Maurie Markman, MD; David J. Kerr, MD; Kathy D. Miller, MD; Mark G. Kris, MD

Disclosures

June 13, 2011

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Introduction

Maurie Markman, MD: Hello. I'm Maurie Markman, Vice President of Patient Oncology Services and National Director for Medical Oncology at the Cancer Treatment Centers of America in Philadelphia, Pennsylvania.

It is my pleasure to welcome you to the Medscape Oncology Insights Wrap-up for ASCO® 2011. I am joined today by Dr. Kathy Miller, Associate Professor of Medicine at Indiana University School of Medicine in Indianapolis, Indiana; Dr. David Kerr, Professor of Cancer Medicine from the University of Oxford and President of the European Society of Medical Oncology; and Dr. Mark Kris, Chief of Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York City.

What we would like to do in this wrap-up session is to hear from each of us about some of the exciting abstracts, presentations, and discussions that we have heard at this really exciting meeting. I would like to start with Kathy, who was the program chair for the meeting. What was your take on the meeting? What have you seen and heard?

More Than One Way to a Survival Advantage

Kathy D. Miller, MD: The meeting was exciting and filled with a sense of energy, particularly around the plenary. We are used to the plenary having the obligatory lung cancer abstract, breast cancer abstract, colon cancer abstract, and prostate cancer abstract, and then a less common "tumor to be named later," depending on the data. This year was a very different plenary. We talked about GIST [gastrointestinal stromal tumors],[1] 2 pediatric studies -- ALL [acute lymphoblastic leukemia][2] and neuroblastoma,[3] and 2 melanoma studies.[4,5]

For the first time in my memory, all of the studies in the plenary showed a significant survival advantage, which is really what we want to achieve. It was also striking to me that they got to those survival advantages in different ways -- for instance, by giving a drug that's already used, longer, in terms of the adjuvant GIST study.[1] There had been a lot of debate in the GIST community that perhaps the drug was so effective in people with metastatic disease that you didn't really need to give adjuvant therapy for a longer time or maybe you didn't need to give it at all. You could just catch up and treat these folks when they recurred, and that was definitely not true. A longer duration of therapy, 3 years instead of 1, improved survival, so although you might ameliorate some of the death or delay it, you didn't fully catch up.

Two pediatric studies mentioned not a single new drug. I'm not sure you could find a drug in the pediatric studies that wasn't in widespread use by 1980 or earlier. Yet, using those drugs in a more optimal way by changing the schedules or changing the combinations -- in ALL,[2] the most common hematologic tumor, or in neuroblastoma,[3] the most common solid tumor -- also improved survival.

In melanoma, we are reaping the fruits of biology. Immunotherapy works. It works upfront in addition to DTIC [dacarbazine] and compared with DTIC alone. In the discussion about melanoma, Dr. Kim Margolin quite properly challenged us all to think about what DTIC has to do with this result, and should we just be using immunotherapy? In this not inconsequential subset of patients with BRAF mutations with melanoma, inhibiting BRAF gave amazing responses, improvements in symptom control, improvements in progression-free survival, and probably -- although the survival data are still early and will be complicated by late crossover in the trial -- an improvement in survival. It has been a long time since we have had something to celebrate in melanoma. So it was a great plenary session with a lot of news in areas that we don't frequently recognize in that kind of big forum.

Converting Cancer to a Chronic Disease

Dr. Markman: I agree with you entirely on the plenary session. It was spectacular, but one of the things that was notable to me in the imatinib discussion[1] was the focus on beginning to call GIST a chronic disease and to raise the question of continuing therapy, not 1 year, 2 years, 3 years, but perhaps for the remainder of the person's life. There is not an answer to that, but it begins to address the question. Of course, we are not likely to do a trial where the endpoint is 15 years down the line taking the drugs, but it brings this question to the forefront. Any comment about that?

Dr. Miller: Well, it does, and with some data to support the contention that certainly longer than 3 years -- although it is tough to know if indefinite is the right length of time -- might be better. In this adjuvant trial, within 6-12 months after you stopped the imatinib therapy, people started progressing in pretty substantial numbers. That had been seen in a previous trial of patients with metastatic disease but who had either had a response or had been stable on imatinib for several years and were then randomly assigned to discontinue therapy at 1, 3, or 5 years. In each of those discontinuation arms, within a very predictable 6-12 months of stopping therapy, people started progressing, even if they had been in a stable response for 5 years. Whether this truly means indefinite or for a whole lot longer than 3 years or as long as other health problems and toxicity don't intervene, I'm not sure we know, but it's not such an odd idea. We have that concept with hormone therapy in patients with estrogen receptor-positive breast cancer. We have all taken care of those patients -- I have someone in my practice right now whose first relapse was 29 years after diagnosis. Certainly, adding 5 years of an aromatase inhibitor (AI) after 5 years of tamoxifen -- that's now 10 years of therapy -- was superior. We are now investigating whether 10 years of an AI might be superior, so that's another setting where a really long duration of therapy has a proven benefit. We are now starting to revisit how long is long enough or is there such a thing as long enough if the patient is still alive and without relapse and still otherwise healthy?

