Giorgio V. Scagliotti, MD; Tony Mok, MD


October 12, 2012

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Giorgio V. Scagliotti, MD: Hello. I am Giorgio Scagliotti, Professor of Medical Oncology and Chief of the Department of Clinical and Biological Sciences at the University of Torino at San Luigi Hospital in the same city in Italy. Welcome to this edition of Medscape Oncology Insights in lung cancer. Today, we will highlight for you several significant studies in lung cancer presented at the 2012 Annual Congress of the European Society for Medical Oncology (ESMO). Joining me today is Dr. Tony Mok, my close friend and Clinical Professor of the Department of Clinical Oncology at the Chinese University in Hong Kong and the Prince of Wales Hospital in Hong Kong. Welcome, Tony.

LUX-Lung 3: Improved Quality of Life, as Expected

Dr. Scagliotti: Let's discuss the latest achievements and the additional information that came from this meeting, starting with LUX-Lung 3 and the quality-of-life data.[1]

Tony Mok, MD: LUX-Lung 3 is the seventh randomized study that compared EGFR/TKI [epidermal growth factor receptor/tyrosine kinase inhibitor] with chemotherapy in a biomarker-selected population. However, we must note that LUX-Lung 3 is special, in the sense that it is the first one on an irreversible TKI and the control arm is pemetrexed and cisplatin -- which is actually the standard of care, after your study, for patients with adenocarcinoma. So in a sense, it is still a very strongly positive study, with a significant difference in progression-free survival.

This time at ESMO, they talked about the quality-of-life data, and it was no surprise that there is a significant improvement in the total quality of life, and the time to deterioration to lung cancer symptoms (including cough and pain) is also improved compared with the control arm. All these findings are compatible with other comparative studies, including EURTAC[2] and IPASS,[3]which show evidence of improvement in quality of life using the TKI as a first-line therapy for patients with the mutation.

PFS vs OS: Why the Disparity?

Dr. Scagliotti: One issue that physicians in the community always mention is that with these studies, you are reporting a huge improvement in the response rate in the EGFR/TKI arm compared with chemotherapy, and a huge improvement in progression-free survival, but you are not able to show any difference in overall survival. Can you briefly explain the point?

Dr. Mok: I actually had a debate on this topic at this ESMO meeting with Dr. Benjamin Besse from Paris. I was on the "pro" side, and he was on the "con" side. One of the important messages I gave is that you do the testing for the patient and say, "You test positive, but let's start you on chemotherapy." This is the weirdest thing that you can tell a patient. There is much evidence that the patient will feel better, with improved quality-of-life, and also have a significant tumor response very quickly, which is unlikely to occur with chemotherapy at this stage. Then, of course, there is no overall survival benefit, suggesting that if the chemotherapy fails and you go on a TKI as a second-line treatment, you may still have the benefit. The benefit to the patient is, in a sense, that any time during the course of the trial the patient may crossover from chemotherapy to a TKI, which affects overall survival data, but what if the patient never gets the chance to receive a TKI after chemotherapy? This happened. If you look at multiple randomized studies, a consistent observation is that some of the patients who received first-line chemotherapy never received a TKI.

Reversible and Irreversible TKIs

Dr. Scagliotti: On the basis of your large experience in this field, can you comment about the differences in the level of activity, and toxicity profiles, between reversible EGFR/TKI therapy (such as erlotinib and gefitinib) and irreversible EGFR/TKI therapy, such as afatinib?

Dr. Mok: My experience is on therapy in the early stage of drug development of reversible and irreversible TKIs that subsequently became standard drugs in Asia, and my research experience is with both dacomitinib and afatinib. There is consistent evidence that irreversible TKIs are associated with a high incidence of skin toxicity and diarrhea, and also some mucositis.

If you look at LUX-Lung 2,[4] which is a single-arm study on afatinib in patients with an EGFR mutation conducted mostly in Taiwan and the United States, and also at the toxicity data from LUX-Lung 3, 10%-15% of patients may have grade 3 or above rash or diarrhea and close to 10% of them will have the mucositis, but it is dose-related and you have to make your intervention early. For afatinib, a 40-mg dose is much better tolerated than 50 mg, so in LUX-Lung 2, most patients received 50 mg and a portion received 40 mg. The toxicity with 40 mg is a lot better than with the 50-mg dose, and in LUX-Lung 3, they used 40 mg.

