being presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO®). Joining me today is Professor Giorgio Scagliotti, Professor of Medical Oncology and Chief of the Department of Clinical and Biological Sciences at the University of Torino and the San Luigi Hospital in Torino, Italy. Giorgio is a leader in worldwide oncology care and research, particularly in Europe, and today we are going to talk about his special perspectives on the data. Welcome, Giorgio.

Giorgio V. Scagliotti, MD: Hi, Mark.

Spotlight on Mutations and Immunotherapy

Dr. Kris: We are at ASCO® and seeing the information coming out. I would like to hear from you: What do you think is the single most important piece of information you have heard here that can affect lung cancer care and research?

Dr. Scagliotti: In this period of time, we are going through a transition, incorporating important news about the epidermal growth factor receptor (EGFR) mutations and the ALK translocated tumors. At this meeting we are hearing about 2 important developments that add to the information we received in recent years: the new but rare mutations, ROS1 and RET translocated tumors, and another study done in fully genotyped tumors for EGFR mutations. There were also a couple of interesting findings related to the potential role of immunotherapy in the field of lung cancer, and additional (but not new) information about the role of pemetrexed in the maintenance setting. Other news is not going to change our clinical practice too much at the present time.

Dr. Kris: I agree with you that from the different abstracts, some changes will happen in the next few months or years. Let's go through them one at a time.

Immunotherapy Finally Works

Dr. Kris: I would like to first talk about the immunotherapy advances and particularly the PD1 trial.Multiple abstracts were presented, and one in lung cancer in particular by Dr. Brahmer from Johns Hopkins[1] showed that the PD1 antibody is a very specific immune modulator. I always wanted to develop immune therapies, but they never seemed to work; their promise was never fulfilled. In this trial, they were able to show, in a cohort of lung cancer patients who had previous therapy and whose cancers grew despite therapy, that using the anti-PD1 antibody actually led to regressions. I was very impressed by that -- there were many regressions and the regressions lasted for a year or more. Giorgio, what are your thoughts on those data?

Dr. Scagliotti: Overall the concept is quite fascinating. It is not new, because the role of immunotherapy, and the search for a rollover immunotherapy, is an old concept going back to the 1980s. Unfortunately, we didn't have any success in beating the tumor through immunopotentiation. We have some ongoing studies in which we are trying to explore this possibility. The study presented yesterday showed long-lasting responses.[1]The anti-PD1 monoclonal antibody is a new generation of molecules preceded, for instance, by ipilimumab, which was already explored in the field of lung cancer. With ipilimumab, they saw response in squamous cell lung cancer, and in this trial of the anti-PD1 monoclonal antibody they saw more response in squamous cell. This trial has some limitations because we are talking a phase 1-2 clinical trial, and we already know a lot about overestimation of the results through phase 1 and early phase 2 clinical trials. We need to be careful, but at least the concept is worth being investigated in a larger cohort.

Dr. Kris: What was of great interest to me was the fact that this is a more specific modulator of the immune system. It goes against the real problem and, that is, you would think that the body would find a way to identify cancer cells and destroy them as it would any other type of foreign invader (cancers have all these different proteins and things like that), but that doesn't happen. The PD1, however, seems to be a critical part of the pathway that turns off the natural immune defense that you would expect. Also, it's not a nonspecific stimulator of immunity; it focuses on this one area. I am also excited about it because as much as we have gained from all of our targeted therapies, none of them, in patients with metastatic disease, has achieved a cure. We have to find a way to take that next step. What we really want to do is cure our patients, and this is coming in with a totally different and really complementary approach. The people who are working in the melanoma field are already doing this; they are using a targeted therapy and ipilimumab. We can clearly see how in the next few months or years we are going to have those same kinds of strategies.

Dr. Scagliotti: You need also to acknowledge that the antigenicity of melanoma is different from the antigenicity of non-small cell lung cancer.

Dr. Kris: That is true, and again, they are different targets, different diseases, and different contacts, but at least it gives us a way to go.

Afatinib Effective, but Watch Toxicities

Dr. Kris: The other development -- and many people were waiting for this -- were the data from the randomized LUX-Lung trial[2] of patients with EGFR mutations who received either initial afatinib or our standard chemotherapy, the combination of pemetrexed and cisplatin. There were similar data years ago from the IPASS trial,[3] but it was carboplatin and paclitaxel, and thanks to work that you did, there is the feeling that that combination may not have been our best and most effective chemotherapy regimen, that a pemetrexed-based regimen with cisplatin would be the best one that we have. The folks who put this trial together have shown that afatinib leads to more responses, better symptomatic outcomes, and better progression-free survival. What are your thoughts about that trial, and how do you think it will affect care in Italy and throughout Europe?