Good Reason to Put Things to the Test

Mark G. Kris, MD: I had a couple more comments about that imatinib trial.[1] I thought that was the most exciting trial; not that the other observations weren't really important too. The first thing is that I love it when our expectations are exceeded and when our ideas are challenged. Everybody in the community felt that you were going to have, at best, a progression-free survival benefit, and lo and behold, there was a survival benefit. It just tells us how we have to put things to the test. We can't just assume. I think one of the reasons that they previously gave shorter courses is that they were afraid patients would get acquired resistance, and they felt that if we bring on resistance, we're going to somehow jeopardize a patient's health. We can give them the drug later on. But as it turned out, that was incorrect. That supports the idea of maybe continuing that drug chronically. To me, one of the biggest findings was that they did not see acquired resistance. In fact, giving more drug led to longer disease-free survival and a better overall survival -- cures -- so I thought that was a great trial.

Treatment Duration: How Long Is Long Enough?

Dr. Markman: I bring that up because I do think these are important issues. In my own area of research, ovarian cancer, we had the experience in the early part of my career of thinking that giving therapy for long periods of time was a very good idea until we realized 10%-15% of patients who were probably cured developed acute leukemia. Now, these were clearly different drugs, but the long-term toxicities of doxorubicin, etc., or the long-term toxicities of drugs that might cause neuropathy, but this may be a whole different group of drugs --

Dr. Kris: With imatinib, though, we have some information because of the experience with chronic myelogenous leukemia. We have a lot more years of chronic use knowing that, blessedly, we don't have those kinds of problems. The other great thing about this is the lung cancer community is now thinking about giving erlotinib to patients with EGFR (epidermal growth factor receptor) mutations in the adjuvant setting. We have these same kinds of questions. How long are you going to give it? Are you going to get acquired resistance? Our supposition was that you are only going to improve disease-free survival. You are not going to improve overall survival. To me, all of that was challenged this week. That's a great thing.

Dr. Miller: Not being a lung cancer specialist, I don't understand why that's the supposition, and it's one of the most active drugs you have in the metastatic setting in patients who have activating EGFR mutations. If there is anything that would improve survival in the adjuvant setting, I would be putting my money on that.

Dr. Kris: Amen. You're speaking to the converted on that one.

David J. Kerr, MD: But there are theoretical worries that you're selecting clones that might be resistant, and therefore it comes back.

Dr. Kris: But it didn't happen.

Dr. Kerr: Exactly. Remember how, in the old days, when we were selecting drug-resistant cell lines, it would be tiny concentrations for prolonged periods, and folks would throw their hands up? But the whole duration of treatment thing for us in gastrointestinal (GI) cancer, we're stepping in the opposite direction. We're running some big studies looking at 6 vs 3 months. We are asking, "Is less as good as more?" and seeing if we can adjust the pharmacoeconomics in that way. We're still searching for our quasi-adjuvant tamoxifen in GI cancer. We thought we had it with the COX-2 inhibitors, but we have not quite been able to complete those studies for a whole range of different reasons. I think that whole paradigm is up in the air, as you say, the old theoretical stuff, the Goldie-Coldman model, all the stuff that we learned as kids about drug-resistant colonies. I think that's been swept away now.

Drug Toxicity at 30 Years: A Victory?

Dr. Miller: So the duration question is going to be very dependent on the drug and the mechanism of action. I have worried a lot about long-term toxicity as the principal investigator of a large-scale, adjuvant trial with a drug for which we don't have 30 years of experience. On the one hand, if it keeps ladies from dying of their breast cancer so that more of them are alive to befall a toxicity that's not apparent for 20 or 30 years, I'll apologize, but I'm still going to claim victory. Death from your disease early is a fabulous and effective way of preventing long-term toxicity. I don't mean to minimize those issues. They are quite real, but we do have to recognize that they have only become considerations in relatively recent days when we actually have effective therapies and a sufficient number of long-term survivors, so that we can start to shift [to the question]: now that we cure most of our patients, how do we still cure most of them without long-term toxicities? In some of these areas, I'm not sure we're quite at the point of making that shift in the major goals of our therapy.