Dr. Scagliotti: The concern comes from this 15%-20% of patients with grade 2 and grade 3 diarrhea or gastrointestinal toxicities that are, at least for the patients, quite uncomfortable. Do you think that we need to move to preventive strategies to avoid this?

Dr. Mok: Definitely. When you do a large randomized study like this, there are multiple centers involved, and some of the centers may not be as experienced in terms of management of toxicity. One strategy is early management. When a patient has more than grade 2-3 diarrhea, they should start taking an antidiarrheal drug, and usually that can prevent further deterioration quite nicely. There should be a lot of educational programs on managing toxicity when this drug becomes available in the market.

Dr. Scagliotti: Do you believe that it is worth doing a study comparing reversible TKIs vs irreversible TKIs?

Dr. Mok: Definitely. Such a study is ongoing. There is a LUX-Lung 7, which is a randomized, phase 2B study comparing afatinib with gefitinib. Target enrollment is 270 patients, and they have already enrolled close to one half of that number, so we will have some answers eventually. With respect to the other irreversible TKI, dacomitinib, there is no concrete plan, but some press releases have suggested that they may be engaging in a phase 3 study in the near future.

Crizotinib: Standard of Care for ALK-Positive Disease

Dr. Scagliotti: Let me switch now to other important studies that will be presented during this meeting. We don't have time to talk much about sorafenib vs placebo (the MISSION study)[5]that will be presented at this meeting, but let's focus on the crizotinib story. At this meeting, an important phase 3 study[6] is being presented; this study compared second-line crizotinib (the ALK [anaplastic lymphoma kinase] inhibitor) vs the standard of care (pemetrexed or docetaxel). Can you briefly comment on the results of this study?

Dr. Mok: Crizotinib was approved on the basis of phase 2 data that were published in the New England Journal of Medicine in 2010.[7] This was the first phase 3 as a second-line study in patients who were ALK-positive, with crizotinib vs single-agent pemetrexed or single-agent docetaxel. The result is positive. The primary endpoint of progression-free survival was met, and there is a significant difference between the crizotinib arm and the chemotherapy arm.

They also looked at the subgroup of patients who received pemetrexed and docetaxel, and the response rate of pemetrexed is quite good in this special subgroup -- close to 20%. In the study arm, which is the crizotinib arm, the response rate is about 50% -- close to 60% -- which is compatible with what they observed in their phase 2 study. Overall, this is the first randomized phase 3 study establishing the use of crizotinib in this biomarker-selected population.

I will throw this back to you. Do you think we need a phase 3 study for this kind of situation? We have an oncogenic driver and excellent results in phase 2. Now they have a nicely done phase 3 trial, but the drug is already registered. Do you think that in the future, we need to do that for every single oncogenic driver in that situation?

Dr. Scagliotti: I don't think so, because I am extremely excited and convinced about the new drug when I see these huge waterfall plots showing that 80% of the patients who were treated with one specific agent experienced tumor shrinkage, and when the objective response rate according to the RECIST [Response Evaluation Criteria In Solid Tumors] exceeds 50%, that is already a sign of activity. I don't care about following up thousands of patients for progression-free survival. I don't care if there is no difference in survival because, as you said before, if you are oncogene-addicted, you are still oncogene-addicted in second-line, third-line, fourth-line, and fifth-line therapy. We have already seen these findings in the early phase 2 single-agent studies, when we saw responses after 5 lines of chemotherapy; consequently, the general concept of oncogene addiction, for me, is important.

Unusual Toxicity Profile of Crizotinib

Dr. Scagliotti: Before finishing up, can you touch base briefly about the unique toxicity profile of crizotinib with the visual problems that the patients have reported?

