Mark G. Kris, MD; Kathy D. Miller, MD; Bruce D. Cheson, MD; Louis M. Weiner, MD


June 09, 2014

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Oncology Now and in the Next 50 Years

Mark G. Kris, MD: Hello. I'm Mark Kris, Chief of Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. Welcome to Medscape Oncology's Wrap-up of the 2014 Annual Meeting of the American Society of Clinical Oncology (ASCO®). I'm joined today by several colleagues: Dr. Kathy Miller, Associate Professor of Medicine at the Indiana University School of Medicine in Indianapolis; Dr. Bruce Cheson, Deputy Chief of Hematology/Oncology and Head of Hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center; and Dr. Louis Weiner, Director of the Lombardi Comprehensive Cancer Center and Chair of the Department of Oncology at Georgetown University in Washington, DC.

This year celebrates the 50th anniversary, a milestone for the society and the whole field of oncology. Kathy, what has impressed you most about the meeting?

Breast Cancer: ALTTO's Unexpected Result

Kathy D. Miller, MD: In breast cancer we have some really practice-changing results and some results that challenge some of our assumptions. Let's start with the one that is challenging for us, the ALTTO trial,[1] which you'll recall enrolled 8000-plus patients with HER2-positive disease to look at the best way to inhibit HER2: the standard arm of trastuzumab alone; an arm of lapatinib alone, which failed early; 2 arms using both agents, the combination arm, which we had the best hope for; and a sequential arm.

We've seen improvements with combined HER2 blockade with trastuzumab and lapatinib in the metastatic setting.[2] On the basis of results in the neoadjuvant setting,[3] many of us assumed that ALTTO would be a positive trial and that we just needed to wait for the results. As of today's plenary session, we wait no longer; the trial is not positive. There was no improvement in disease-free survival or overall survival with the combination. There were toxicity and compliance issues that might underlie that failure, but it is a failure. I think it gives us pause, and we may need to rethink our enthusiasm about the neoadjuvant strategy as a way to identify the sure bets in the adjuvant setting.

Dr. Kris: Were there any preclinical data that would have predicted this, or were you blindsided by this result?

Dr. Miller: I think the preclinical data supported that combined therapy would be helpful. We've seen a lot of preclinical combinations that found improvement in results. We had neoadjuvant therapy that found improvement with pathologic complete response (pCR) rates as the endpoint,[3] and we had a trial in the metastatic setting in patients who had progressed on trastuzumab that combination therapy was better than single-agent therapy.[2] We've seen similar results with a different dual strategy with pertuzumab and trastuzumab in the metastatic setting[4] and in the neoadjuvant setting,[5] also supported by preclinical data. There is an ongoing adjuvant trial -- also large; several thousand patients -- called the AFFINITY trial.[6] That trial has finished enrolling. We're still waiting for its results. I think a day or so ago many would have thought that that trial was also a sure bet and that we would be then pondering which dual HER2 inhibition therapy was superior. We'll need to wait for AFFINITY; it is one trial with one combination. It may not tell us the whole story, but I think it does mean that we need to be cautious about pCR as telling us exactly the final answer, and that those therapies shouldn't move rapidly into the adjuvant setting outside of a trial on the basis of neoadjuvant results.

Dr. Kris: Do you use neoadjuvant therapy as a standard in your practice?

Dr. Miller: We use a lot of neoadjuvant therapy. Our biggest criterion, if you will, for using neoadjuvant therapy is that I am convinced that this woman needs adjuvant systemic therapy. That's our biggest discriminator, because despite the enthusiasm for pCR as an endpoint, the reason we treat people in the neoadjuvant setting is the same as the reason we treat people in the adjuvant setting: to treat distant metastatic disease that would become life-threatening if this woman only received local therapy.

Dr. Kris: Bruce, what for you was the most important moment of this meeting?