Dr. Scagliotti: This is the fifth or the sixth trial that addressed the same question -- what EGFR-TKIs [tyrosine kinase inhibitors] can do compared with chemotherapy when administered as front-line therapy. We have other studies using gefitinib and erlotinib that showed clearly that EGFR-TKIs are associated with much better progression-free survival, much more response, and a better quality of life. I don't care if there is no improvement in survival between the 2 arms because obviously if you are dealing with an oncogenic-addicted tumor, the activity of the agent is still there in second- and third line, so you don't see any benefit in overall survival. What is much more important to me is the absolute numbers in terms of overall survival. Ten years ago, patients with stage 4 non-small cell in cancer did not survive more than 1 year, and now in this patient population, we are seeing 24-month survival and even longer. The results of this study are fully consistent with the results of the other studies.

For me, the LUX-Lung study is not going to change anything, even if there are some additional properties from these agents compared with gefitinib and erlotinib. It is a matter of fact that there is, in terms of primary endpoint, an improvement in progression-free survival. I have some concerns because every kind of mutation was included in the study, and we know that exon 19 and exon 21 are the most sensitizing mutations. In addition, there are some imbalances in the patient characteristics that may potentially jeopardize the data a little bit -- not too much.

The other important information that we got from this study (and this is one of the first studies in which cisplatin and pemetrexed was the control arm) is that the number of responses and the progression-free survival in the chemotherapy arm were much better than what we saw in the registration study for pemetrexed. The bottom line is that the activity of chemotherapy is much better in this special patient population that is mainly represented by adenocarcinoma and the high proportion of never smokers.

Dr. Kris: I agree with your last comment that it was an amazing observation about why these patients who have EGFR mutations have much better results with standard chemotherapy as well. It is actually a great topic for research. I am surprised that more people haven't gone after that already. Even with the improved outcomes with chemotherapy, afatinib was still more effective in terms of response than in progression-free survival. Do you think that having a third agent will be helpful in Europe?

Dr. Scagliotti: My personal expectation is that that specific agent is not going to change anything in the prescriptions of the community physicians. This is just a matter of individual physician decision. But in terms of science, it is not going to change anything. Personally, I am a little bit concerned about the toxicity profile of this irreversible EGFR-TKI -- the gastrointestinal and skin toxicity, but especially the gastrointestinal toxicity – because this type of patient, on the average, takes an EGFR-TKI for an extremely long period of time. When we talk about a median survival of almost 11 months, we are talking about 50% of the population, so another 50% of the population is getting the drug for more than 11 months. This is something that we need to take into consideration unless we are able to minimize the gastrointestinal toxicity.

The Waiting Room Tells the Story

Dr. Kris: I share your thoughts and concerns on that. We have been able to use afatinib in a lot of different clinical trials. By adjusting the dose to an individual patient's tolerance, the drug usually can be continued for a long time. This is another example of how this whole EGFR story has changed our thinking. It used to be about pushing a drug to toxicity and being able to give it. But now, a grade 1 toxicity going on for 2 years is intolerable to a patient, and it's a whole different ball game -- in a good way. I love having people on it for years. Your comment about people living for years, it's really extraordinary. A great thing happened to me a few months ago. A patient I had been taking care of for about 8 years, who has been through many different types and lines of therapy, came up to me and said, "Dr. Kris, I have been sitting in your waiting room now for 8 years, and I have to tell you something: The patients with me in the waiting room look so much better."

Dr. Scagliotti: Yes, it's true.

Dr. Kris: It is true, but to hear it from someone who has lived through it, that is the amazing thing about these drugs.

Getting the Dose Right

Dr. Scagliotti: May I ask you a question?

Dr. Kris: Sure.

Dr. Scagliotti: Do you believe that the recommended doses for erlotinib and afatinib in the EGFR mutations are really the best doses?

Dr. Kris: I don't, and starting with primary data, these phase 1 trials were not conducted in a mutated population. I am quite certain that the toxicity profile is different. The other thing that we noticed in the laboratory is that the ability to inhibit a mutated kinase requires a much lower dose of the drug.

