Kathy D. Miller, MD; David J. Kerr, MD; Bruce D. Cheson, MD; Maurie Markman, MD


June 12, 2012

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Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at the Indiana University School of Medicine in Indianapolis. I would like to welcome you to Medscape Oncology Insights, our annual wrap-up of the 2012 meeting of the American Society of Clinical Oncology (ASCO®). I am joined today by several of my colleagues: Dr. David Kerr, Professor of Cancer Medicine from the University of Oxford and former President of the European Society of Medical Oncology; Dr. Bruce Cheson, Deputy Chief of Hematology and Oncology, and Head of Hematology at the Georgetown University Hospital and Lombardi Comprehensive Cancer Center in Washington, DC; and last but not least, Dr. Maurie Markman, Vice President, Patient Oncology Services, and National Director for Medical Oncology, Cancer Treatment Centers of America, based in Philadelphia. Thank you all for joining us today.

Maurie, let's start with you. When you think about highlights of this year's ASCO® meeting for genitourinary (GU) and ovarian cancers, what are you taking home?

Ovarian Cancer: Clear Benefit With Bevacizumab

Maurie Markman, MD: There was a very interesting session, because of what was seen and what was not seen. The surprise for me was the randomized phase 3 trial[1] that looked at the question of bevacizumab plus chemotherapy vs chemotherapy alone in platinum-resistant ovarian cancer. Everyone would have predicted, on the basis of 30-plus years of research in this area, that it would be a negative trial, as all past trials have been. In fact, I was convinced it would be a negative trial because there were no press releases ahead of time. That usually tells you the story.

It turns out that the combination of bevacizumab and chemotherapy substantially improved progression-free survival in this setting -- the first time this has ever been seen. I would suspect, however, that what most people take away from it is the fact that there was a tripling of the objective response rate, and clear evidence of patient benefit. This was very much a surprise; I don't think anyone expected this.

The next question is going to be, what happens next? Is this drug going to receive regulatory approval on this basis? This is clearly an unmet need. That was a real positive.

On the other hand, one could argue that in contrast to other things that we will hear about, there is still no target of therapy in any of the gynecologic cancers. We haven't found anything that would suggest an epidermal growth factor receptor (EGFR) mutation, or anything to suggest a KRAS mutation or anything that could point to where we need to go in this area. On the one hand, that is a very interesting finding, from the perspective of biology. But it is quite discouraging from the perspective of drug development.

Dr. Miller: The Cancer Genome Atlas (TCGA) data had to be discouraging. Essentially, every ovarian tumor is a different ovarian tumor.

Dr. Markman: Absolutely.

Dr. Miller: You have 10,000 rare diseases.

Dr. Markman: Other than p53, and we have known of that mutation for decades. It is universal, certainly in the high-grade cancers. But we don't know how to deal with it. Other than that, the number of mutations found per tumor is enormous, and there are no patterns. So we have to do a lot of thinking. That is, the smart biologists have to do a lot of thinking.

Lymphoma: Chemotherapy? Enough Is Enough

Dr. Miller: Bruce, you spend a lot of your time focusing on the hematology side of malignancies. With the American Society of Hematology (ASH) and a whole separate meeting, sometimes it seems as though hematology doesn't get as much attention at ASCO®. Was there any big news in the hematologic malignancies that people need to know about?

Bruce D. Cheson, MD: There were not. However, this has the potential to be an historic meeting, because we are going to finally learn that "enough is enough" with chemotherapy, and we are at that point.

We saw some very historic presentations. We saw rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), vs rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), vs rituximab, fludarabine, and mitoxantrone (RFM) -- where basically the only difference is in toxicity.[2]

Dr. Miller: "Pick your poison" -- toxicity, but you will get to the same place.

Dr. Cheson: Yes. We also saw that R-bendamustine was better than R-CHOP,[3] but there are questions about the R-CHOP arm looking kind of lame. We were thinking, where are we going in follicular lymphoma?

Where we are going is what John Leonard and colleagues[4] presented in the relapse setting, and that's biological agents. We have lots of those. We have lots of targeted agents. I predict that in the next year, instead of hearing more about R-CHOP and R-bendamustine, we are going to be hearing more about the GS-1101s; the PI3-kinase inhibitors; ibrutinib, the Bruton tyrosine kinase (BTK) inhibitor; and those drugs which we in the Cancer and Leukemia Group B (CLGB) (now Alliance) have been planning on combining with biological strategies. We are going to be trying to get rid of chemotherapy. This may be, hopefully, the last meeting we hear about regimen A vs regimen B. It's kind of sickening.

We have the same situation in Hodgkin lymphoma -- where we cure, depending on the stage, up to 90% of people, and at this meeting we see adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) vs bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) again for about the fourth iteration. Lo and behold, there is no survival difference.

We saw lots of that, but now we have other drugs. We have brentuximab vedotin, which is an antibody/drug conjugate. It is anti-CD30, linked to auristatin, a tubulin poison, which in transplant-refractory patients had a 75% response rate. There weren't any data at this meeting. The data on that drug were presented at ASH. But there are now trials incorporating brentuximab/vedotin, not only in second-line treatment, but we are now moving it up into front-line.