Blood Cancers: New Agents Push Chemo Out the Door

Bruce D. Cheson, MD: I can't say that there is a most important moment, but we are on the path that a number of us have been working on for a decade or more: to get rid of chemotherapy for chronic lymphocytic leukemia and lymphomas. There were several papers at this meeting which supported this possibility. For example, we saw early data on aggressive large cell lymphoma in the relapse setting, in which an antibody-drug conjugate yielded response rates of 40% lasting a number of months,[7] a good signal and a good start. One of the antibody-drug conjugates that has been most exciting and is now approved is brentuximab vedotin in Hodgkin lymphoma; in patients who had failed the stem cell transplant, it has achieved response rates of 76%,[8] some of them lasting a year or longer, even 2 years.

At this meeting, Massimo Federico[9] presented a small study that used brentuximab frontline in Hodgkin lymphoma without initial chemotherapy. Brentuximab was followed by chemotherapy because chemotherapy is curative and you don't want to take that risk. There was an 83% response rate with this antibody drug conjugate in frontline. It's now being combined with chemotherapy, systematically dropping off some of the drugs in the standard chemotherapy regimens, substituting biological therapies for nonspecific toxic chemotherapy.

Where this seems to have really stimulated the greatest amount of interest has been chronic lymphocytic leukemia. Early this year the drug ibrutinib was approved by the FDA. This is a Bruton tyrosine kinase inhibitor, one of the pathways downstream from the B-cell receptor along with the spleen tyrosine kinase (Syk) and PI3 kinase. Ibrutinib achieves responses in the vast majority of patients with relapsed/refractory disease, and at this meeting, Susan O'Brien[10] presented 3-year follow-up of early, exciting phase 1 data showing that 78% of patients responded.The duration of response median has not yet been reached. If you look at the really bad actors, 17p-deletion patients, their usual median survival upfront is less than a year. They had a response rate of almost 60% to this pill, and the median duration of response was over 2 years -- and that's in the relapsed/refractory setting in patients who received several prior regimens. It's very exciting data. Another study, called the RESONATE trial,[11] which was a late-breaking abstract, compared oral ibrutinib to ofatumumab, an anti-CD20 monoclonal antibody, which is a standard treatment for relapse patients. Ibrutinib blew anti-CD20 off the map in response rate -- by almost a 10-fold improvement in response rate, progression free, and even overall survival. We're slowly getting rid of chemotherapy and less than impressive biological therapies, and moving towards not so much single agents but perhaps combinations.

New Agents Don't Necessarily Make Good Partners

Dr. Cheson: We heard data on GS-9973, a Syk inhibitor, which by itself was well tolerated and active in relapsed/refractory CLL.[12] There is another that will soon be on the market called idelalisib, which is a PI3 kinase inhibitor. It was well tolerated -- some diarrhea but nothing terribly exciting. We were in a study to put the two of them together, which to our dismal surprise was shut down early because of 9 cases of pneumonitis, generally reversible, and 2 cases of central nervous toxicity, sort of a disequilibrium syndrome.[13] Even though we have these wonderful tools now that will get us to the point of a chemo-free world -- at least in hematologic cancers -- you've got to be careful in how you put them together. We've done a number of studies in Alliance, formerly CLGB, where we tried to put several of these together and ran into some trouble.

This is a time which we never thought we'd ever get to. We are taking pills. You're getting rid of disease or at least putting it into partial remission, getting rid of symptoms, making cell counts better without subjecting patients to noxious substances -- not that these agents don't have their side effects. But it's a far cry from chemotherapy.

Dr. Kris: It sounds like you've got your work cut out for you over the next decade, trying to figure out how to combine, sequence, and match toxicities.

Dr. Cheson: Absolutely. And trying to identify which patient is a candidate for which drug. We're already finding mutations that are occurring that make patients resistant to these agents. Already there are second-generation PI3Ks and BTKs rapidly coming down the pike that have less toxicity and that seem more active. It's rapidly changing. We need to continue to do correlative science with these clinical trials, even if the agents are on the market. We have to get patients on clinical trials so we know the best way to use these agents. Who is going to benefit? Who isn't? Maybe eventually we'll get the right combination to cure these patients so they won't have to take the drugs indefinitely.

