Mark G. Kris, MD; Luis Paz-Ares, MD, PhD


June 19, 2014

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Mark G. Kris, MD: Hello. I am Mark Kris, Chair of Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. Welcome to this edition of Medscape Oncology Insights on lung cancer, coming to you from the 2014 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

Joining me today is Dr. Luis Paz-Ares, Head of the Oncology Service at the Institute of Biomedicine in Seville and the University Hospital in Seville. Welcome, Luis.

Luis Paz-Ares, MD, PhD: Thank you.

EGFR-TKI Resistance Solved

Dr. Kris: We have heard a lot of interesting information, some of it frankly exciting. I would like to hear what has caught your attention here.

Dr. Paz-Ares: There have been quite a few new data. For me, the most impressive were the trials[1,2] on the epidermal growth factor receptor (EGFR) T790M mutant inhibitors. The inhibitors of this resistant kinase have shown very impressive results, with 60%-70% of patients having a response, and 80%-90% having disease control. And their responses seem to be quite long-lasting.

This is all the more fascinating because those inhibitors are not "touching much"; the side effects are minor -- very little rash or diarrhea. Overall, this is very good news for patients with EGFR mutations when they develop disease resistant to classic EGFR-tyrosine kinase inhibitors (TKIs).

Dr. Kris: I agree. This is an amazing story and what we all aspire to do here. They found a clinical problem -- T790M resistance -- which affects 60% of people treated with an EGFR-TKI. They went back to the laboratory and found a drug that would specifically target those double-mutant cancers and not hit the wild-type, and it worked very well; the response is more than 50%, without inhibiting the wild type. It's a great story. When we saw the data yesterday, they were quite clean. The drugs worked. There was little doubt about that. The side effects were expected and manageable and will not be impediments to using those drugs. We hope that they are going to be in our pharmacies right away.

Dr. Paz-Ares: This benefit is going to be added to the earlier benefit from EGFR TKIs. I would expect these drugs to have a clear impact on survival in those patients, perhaps going from 2.5 to 3.5 years, for example. We will see what happens when more mature data are available, but this is very good news.

Dr. Kris: These drugs are also very effective against single mutants, so you could easily see -- and these trials are already underway -- giving these drugs up front. Imagine giving erlotinib or gefitinib with no side effects and preventing or delaying T790M. That would be an amazing opportunity for our patients.

Onartuzumab: Failure of Therapy or Patient Selection?

Dr. Kris: That was good news, but there was some news that we didn't expect, about the onartuzumab (MetMab) trial.[3] Do you want to comment on that?

Dr. Paz-Ares: Yes. Unfortunately, the trial is clearly negative, so there is no benefit for the addition of this monoclonal antibody against MET when added to erlotinib, compared with erlotinib alone, as a treatment for patients already treated with chemotherapy.

My take here is that possibly, looking back to the data we had before, we are now treating patients with tumors that do have the target -- the MET. However, MET is not important to the behavior of the cells in all cases. We only know that the MET receptor is there because we have done an immunocytochemistry test. However, we don't have much data about the biological meaning of expression by itself in cell lines. Therefore, this is possibly not the failure of a therapy but a failure of the way of selecting patients. We might not have had the right biomarker.

There were some nice data during this ASCO, a very small trial[4] in a cohort of patients with amplified MET non-small cell lung cancer. Those patients had been treated with a specific inhibitor -- in this case, a small molecule (crizotinib), and they had some very nice response rates.

Right Target, Right Drug, Right Patient

Dr. Kris: You have pointed to the lesson that we can learn here. Neal Rosen, who I work with, constantly points out that you have to have the right target, and then you have to have the right drug. And I would add that you have to have the right patient.

Dr. Paz-Ares: Absolutely.

Dr. Kris: Probably in the onartuzumab trial, some of the steps were missed. As you point out, when you have a different target -- in this case, amplification of MET, and you have a drug that very potently inhibits MET kinase in the amplified patients -- you have a very different result. It's not that targeting MET isn't a good strategy. Targeting MET protein with onartuzumab wasn't a good strategy.