Dr. Mok: The visual problem is quite common; 50%-60% of patients may have it. There was a nice poster[8] at this ESMO meeting talking about the impact of the visual disturbance on the patient. In this report, more than 60%-70% of patients with visual disturbances are not bothered by it. When changing from a light environment to another one, patients might have wavy lines in the corner of their visual field, but it does not have a huge impact on vision.

What is actually of greater concern is hepatotoxicity. After 1400 cases, they have had a few drug-related, major episodes of hepatotoxicity and 2 fatal events, so all patients going on this drug need to have close monitoring. It doesn't happen often, but if it does happen, we should withdraw the drug quickly.

Dr. Scagliotti: Yes. But the therapeutic window is favorable -- it is definitely positive.

Dr. Mok: It is a very well-tolerated drug, in my experience.

Crizotinib of Benefit to ROS1-Positive Patients

Dr. Scagliotti: One additional point before we finish is this fortunate story of the activity of crizotinib against ROS1 translocation. We know that the ROS1 translocation is something that we can observe in 1.5%- 2% of our patients, mainly with adenocarcinoma, who are never smokers or light smokers. If you are standing in front of a patient with an ROS1 translocation tumor, you need to consider whether to treat him or her with chemotherapy or crizotinib. Can you briefly summarize this for us?

Dr. Mok: That is exactly why I asked you that question, because ROS1 is a neighbor TKI of ALK1. We had some excellent results on the first 14 patients, reported by Alice Shaw and colleagues[9,10]at both the American Society of Clinical Oncology (ASCO©) and ESMO meetings this year, where they showed the waterfall curve -- a very nice, dramatic, more than 50% response rate, but it is going to be about 1%-1.5% of the population who have it. We can never do a randomized study on this molecular target, so are we going to approve the drug crizotinib for ROS1 tumors? There are some debates between the regulatory bodies and the clinicians.

I agree with you entirely that we see high activity. We see low toxicity with the drug, so we should definitely have more extensive experience in phase 2 and consideration of acceptance of this drug without a phase 3 trial, because it would be almost impossible to do a phase 3 trial.

A Drug for Every Mutation?

Dr. Scagliotti: We have a spectrum of genomic alterations, at least in adenocarcinoma. I am not talking about the issue of genomic alterations in squamous cell cancer, but in adenocarcinoma, we have several mutations. Do you believe that all these mutations will be targeted by 1 or more specific agents? Let's say we have 2% HER2 mutations. Can we do a trastuzumab study in those patients? We have the BRAF mutation. Can we find a BRAF-inhibiting agent for this 1% of patients with BRAF-mutated tumors?

Dr. Mok: It is not just a matter of the drug targeting the target. It is a matter of how important the target is. There are the definite driver oncogenes, and like with EGFR and ALK, we know the definite driver oncogene, but is overexpression of HER2 always a driver oncogene, or should it be a HER2 mutation that is a driver oncogene? We have to clarify that -- and then there are a number of others, including PI3K.

We will have to define the nature a little bit better. If a driver oncogene, probably a single agent, will give you a nice waterfall plot curve, but it is not a driver oncogene, we may potentially require multiple targets before we can have a significant result and control the cancer.

The future is there. We still need to know the presence or absence of the target, and then once we have a potential target, we have to do the biomarker single-arm study to document efficacy. If we are way up there with 50%-60% response rate and long duration of control, we could win.

Dr. Scagliotti: As a clinical investigator, do you recommend that clinicians do a rebiopsy at the time of the progression in these patients with oncogenetic tumors?

Dr. Mok: Most definitely, but hopefully we can do it within the clinical trial setting. The reason is that we have started to observe that the mechanism of resistance is very diverse, both for EGFR and for ALK. ALK, in particular, has many different mechanisms. Without knowing the mechanism of resistance, we may be blindly treating those patients. So for us to learn better how to manage resistance, we biopsy, then try different drugs again. Understanding the specific mechanism of resistance is how we are going to gain our knowledge.

Closing Remarks

Dr. Scagliotti: Thank you so much for your comments, Tony. Thank you for joining us for this edition of Medscape Oncology Insights. This is Giorgio Scagliotti, reporting from ESMO 2012.