Colorectal Cancer: 10 Years of Improved Median Survival

Dr. Kris: Lou, how about you? What is your special moment here at ASCO?

Louis M. Weiner, MD: There were 3, actually. The first one was what a huge meeting this is. I mean, unbelievable. The second: I've always been interested in immunotherapy and I can remember a time not many years ago when I could skim the immunotherapy abstracts in the book and it would take me about a minute, and then I would try to find a relevant abstract to go hear the presentation. Now, I can't get through everything. I can't get to all the abstracts this year.

I want to go back and talk about immunotherapy for a minute. From a disease-management perspective, I see GI cancer patients. It's not always about new drugs but about using drugs well in order to change practice and make our patients' lives better. The plenary session abstract presented by Alan Venook[14] looked at a variety of different strategies for treating advanced colon cancer and found no essential difference in how you mix and match the various active agents together in frontline. But what was really critically important was that the median survival was somewhere between 29 and 30 months for this group of patients with first-line metastatic disease. The median survival when I finished my training for metastatic colon cancer was roughly a year, maybe even a little bit less.

Dr. Kris: That is what I grew up with. That was the right answer on the board exam when I took the boards.

Dr. Weiner: Exactly. When the Hurwitz study[15] came out 10 years ago looking at the combination of irinotecan, 5-FU, and leucovorin plus or minus bevacizumab, we were thrilled because the median survival was up around 19 to 20 months. A decade later, we're out at 30 months median survival with the same group of drugs that we had available 10 years ago. But now we've learned that you have to use them all at one time or another during someone's disease. You've got to use them wisely. You have to parse them out appropriately. If you do that, you can actually help folks live a lot longer. If a new drug had come out in the past 10 years that increased median survival in first-line metastatic disease from 20 to 30 months, there would be champagne corks popping all over the place. So I think we have to celebrate these advantages.

Immunotherapy: Finding Cancer's Achilles Heel

Dr. Weiner: The other thing that really excited me, and it's going to be parenthetical to the immunotherapy stuff, was a presentation by Jerome Galon[16] from INSERM (Institut National de la Santé et de la Recherche Médicale)in Paris.He's developed something called the Immunoscore®, which is a way of looking at early-stage colorectal cancer biopsy samples and quantifying the number and type of T cells that are infiltrating the tumor. He's been able to show over a period of a decade, with very elegant high-profile publications, that the greater the density of activated T cells in the tumor, the more likely someone is to be cured. It actually trumps classic Duke staging or other kinds of TNM staging for colon cancer. This teaches us something that is very, very critical. When a cancer is developing, it has only one enemy: the body's immune system. The cancer has to solve that problem in order to thrive and survive in the patient. Once the cancer finds that critical feature that allows it to thrive and survive, that becomes its dominant mechanism for defeating the immune system. It also becomes the Achilles heel of the cancer.

Studies that have been published[17] and studies presented here[18] show the value of ipilimumab and the PD-L1 and PD-1 inhibitors. They clearly demonstrate that when that pathway is the particular Achilles heel of the cancer, you get tremendously exciting clinical results. One of the most exciting aspects is actually a follow-up of a study that was presented here last year in melanoma. (It's not one of my areas of disease expertise, but you have to pay attention to this stuff if you're interested in immunotherapy.)

Dr. Kris: In my institution, in particular.