The other cautionary note here is that we who do clinical trials very often look for the silver lining when things don't work out. And the truth was, that original randomized phase 2 trial was a negative trial.[5] In retrospect, they found a subgroup who appeared to have some benefit. However, they never went back and did a formal trial testing that hypothesis. That is another take-home lesson: When you have an observation from a subgroup, you need to test that in and of itself before going to a phase 3 trial.

Dr. Paz-Ares: The observation on the MetMab-positive patients in the phase 2 study was mainly a secondary observation (which is a good hypothesis), rather than data that are confirmed. This trial has somehow been a consequence of this reading. Of course, it's very easy to say now that the trial was wrong, but we are doing the analysis in retrospect.

Dr. Kris: In thoracic oncology, however, we have done this over and over again. I have a lot of experience with treating people with EGFR-TKI inhibitors who did not have tumors that were dependent on that pathway. We all know how that turned out, but we need to learn from what we have here. That is the message today. People need to understand that although we have this negative data for MET protein expression with onartuzumab, we have some very exciting data with crizotinib, and it is a drug that we have right now.

A New Drug for Squamous Cell?

Dr. Kris: We also seem to have a drug that is moving toward approval in squamous cancer. Can you talk about that a little bit?

Dr. Paz-Ares: Right. This is necitumumab, which is a monoclonal antibody against the external domain of the receptor. The drug itself is quite similar to cetuximab, which we have known for a long time. In this trial,[6] patients with squamous cell carcinoma advanced disease were randomly assigned to receive typical chemotherapy (cisplatin plus gemcitabine) with or without the monoclonal antibody.

At the end of the day, the top-line results are that there is some increase in overall survival for patients treated with the combination of chemotherapy plus necitumumab. Of course, the benefit is not huge. But I would say that it's a relevant advance in a disease such as squamous cell carcinoma, where there have been very few advances during the past 2 decades.

Dr. Kris: And that result is going to help cause a resurgence of interest in research in that area, which will be helpful for our patients. Squamous cell represents one fourth of patients with lung cancer, so it's not a tiny subgroup. It is very important that we focus on them.

Crizotinib: A Higher PROFILE in Europe?

Dr. Kris: Before we move away from targeted therapies, there were some data about the use of crizotinib and comparing it with chemotherapy. The approval here in the United States is that for any line of therapy in anaplastic lymphoma kinase (ALK)-positive patients, crizotinib could be used, but it's not true worldwide. How does this PROFILE trial[7] affect care in Europe?

Dr. Paz-Ares: The PROFILE 1014 trial compared standard cisplatin-based chemotherapy vs crizotinib for patients with ALK-rearrangement who had not received previous treatment. For us in Europe, this has really been a problem. We were not allowed to treat our patients with crizotinib even though we knew that it probably was the best treatment because of the second-line trials.

Now we have confirmation that crizotinib seems to be the best option for those patients -- it is more efficacious, and it's less toxic than chemotherapy. This is going to be very important for our patients because our payers might now allow us to use this therapeutic option once the drug has been registered.

Dr. Kris: It is another very helpful trial. It's my understanding that in Asia as well, that will help provide access to the drug, which has had such dramatic benefits, to our patients.

Dr. Paz-Ares: That is a good example of a trial for which we expect certain results on scientific grounds, but the results are very important and pragmatic for our clinical practice because our regulatory agencies really need those results to allow us to prescribe the drugs.

Immunotherapy Making Its Mark in Lung Cancer

Dr. Kris: We need to also remark on the number of trials that we have seen of therapies targeting T cells -- those antibodies targeting PD-1 and PD-L1, and antibodies targeting the CTLA-4. Four different molecules against PD-1 and PD-L1 were presented at the meeting,[8,9,10,11] and a couple of different molecules against CTLA-4.[12,13] Consistently, there was activity across the spectrum of types of lung cancer, across the spectrum of genotypes, and they all seem to be moving forward pretty quickly.