So, we have the tools; it's just a question of being smart enough, and figuring out how to put them together in a coherent fashion, on the basis of scientific rationale. The most important thing I took away from this meeting is, enough is enough. You can pick your poison, as you put it. But don't hold on to it for dear life, because there are new, very exciting drugs coming along that are being combined in a biological fashion.

Breast Cancer: Targeted Therapies Are Clear Winners

Dr. Miller: You might have snuck into a breast cancer session, because that is how I would summarize the breast cancer world this year as well. We saw adjuvant trials, metastatic trials, comparing one chemotherapy regimen with another. To summarize a lot of data, pick your third-generation adjuvant chemotherapy regimen and the toxicity will differ, depending on the drugs, but the efficacy doesn't differ at all. In the metastatic setting, newer wasn't better. It brought more toxicity, which then led to more dose reductions, which hampered efficacy.

So when we thought we were getting newer and better drugs, they didn't actually do better for our patients. It sounded a little bit like ABVD vs BEACOPP in Hodgkin disease.

Dr. Cheson: We have to get rid of chemotherapy.

Dr. Miller: Targeted therapies, either with direct molecular targets or antibody/ drug conjugates, were the clear winners, with major improvements in efficacy and substantially less toxicity. I would be quite happy if I didn't have to look at another basic chemotherapy study in breast cancer again. Was that the case in the gastrointestinal (GI) studies as well, David?

GI Phenotypes and 5 Daughters of Eve

David J. Kerr, MD: It was. We are seeing mildly disappointing and moderately good results. The big, well-designed study, REAL 3,[5] looking at the role of panitumumab with combination chemotherapy, had negative findings. Panitumumab seemed to do a bit worse, which was somewhat disappointing.

Some positives are coming out in colorectal cancer. The antiangiogenic therapies look as if they are here to stay. A nice randomized trial[6] looking at discontinuation or continuation of bevacizumab following progression in first-line chemotherapy shows that the bevacizumab follow-through has significant advantages, in terms of progression-free survival.

An interesting, clever, genetically designed drug, aflibercept, which is a vascular endothelial growth factor (VGEF) trap, showed very promising activity in second- line therapy.[7] So something is holding true there. We have a new drug, regorafenib, which is one of these oral multitargeted kinase inhibitors, that seems to have an important clinically useful role to play in third-line chemotherapy.

For me, the take-home message, in contradistinction to Maurie, is that we are starting to get a feel for the different molecular phenotypes for colorectal cancer. It looks as though there may be 5 daughters of Eve, and it needs to be confirmed. We need to internationalize what we are doing. It looks as though some patterns are starting to emerge that will allow us to make prognostic inferences, possibly treatment-wise, and so on. Things are starting to stack up for us, in terms of driver mutations, therapeutics, and providing the patient with better information, so this is somewhat luckier than the situation with ovarian just now.

How Do We Eliminate Chemotherapy?

Dr. Miller: When we look ahead, we would all love to get rid of chemotherapy. How do we do that? By understanding the biology, which is the easy answer. Bruce, you mentioned that we do tend to cling to our chemotherapy regimens. We have been having discussions about how to do this in breast cancer, and there is a great reluctance to give up the regimens that have gotten us to where we are.

Dr. Cheson: Reluctance from the doctor, but not from the patient.

Dr. Miller: So how do we move forward?

Dr. Cheson: There are a couple of ways. First is a better understanding of tumor biology. We have been sitting around doing what we do for so long. Now we have some tools, but we need to know how to apply them. At every clinical trial in CLGB (now Alliance), we have correlative science. We are doing natural killer (NK) cell numbers and functions. We are doing microarrays so that we can understand which regimen works in which patient. It may not be like your field (gynecologic cancer), where every patient has their own disease, which is what I get accused of saying in lymphoma all the time. I am glad someone else has that problem.

We have the drugs. We need to know how to put them together, but which patients should we target? Then, we need to figure out how to move them up front -- such drugs as brentuximab, the Hodgkin drug, and anti-CD30, which in anaplastic large cell lymphoma has an 86% response rate in relapsed patients. In a good clinical trial, we need to take a risk and just do it. If a drug is 86% effective in the refractory setting, it is not going to be worse up front.

There are those who will say, "Well, the response may not last as long." But there are several ways you can introduce these drugs in an up-front setting, such as window-of-opportunity studies, Or, you can first tack them on to some chemotherapy and then try and wean off the chemotherapy.

There are a number of ways to do it. You just have to do it. You have to take a risk and view it as a challenge. You have to say, "We have had enough of this; let's move on." We have the tools; let's do it.

I-SPY: New Paradigm for Clinical Trials?

Dr. Miller: Maurie, you know I can't resist, because this issue of clinical trials came up last year when we were talking about melanoma data, with striking activity reported by the BRAF investigators. Are you going to do those trials? Are you willing to take that risk?

Dr. Markman: Obviously, you have to look at the individual cancers. Consider the report that said breast cancer had 10 different cancers, maybe more. It is going to be harder and harder to do randomized trials in 10 subsets, even in a disease that is as common as breast cancer.

