Giorgio V. Scagliotti, MD, PhD; Thierry Le Chevalier, MD


October 05, 2011

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Lung Cancer: A Multidisciplinary Approach

Giorgio V. Scagliotti, MD, PhD: Hello. I am Giorgio Scagliotti, Professor of Respiratory Medicine at the University of Torino and Chief of the Department of Clinical and Biological Sciences at the San Luigi Gonzaga Hospital in Torino, Italy. Welcome to this edition of Medscape Oncology Insights.

Today, we will look at the ongoing research areas in lung cancer and some of the studies presented at the 2011 European Multidisciplinary Cancer Congress, being held in beautiful Stockholm. Joining me today is Dr. Thierry Le Chevalier, Professor and Chief of the Department of Medicine at the Institut Gustave Roussy in Villejuif, France.

Welcome, Thierry, to this discussion. In your expert opinion, what research areas discussed at this meeting do you consider of particular relevance for the management of lung cancer in the clinical setting?

Thierry Le Chevalier, MD: When we organized this meeting, we tried to cover all aspects of treatment, including surgery, radiation therapy, imaging, chemotherapy, and targeted agents. We have to mostly focus on areas of medical treatments and, of course, on targeted agents. There are also some interesting data on surgery and some aspects of limited surgery and adjuvant treatment and the origin of disease. This is probably mostly covered by targeted agents and translational research -- where we are today.

Target Control: Can it Cure Disease?

Dr. Scagliotti: In the last couple of years, we had a lot of excitement in the field of non-small cell lung cancer. We were used to treating all patients with the same chemotherapy regimens, obviously with some minor differences based on the expertise of each individual physician or medical oncologist. Now, in the last 2-3 years, we have had an explosion of genomic research in lung cancer. What do we have ahead of us?

Dr. Le Chevalier: There are 2 different aspects to what is ahead. The first is translational research by itself and the fact that we have seen and identified more potential targets. We don't know whether those targets are dominating the cancer process and are able, if they are well controlled, to cure or at least prolong survival.

The major issue is that in 10%-20% of patients with adenocarcinomas, we now have therapeutic targets that cover more than 50% of adenocarcinomas. We are seeing targeted and personalized treatments appearing in the landscape for squamous cell carcinoma. The most difficult issue that we may have today is the global strategy for the patient. We are improving the strategy against the tumor, but we must not forget that the enemy is the tumor and the partner is the patient.

Dr. Scagliotti: You are addressing an important issue that is still at an extremely experimental level, and that is the interaction between the cancer genome and the host genome. This is an important question mark, but let's imagine for one second that you are standing in front of a community-based medical oncologist who is asking you, based on your expertise, which kind of targeted therapies do we already have available for treating our patients in the clinical setting?

A Shooting Gallery of Targets

Dr. Le Chevalier: The most established target, of course, is the epidermal growth factor receptor (EGFR) mutation. We have known for the last 5-6 years that a mutation is highly predictive of a sensitivity to EGFR inhibitors, particularly to tyrosine kinase inhibitors. This is an enormous improvement for many patients, particularly those who are nonsmokers or light smokers, and more women than men, but overall that covers around 15% of our adenocarcinomas in the Western countries, which is a substantial number. We have seen a small niche with extraordinary activity if we look at crizotinib ALK translocations. This represents a small minority of patients, but the results are very exciting and prolonged. Now we are more frequently seeing some classical mutations like KRAS, and we are at the beginning of specific treatments for patients who have KRAS mutations.

Dr. Scagliotti: This was my next question. Is it true that we can detect some kind of mutations in 50% of our patients with adenocarcinoma? They are mainly never-smokers and light smokers, and 20%-25% of patients with adenocarcinoma have a KRAS mutation. Apparently we don't have any agent -- after more than 30 years of research -- that is able to fight or to control KRAS mutant tumors. Do you foresee something in the near future for these kinds of tumors?

Dr. Le Chevalier: We are at the beginning with KRAS mutations, but we have seen some signals, such as the role of antiangiogenic tyrosine kinase inhibitors, that have given some promising early results. We can't establish a protocol with a guarantee of activity, but that's the beginning. And for those of us who are in clinical research, it's a very exciting signal.

With respect to squamous cell cancer, we have some fibroblast growth factor inhibitors that give some signals too. Of course, it's too early. We can expect that within the next 5-8 years we should have 1 or 2 driving targets for a great proportion of non-small cell lung cancers, for which we will be able to create a strategy of treatment.

The problem is that we are mostly speaking about patients in the metastatic setting. For those patients, we will be unable to prolong survival. We know that the survival of an advanced non-small cell lung cancer is poor. It's around a year to 15 months, so even if we double that, survival between 2 and 3 years at best remains an enormous issue. We have to introduce these biological data, these identified targets, in the armamentarium at an earlier stage. At the moment, we don't know how to do this in the adjuvant setting.

Dodging Acquired Resistance

Dr. Scagliotti: The major point against the widespread use of these targeted therapies in the early stages is the fact that we already saw in advanced disease that you can have a driver mutation. You can have an effective agent against the driver mutation, but at after 9-10 months, the patient relapses. This leads me to the interesting and complicated field of acquired resistance to TKI and crizotinib. What's going on in this field?

Dr. Le Chevalier: Many companies are working on that. In academia, we are working on that. Up to now, most of our data are theoretical and have no clear impact on patients. We have some drugs in case of EGFR-mutated patients with an acquired resistance. We have some signals. We have no clear activity or prolonged activity for these patients.

Personalized Chemotherapy

Dr. Scagliotti: Let me move to another question. It's quite unlikely that in a reasonable timeframe we will be able to find or to discover important and relevant mutations in all of our patients with non-small cell lung cancer. Reasonably, we will be able to treat 30%-40% of our patients whose tumors have some kind of mutation. That leaves at least 50% of patients who will be treated with classic chemotherapy. What do you see in the near future, and do you envision a modern interpretation of the classical chemotherapies?

Dr. Le Chevalier: That is another part of what we call personalized medicine. You were among the first, with pemetrexed, to show us that in non-small cell lung cancer, one of our major drugs used daily was more active in adenocarcinomas and in large cell cancer than in squamous cell cancer, where it did not work. We have believed for years that small cell lung cancer had to be treated in the same way. We know today that it's not the most appropriate. We still do not have absolute proof that choosing our cytotoxic agents according to some biomarkers is really relevant and active, but we are on the way. Some markers, such as beta-tubulin, RRM1, and ERCC1, are in front of us. We have to work better on that. We have some interesting signals but not enough to use in daily clinical practice today.

Who Benefits From Adjuvant Therapy?

Dr. Scagliotti: Before we end, could you make a short comment about multimodal adjuvant therapy in early-stage, completely resected non-small cell lung cancer? You did an important study in the adjuvant setting, so I would like to get from you a sense of what is going on. What is the standard 10 years later?

Dr. Le Chevalier: With the IALT study,[1]I think that we have proven that there is a small benefit of adjuvant chemotherapy in non-small cell lung cancer. That has become a standard in the management of these patients. What we have not done what was done 15-20 years ago in breast cancer and 10 years ago in colon cancer, which is to select which of our patients are the most likely to benefit from this adjuvant chemotherapy. We give it to all patients. That's certainly not the best way to use adjuvant chemotherapy. We still have a lot to do to improve the indications for adjuvant chemotherapy.

Closing Remarks

Dr. Scagliotti: Thank you so much, Thierry, for joining me in this edition of Medscape Oncology Insights. This is Giorgio Scagliotti signing off from the Multidisciplinary Congress in Stockholm.


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