Dr. Paz-Ares: Yes. The results are very consistent from one drug to another, and they are very consistent between previously treated and untreated patients. I expect that in a very few months, we will start having the final results of some of the randomized trials. Of course, the drugs are moving to earlier stages of the disease. There are several trials in the first-line setting, particularly for tumors with PD-L1 expression. I suppose that in the next few months, some new trials will be starting in the adjuvant and neoadjuvant settings.

Dr. Kris: Yes, absolutely. We have those trials in the planning stages at our institution and other institutions here in the United States, so we are going to see that as well.

Adjuvant Therapy With EGFR Inhibitors

Dr. Kris: Speaking about the adjuvant setting, data on the RADIANT trial[14] were presented for the first time, and also the SELECT trial,[15] in which an EGFR-TKI inhibitor (in this case erlotinib) was given to patients after successful surgeries. What is your take on those data?

Dr. Paz-Ares: Going back to what you said about the right patient, right drug, and right tumor, if you have a patient with a tumor that is not driven by EGFR, I don't think it's worth it. This is the first message. EGFR-TKIs are not to be used in the adjuvant setting for those patients.

It is different for patients with EGFR-activated mutations. At the present time, the data are not robust enough to recommend treatment for those patients. But I think the data are adequate to be discussed with patients. It is my view that maybe, if we were able to launch a large trial with enough duration of treatment, we would be able to show some benefit, as has been shown in other disease settings, driven by a single genetic alteration. Of course, we don't have the data so far. I wouldn't conclude, however, that those treatments are not effective for those patients. I would just say that we haven't done the right trial yet.

Dr. Kris: I would agree with you, but I have been a big proponent of this for a long time now. Our experience at Memorial Sloan-Kettering with gefitinib and erlotinib in the adjuvant setting (and we participated in the SELECT trial and now the EGFR mutant cohort that was part of the RADIANT trial) is absolutely consistent in the ability to improve progression-free survival and in the tantalizing indication that it could improve overall survival. Plus, adjuvant treatment is basically safe and reasonably tolerated, particularly when you adjust the dose of erlotinib.

I was very impressed a few years ago at the plenary session with the data for imatinib in gastrointestinal stromal tumors,[16] in which a longer duration of therapy makes sense. And it not only improved progression-free survival, but ultimately it improved overall survival as well.

Dr. Paz-Ares: That was my point. We haven't shown yet very definitively that those treatments work for those patients. However, it is likely that they work, and we can show it if we do the right trials.

So far, only some data, such as what you have proportionately from your institution, are actually backing these hypotheses, that I think it's worthwhile to pursue it.

Dr. Kris: The unfortunate issue, however, is that the clinical trial that could answer that question is about to be initiated here in the United States, but they are estimating 10 years to get a readout. Physicians are going to have to make decisions much earlier than 10 years without the data, and looking at these data is quite important.

Top Practice-Changing Points

Dr. Kris: What change of practice are you going to make after attending this meeting when you get home and start seeing patients later this week, maybe on Thursday or Friday?

Dr. Paz-Ares: At the present time, we have a number of trials with the EGFR T790M inhibitors, and anytime I can, if a patient of mine has an EGFR-mutant tumor, at the time of resistance, I will try to do a new biopsy because this is going to be crucial to determine the next treatment.

The second reading from those trials is that anytime that I can offer to my patients these T790M inhibitors, I will do so. This is possibly the most important message I have learned about lung cancer at this ASCO.

Dr. Kris: That's great. I couldn't agree with you more. We have been biopsying a lot for research purposes. People often ask how this affects the patient. Your point is that these new generations of drugs -- and three were presented here, but there are even more in development -- are going to be here pretty quickly, and we should be ready for them. When your patients have progression, do that biopsy and find T790M.

With that, I would like to thank you for joining me today. And thank you for joining us in this edition of Medscape Oncology Insights. This is Mark Kris, reporting from ASCO 2014.


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