Dr. Markman: Just to complete that discussion, we had this incredibly exciting study in the ovarian cancer section presented by Professor Ledermann[6] looking at a PARP inhibitor given as a maintenance strategy as a single agent in serous tumors where it's not only known that patients have BRCA-1 and BRCA-2 abnormalities, but also a "BRCA-ness" profile [in which] a high percentage of these patients will have molecular abnormalities that look like BRCA-1 and BRCA-2 abnormalities. It was a randomized, phase 2 small study that had a spectacular -- for a randomized, phase 2 trial -- impact on progression-free survival, which of course is going to lead to a phase 3 trial. This is very interesting relating to the question of how long you continue therapy, if you want to think about a drug that you might be worried about, a drug that interferes with DNA repair, so it's a question. We'll have to see, but these are very exciting, very interesting times. This may be a great strategy. It may be a very toxic strategy.

Dr. Kerr: I've been following this discussion. With Jonathan [Ledermann] driving that [study][6] into a phase 3 setting, do you think he should be approaching duration? Should it just be a standard drug A vs drug B type phase 3 study or should he be thinking about duration, factoring it in, doing quasi-factorial designs to address that? Should we cram as many questions as we can in a single trial?

Dr. Markman: Well, the complexity of all that is this is still a drug-registration strategy. I'm sure the company's first thought is: How do we get the drug to market? But I think that's absolutely correct. That would be an exciting way to look at it, and that would offer a lot of attraction to individuals entering the trial. You might very well have a randomized discontinuation, but discontinuation at various times (6 months, 12 months, a year and a half) to try to get at this question of duration. As you said, in the GI area, and certainly in many of the cancers (breast cancer was "a shorter duration is better or at least wasn't worse, and probably less toxic") we need to ask the opposite question now because of the duration.

Dr Kris: Lung cancer too. There was an abstract[7] presented yesterday about continuing therapy. It's interesting, when you look at the entirety of the lung cancer treatment for stage 4 patients, the longer duration of treatment, more cycles of the agents you have started with, switching to a second agent, even while you still are in response, like the PARP trial[6] that you talked about, when you look at all of them, almost every trial shows some positive effect. Now they are conducting specific trials to prove that. We just heard one presented yesterday by Dr. Paz-Ares[8] that [found that] continuing pemetrexed improved disease-free survival.

The other thing about the drugs that we have now is you can give them long term. Imagine, how are you going to give paclitaxel long term? We have been down that road, but you can give an imatinib, you can give a pemetrexed, and you probably can give that PARP inhibitor as well.

Finding the Optimal Duration...and Paying for It

Dr. Miller: In moving to the adjuvant setting with these new agents, we don't have information to really, in a scientific way, inform a selection of the duration of therapy. So it's often driven by pragmatic questions and some regulatory [questions]. How long are you going to take to get the result? But also the thought that if you do the trial and you don't see a difference, you don't want to have given the drug for such a short duration that everybody is sniping at you that this would have worked but you only gave it for 3 weeks. It has to be given longer; somewhere in the neighborhood of a year has become the common stomping ground. If you give it for a year and it doesn't work, it becomes hard, although some have managed to do so, but it becomes hard to claim that the problem is just that you did not give it long enough. If a year works, then you do have the duration problem of going up and down from there to try to find optimal [duration].

Dr. Kris: Maybe by drug class, if I was going to design a trial of a tyrosine kinase inhibitor now, maybe 3 years is the way to go at least on the basis of that trial; at least it's a stepping stone. Maybe chronic therapy is the right one.

Dr. Markman: You have to be concerned about the issue of cost. Bevacizumab in some tumor types was suggested as "the longer, the better," and that may be great, but the cost becomes an issue with a maintenance strategy, and I'm sure that will be true of all the new drugs. Obviously, what we're talking about is the evidence in benefit. We definitely have to deal with the question of how do we afford it, which we're not going to solve here. David, comments about the meeting, as the visitor from afar?

Cancer Control: The Global Challenge

Dr. Kerr: Visitor from afar. Strange accent. Kathy's description of the plenary session was great. There was a buzz about it, but let me take a completely different tack, and the buzz that I took away from the meeting is that sense that we're still part of a small village in a global community of cancer experts. More than half the attendees at this meeting are out-of-towners. We have the people with strange accents like me. Frances Bacon said "knowledge is power," meaning you keep it to yourself, whereas here, we're the opposite. We share knowledge. The people who come to conventions have that love of wisdom and sharing it. Here we are doing it.