Dr. Scagliotti: Yes, that was my sense.

Dr. Kris: There are some manuscripts on this. Dan Costa's group[4] from Boston has collected data on patients receiving 25 mg of erlotinib and found that for those patients in whom the dose was titrated to tolerance, many of them had very long survival and very good tolerance.That is a message as the afatinib trial comes out: You need to pay attention to toxicity, because you have to be ready for this patient to be on the drug for long periods of time -- perhaps lifelong in my way of thinking -- and you have to adjust that dose just as you would any drug, just as you would with myelosuppression. Rash and diarrhea are not trivial toxicities, particularly when they go on for years.

New Targets: ROS1 and RET

Dr. Kris: I was excited at the meeting to hear about the 2 new targets that were presented: ROS and RET. Would you like to give us your thoughts on those?

Dr. Scagliotti: This is the other amazing piece of the story because we got information at the beginning of this year about the ROS1 translocated tumor.[5]We got this information about the RET translocated tumor.[6]We are talking about 1.5% of our patients with adenocarcinoma. I estimate the number of patients. In Italy, when we talk about 1.52% of all patients with adenocarcinoma, we are talking about 1000-1200 patients a year, and I believe that you need to multiply that by 5 for the United States. It is a minority of our patients, but this is another piece of the oncogenic-addicted tumors.

We have 2 important pieces of information for the ROS1 translocated tumors. We heard in the presentation from Dr. Shaw[7] that even if we treated only a few patients with the ROS translocation, the vast majority of patients with ROS1 translocation treated with crizotinib will have tumor shrinkage. We cannot say too much about the time to progressive disease, but we saw a couple of examples of dramatic responses. In the case presented by Dr. Shaw, there was a quick improvement in a few days. The patient had been on permanent oxygen therapy, and he was off of oxygen in a few days. For me, that was the main message. The other important piece of information is related to the RET translocated tumors. We don't have data, but we already have agents available. That is another piece of information.

Dr. Kris: And the ROS1 too. In the United States, where we have crizotinib available, we already have a drug on the market that could be used to treat patients with ROS1-driven tumors.

Dr. Scagliotti: That is an issue for us in Europe, because if we get information about a ROS translocated tumor, we cannot treat the patients because we are not able to use crizotinib. Crizotinib is not yet registered in Europe, and that is a big practical issue and also an ethical issue, if you consider the ethical point of view.

Dr. Kris: We are lucky to have crizotinib available here. Our Food and Drug Administration approved that drug very quickly. It has been available since last August. Not only does it treat the ALK and the ROS1 mutations, it also treats people with MET-amplification; so, we have 1 drug that goes after 3 targets. Drugs already on the market that could be used to treat RET are sunitinib and vandetanib. To me, that is one of the main reasons that this is an exciting finding, because we don't have to wait for the discovery of a new medicine; the drugs that are already in the pharmacy can be used to fight those diseases.

Dr. Scagliotti: We already have some kind of information available. If you go back to the BATTLE study[8] conducted a few years ago in the United States, they enrolled at least 120-140 patients to either sorafenib or vandetanib. If the patients had outstanding responses, they could verify whether they had the RET translocation or not. This is another piece of information that is going back and forth, just to increase our knowledge.

More Targets to Be Discovered

Dr. Kris: We are doing that as well. Any final comments you would like to make about the meeting, or take-home messages?

Dr. Scagliotti: I believe that we are now going through a transition time. We learned about this rare genomic mutation mainly in adenocarcinoma. We wait to learn much more on squamous cell carcinoma. Why are we going through a transition time? We are going through a transition time because a couple of years from now, we won't be doing sequential genomic testing; we will move to a multiplex platform to increase our ability to systematically screen for this type of rare genomic mutation.

Dr. Kris: We have seen that at the meeting too. There are presentations[9] showing how these multiplex platforms are working today, and I agree with you that they are going to take over, and every patient at diagnosis will have all the relevant genes tested at once. It is the only practical way to move forward.

Dr. Scagliotti: We will be back next year.

Dr. Kris: Giorgio, thank you so much for joining me today and sharing your insights about the meeting and bringing a different perspective than we have here in the United States. I would like to thank all of you, our audience, for joining us for this edition of Medscape Oncology Insights. This is Mark Kris reporting from ASCO® 2012.


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