Dr. Miller: We are actually closer to your problem, where each patient is an individual disease, than to Bruce's situation.

Dr. Markman: We do have to come up with a different clinical trial paradigm as we get to smaller subsets. Of course, the tsunami that many have predicted is here. It wasn't part of the meeting directly, but a half-dozen or dozen companies are now offering whole-genome sequencing. We have to figure out how to use all these things. It may not be as simple as a particular molecular abnormality, but it may be, as many people are saying, particular systems.

For example, in the ovarian cancer area, there are BRCA1 and BRCA2, and there are some drugs that affect those mutations. But a very important study from last year looked at maintenance therapy in the second-line setting with olaparib[8] in tumors that were said to have a BRCA-ness profile. In other words, there is a molecular profile that is similar to that of BRCA1 and BRCA2, and in fact, it was a very positive trial, at least from the perspective of progression-free survival. You may not be able to find a particular molecular abnormality, but there may be patterns. And that may be (in our area, where you can't find an abnormality) much more complicated than just finding a mutation. That may be the way forward in such diseases as ovarian cancer.

Dr. Cheson: Maybe I did wander into the breast meeting, but we need to reconsider how many phase 3 trials we want to do. The I-SPY concept is where we need to be going. You take a regimen that should work in a subset of patients, and you test that and see if it does. Then you can figure out who responded and who didn't, doing various molecular techniques, and then you take the patients who responded and put them in one pile, and enrich that pile. You take the patients who didn't respond, figure out why they didn't respond, and retarget them. After a while, you have high response rates in this one, and you start to improve the outcome in the other one. We need to do this. There is no way around it. It's coming.

I hate to say this, but I think maintenance is for losers, because if you are going to do right, you have to do it up front. Progression-free survival doesn't necessarily correlate with overall survival. It is nice. You don't see the doctor as often. But we need to do this right the first time. I thoroughly agree with you, Maurie -- it is going to be a conglomerate of things, and that is why we have new, exciting drugs coming down the pipeline, such as these PI3-kinase mammalian target of rapamycin (mTOR) hybrid inhibitors. We need to block multiple pathways, because the tumors are damn smart. If you block one, it has all these other ways of getting around you.

More Fun With Something vs Nothing Trials

Dr. Kerr: Indeed, and that comes back to Maurie's point about thinking in systems and programmatically. The answer to Kathy's question -- can we get rid of chemotherapy? -- is no. But can we do better? Think about the huge focus that we have in trying to map biomarkers to the new drugs, often mechanistic. We are not doing enough with the conventional cytotoxic drugs that we have.

We could do a lot more. Genome-wide association studies, looking at patterns of toxicity, so that we can use polymorphisms to say "you get full dose of the drug, you get the reduced dose." We could be using the tools of trade that we have much better. With the new platform technologies, we should be able select patients who do better with 5-fluorouracil (5-FU), with taxane, and so on.

Dr. Cheson: So, how do you study that in randomized trials?

Dr. Kerr: We are lucky in that we have been collecting material from the old days. Makes us something like Dickensian characters. We have hoarded a lot of material from something vs nothing-type trials, and that gives us the opportunity, in that large randomized setting, to develop some of these predictive markers for "yes or no 5-FU, yes or no taxane." So, it is going back to our youths, when we did all that stuff.

Dr. Miller: That is how we made advances in breast cancer. The predecessors in my field collected tumors long before the technology that we now use to interrogate them was even a glint in someone's eye. That may actually have a bigger global impact.

Dr. Kerr: I think so.

Dr. Miller: Although this is the American Society of Clinical Oncology, one third of our members are from outside the United States, one half of the attendees are from outside the United States, and most of the fabulous molecular things we have been talking about are not within reach of most patients globally. But some of our old things are cheap. Perhaps using them in a more intelligent way may actually have more benefit on a global scale.

A Question of Value

Dr. Kerr: Exactly. So you have segued into the concept of value. I was delighted to see the brief stance that ASCO® has taken toward value, and saying that there are some things that we do that don't add value to the care of the patients that we look after. I am a huge fan of US medicine at its the very best, but there's a lot of waste in what we do. The fact that ASCO® is trying to identify this -- 17.5% of the gross domestic product (GDP) is being spent in health now -- I thought that was fantastic. Yes, there is value out there, and we should seek it. We should mine old databases, fiddle with new drugs and old drugs, teach old drugs new tricks, and so on.

Dr. Cheson: Five years from now, you are going to look at this video, and you had a whole list of "mabs and mibs" that you are going to figure out and put together, and all of a sudden, FOLFOX, FOLFIRI will be "pffft." You are going to be combining those biologic agents intelligently, and you are going to get rid of those chemotherapy drugs, I predict.

Dr. Miller: We are out of time for this year, but I am going to book you both for 5 years from now to see whose prediction of the future comes true, where the value lies, and where we can make improvements, because I'm not so sure that they are mutually exclusive. But that's all from this year's Medscape Oncology wrap-up of the Annual Oncology Society Meeting. Thank you again for joining me.


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