Dr. Weiner: I would think so. This actually was presented by Mario Sznol[18] and not by Jedd Wolchok, who did the original publication. The study, which combined both an anti-PD-1 antibody and ipilimumab, an anti-CTLA-4 antibody, showed a really dramatic and rapid rate of response in patients with metastatic melanoma. What I found stunning and a cause for great optimism was that this group of people, who were treated with adequate doses of a combination of these 2 drugs, had a 70% overall clinical benefit rate, which is way, way higher than we've ever seen with melanoma in the past. Many patients had rapid response, and 20% of these patients even had complete response, which previously was unheard of in this disease. The median survival for this group was 39.7 months I think it was -- 39.7 months, almost 3.5 years. You have to recognize that in this particular clinical setting, the typical expected survival would have been about 7 months. This is a real game-changer.

What it points out for all of us is that if we can identify the particular dominant defense mechanism that is being employed by a cancer population -- be it colorectal cancer, melanoma, breast cancer, even lymphoma or leukemia -- and we can identify those critical mechanisms and attack them, we're going to have a real game-changing treatment. Not only may we eliminate cytotoxic chemotherapy, but we might even be able to eliminate targeted therapy and allow the immune system to do that voodoo that it does so well, which is to attack those cancers. Now, in truth, I don't think we're going to get to that place very easily. It will be a long time before we can do that, but I do think that combining these agents and strategies in order to accomplish powerful antitumor actions is in the relatively near future.

From the Clinic to the Lab, and Back Again

Dr. Kris: I guess the common denominator here is that we've gone from a time when we were observing, we were classifying, to a time when we have a greater understanding of the biology of these cancers. For instance, when I came along, there really was no HER2. We didn't know about it. It's all biology-based now, which has opened so many windows. Things that we thought were not possible are possible.

But I'll give you a cautionary note on our old friend chemotherapy. It sure has cured a lot of people, particularly with breast cancer. I think we're going to find new uses for it as well. We've talked about conjugates with chemotherapy drugs, and a good example is breast cancer.[19] Also I think there are many effects on the immune system that can probably be used in a positive way by various chemotherapies. It's not the hammer, though. It's not chemo-plus-this. It's giving the right chemo, the right dose, in the right sequence with these other therapies.

Following up on your example about coming targeted therapies, I think we've seen in the lung cancer space that in KRAS-mutant lung cancers, combining a MEK inhibitor and a PI3K inhibitor, which makes great theoretical sense -- in the lab it's curative -- didn't work out well in patients. However, combining a BRAF inhibitor and a MEK inhibitor in melanoma was just about amazing.[20] Not only did you treat more cancers, but you had less toxicity. I mean, it's just so counterintuitive. One thing you teach your trainees is that if you put 2 drugs together, you're going to have more toxicity. Suddenly, putting a BRAF and MEK inhibitor together in a BRAF-mutant case, you're going to have less toxicity, which is really pretty amazing.

Dr. Miller: You've just made an elegant case for why clinical trials will always be important, because translational medicine goes in both directions. It's taking those observations from the laboratory and developing and testing a therapy, but it's also developing clinical trials that get the observations -- sometimes unexpected -- and feed those back to the laboratory to try to understand what we missed that could explain this.

Dr. Kris: Absolutely. That's been the story in lung cancer. We took clinical observations to the lab, and the lab made discoveries and brought them back.

The Difference Between Efficacy and Effectiveness

Dr. Weiner: One of the themes at this meeting for me has been the nuanced understanding we now have of the difference between efficacy and effectiveness. Right? In colon cancer there were drugs that had efficacy, but in order for them to be more effective we had to do clinical research to understand how to make these treatments work for people. We're not treating cancer. We're treating people. I think that the lesson we're learning at this meeting -- and that we all learn every day in our practices -- is that that's really important.

Dr. Kris: When you shrink the cancer for a week, it really doesn't help the person. That's something that you saw back in the day. But through the hard work of researchers, we've seen a dramatic change in things.

Thank you. I really appreciate hearing from all three of you today. You are really experts in your field and you just picked out the things that were most important, and you made that choice because you know what this means for patients and what it means for the field of research. Thank you for joining us for the Medscape Oncology Wrap-up of ASCO 2014. This is Mark Kris, reporting from Chicago.


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