George Sledge [President of ASCO®] and I ran a joint session this morning on cancer in developing and low-income countries and it was fantastic but terribly frightening. Peter Boyle, an epidemiologist, is telling us that already there are more cancer deaths in the world than AIDS, TB, and malaria combined, and that by 2020, remarkably, 70% of all new incident cancer cases are in the developing world. So the countries least able to deal with it are going to be stuck with this tsunami of cancer coming along. I have to say that ASCO®, the society, has done a really good job internationally of pooling the different cancer societies and patient advocate groups together because there is a really important meeting at the end of September in the United Nations. They're holding a high-level conference on health for only the second time in its history. The first one was on AIDS. This one is on chronic diseases. This gives us an opportunity -- because let's face it, we're cancer advocates -- to see if we can raise our voices in a single choir to influence governmentally what we can do to support our brothers and sisters in the developing world. To me, it seems, of course, that we celebrate the beauty and wonder of the science, as Kathy did, but we are a small family and we are here to do what we can to support and to work with our colleagues elsewhere. So I have a good sense that it can be done. There are good investigators who want to be trained. There are important questions that can be asked, and we can celebrate differences, the genetic diversity from our global trials, the clues and cues that we get from that.

We're running something called the African Genome Project. It's dead interesting, with some really interesting data coming back. I just loved coming to ASCO®, seeing us all mixing together. The feeling, honestly, that we're trying to do something about it. I liked ASCO® for doing that. We at ESMO [European Society for Medical Oncology] are going to do our best, friends across the ocean, and all that stuff.

Dr. Markman: Good.

Dr. Miller: It's interesting that you used that Frances Bacon quote because I used that in the conclusion of a presentation at a special ASCO® AACR [American Association for Cancer Research] Presidential Symposium, but in exactly the opposite way. Knowledge of the cancer biology and increasingly the individual patient's genetic heritage gives us the power to think about how to most properly intervene.

It applies to the international setting as well. They are dealing with cancer at a stage where we were 4 or 5 decades ago with fewer resources, arguably, but in terms of the systems and treatments available and the epidemiologic understanding. Much of that we can do, and I hate to say, part of this is a problem we exported. We exported cigarettes. As the tobacco laws in this country got more stringent, they looked elsewhere for their market share, so we see those problems. We do see AIDS-related malignancies, other virally related malignancies, for which there certainly could be interventions that don't take a new molecularly targeted drug that we in the developed world struggle to figure out if we can afford.

Dr. Kerr: Exactly. The notion of cancer control -- the spectrum of awareness raising, early detection, prevention, treatment, palliation -- it's putting the whole package in place. But building on what you said, look at the examples from lung cancer. The fact that we're doing global trials, that we're picking up subtle but important differences in our colleagues, our patients from Japan, from China, and how those differences translate into a piece of beautiful molecular genetics that segments a patient population for you to treat. If we are part of the village and if we work together, then we learn it's a partnership -- doing trials, learning here -- that benefits us all.

Dr. Kris: I think here in the United States, we are truly going to benefit by the work of the investigators and physicians in China. Half of lung cancer now is in China and they are working very hard. You can actually see that by looking at our abstract book. They are under the pressure of that. They are making discoveries that are going to inform the world's community in dealing with lung cancer. You are exactly right. It's amazing how many abstracts and great ideas come from that region of the world, but they're going to help all of us. Talk about clinical trials -- in China, within a few hundred miles of Shanghai, is a population [equivalent to] the United States. Because of the geography, they can do clinical trials much more efficiently. It may be that the work that is done there is going to inform all of us and they are going to accelerate the pace of research.

Dr. Markman: Mark, any comments specifically on your observations, the lung cancer area, other areas?

Research Direct to Patient: A New Paradigm

Dr. Kris: I still have to pinch myself almost every time I come to a meeting that lung cancer is a model. I was very happy this time to see how lung cancer was moving along to the use of the patient's tumor tissue to decide therapy, on the basis of EGFR discovery. ASCO® had a statement where they came out and said "mutation testing is a standard of care." What that did is it got doctors to say that I'm going to need to get that mutational data and get tissue to make a diagnosis of the presence of an EGFR mutation at diagnosis. That facilitates the best use of EGFR inhibitors. It was interesting because there was another abstract presented yesterday of people who blindly gave EGFR inhibitors in a randomized trial, compared blind EGFR inhibitor to unselected patients with people getting chemotherapy.[9] Chemotherapy was the better result because if you don't know that and you give a targeted therapy to somebody without the target, it doesn't work. There is even the suggestion of worse [outcome] than that.

We saw the data that I presented from 14 centers around the country, about doing this upfront genotyping, using the information to treat patients.[10] The institutional programs at Dana-Farber and Massachusetts General were presented at a session today. This is moving forward. It is available to everybody too. That's the great thing. We're fortunate here in the United States to have laboratories that can do this testing with quick turnarounds. We have gone from it being theoretical and a research project for which you are going to get that patient's tissue, to obtaining the information to treat that patient, and then using that data to help find the best clinical trial for them too. To me, it's just an amazing thing that it has all come together.

Dr. Markman: That's clearly the paradigm for the future in many tumor types. Nobody knows exactly how that's going to play out, what impact that's going to have on outcomes, or what drugs you will use. Lung cancer is clearly in the lead here, but everything says that is where we're going to be, whether it's 2 years or 5 years from now. Of course, everyone knows the other giant in the room is the dramatic reduction in cost associated with whole genome sequencing. The idea was put forward by many that within perhaps 2 years, it will be possible for a cost of $5000 to bring it to the doctor.

Dr. Kris: I loved George Sledge's Presidential Address here. He showed what looked like a watch case with what looked like a golden head drive and there was somebody's genome in there. That's going to happen, and within a few years. A number of centers now are developing comprehensive mutational profiles for every tumor. For colorectal cancer and melanoma; they are pushing the lung agenda too because you now need to genotype those tumors. You have to genotype every melanoma. You have to genotype every colon cancer. We're going to have these kinds of packages. That information is going to be available for everybody. PIC 3CA in gynecology -- that's going to be a huge target. There was a lot of discussion at the meeting about that too, and it's really going to revolutionize things. It is not going to happen in a decade. I guess you shouldn't make these kind of predictions, but it's going to happen within 5 years.

Dr. Kerr: Isn't that an opportunity for more cooperation? I couldn't possibly agree more. We are judging such large amounts of information for an individual patient; the worry is that there are false-positives that we over fit and, therefore, we need to match the cleverness of genetic scientists with the cleverness of the patient populations we put forward, the size, so we match statistical powers.

Dr. Kris: That's why I said 5 years because I think that's what is going to take 5 years.

Keeping an Eye on the Prize

Dr. Miller: I hate to be the naysayer because I truly do agree, although I'm a bit more cautious and have a longer timeline. Getting the information will happen very quickly, but for that information to be useful and provide benefit to our patients we have to know what it means. You can get my patients' genome now and give me the sequence, but I don't have clue what it means and there is the risk -- particularly for areas where we think we understand the biology -- that we make the leap to altering patients' treatments on the basis of assumptions rather than on data, and that might be harmful. That might take us a long time to figure out. Although it doesn't use a molecularly targeted drug, the pediatric ALL study from the plenary[2] is a gorgeous example of that and what I found the most sobering of that presentation with the huge survival advantage.

There were 2 strategies in the dosing and use of methotrexate developed in the 1970s. They were never compared head-to-head. The community picked one on the basis of assumptions as to which would preserve activity and be less toxic, and the collective wisdom of the community was dead wrong. For a sobering thought, imagine the number of kids who died of pediatric ALL needlessly, if rather than assuming 30 years ago that Capizzi methotrexate was better, they had actually studied it. So, I am fully enthralled with the power of the genome, and that's clearly where we will make advances, but we do have to realize that data and information are not the same thing. Getting the data is easy, but making the leap to information is difficult.

Dr. Kris: I disagree that the data are easy.

Dr. Miller: Well, they will become easier and cheaper, so we will get more.

Dr. Kris: You're absolutely right about that. I want to bring you back to something we said before. One of the reasons people didn't give the high-dose methotrexate is that they were worried about toxicity.

Dr. Miller: They were wrong. It was actually less toxic and better.

Dr. Markman: They were wrong, exactly. The importance of testing a hypothesis and keeping your eye on the prize -- and that's curing the patient -- is something George Sledge brought up in his opening lecture. The cure, I believe his words were, is what our patients deserve. We can't forget that. You properly put the brakes on our enthusiasm there. Ultimately, we've got to test these things.

Dr. Miller: I actually don't want to put the brakes on. I want to accelerate it, but with properly designed trials and the recognition that a new test is investigational in the same way a new drug is investigational.

Dr. Kerr: But we've been doing these genome-wide studies and ricocheting SNPs with P values of 10 to -12, the hazard ratio is so small you can hardly see it, so you are right. What use is that despite all these statistics to us in making decisions with a hazard ratio this tiny? We need to work. We need to accumulate and make sense of it.

Dr. Markman: I really want to thank my colleagues for a spectacular discussion. We will continue this next year. Thank you very much. And I want to thank our audience for joining us. For Medscape Oncology Insights Wrap-up of ASCO® 2011, this is Maurie Markman signing off from Chicago.

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