Personal Medicine for Lung Cancer

M. D. Anderson Cancer Center

Cancer Newsline Audio Podcast Series

Date: June 01, 2009

Duration: 0 / 16:39

 

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Doctor Ed Kim:

 

Welcome to Cancer Newsline, a weekly podcast series from the University of Texas, M.D. Anderson Cancer Center. Cancer Newsline helps you stay current with the news on cancer research, diagnosis, treatment, and prevention, providing the latest information on reducing your family's cancer risk. I'm your host, Doctor Ed Kim, Assistant Professor in M.D. Anderson's Department of Thoracic Head and Neck Medical Oncology. Today, in this breaking news edition, we'll be talking about where we are in terms of personal medicine for lung cancer. Offering our patients the most individualized care is obviously a high priority for all of us who treat lung cancer. This topic has garnered a lot of attention this week at the American Society of Clinical Oncology, or ASCO, the largest cancer conference in the world. Today I'll be speaking with my colleague; Doctor Roy Herpst about this shared goal and our research of investigative targeted agents for lung cancer. Doctor Herpst is Professor and Section Chief of Thoracic Medical Oncology in the Department of Thoracic Head and Neck Medical Oncology at M.D. Anderson. Roy thanks so much for joining me today to discuss a topic that obviously means a lot to both of us.

 

Doctor Roy Herpst:

 

Ah thanks! It's a pleasure to be here.

 

Kim:

 

There were several important lung cancer studies that were presented at this years meeting. Can you give us some context of where we are currently with the state of cancer treatment today, and how we're moving in a direction for our patients with the greatest needs?

 

Herpst:

 

It's quite important to note that the therapy for lung cancer really has been improving. In the last several years we have noticed this. Now at the last 3 or 4 ASCO's that now we have specific targeted agents that have shown a survival benefit in this disease, and the two agents, of course, that are FDA approved would be Bevacisumab, which is an antibody that, that targets blood vessels, which are critical for the growth of tumors. Which, when used with chemotherapy, improve survival in the upfront therapy of lung cancer, and then the drug Erlotinib, which is an oral agent, which is used as a single agent to a failed chemotherapy, and includes survival there as well. And both these agents came to the clinic after years of study, many of which were done at M.D. Anderson. So it's very satisfying for us to see those agents now in common use.

 

Kim:

 

Now Doctor Roy Herpst, what pathways do these drugs target and, and why are they relevant in cancer?

 

Herpst:

 

Well we've learned, you know, a great deal in the last few years about how cancer cells grow, what are the critical pathways, what are the critical issues that, that allow them to, to divide and to grow, and to cause patients harm. One is a pathway known as the epidermal growth factor receptor pathway. That's what this drug Erlotinib targets and that's a pathway, which is up regulated and, and quite active in most patients with lung cancer. If you block that the cancer cells won't grow as well, they won't spread as well, they won't be as metastatic, and hopefully you can control the disease. The other pathway that I mentioned was angiogenesis. The idea that if you have a tumor, for a tumor to grow in its primary location, and also for it have the ability to pass through the bloodstream, spread and take up roots someplace else, it needs to form and induce new blood vessels, process of angiogenesis. And the drug Bevacisumab works to target that pathway as well. So with these two agents we, we certainly have improvements in the, in the daily care of patients with lung cancer. Though we don't want to stop there, the, the idea now is how can we do better? There are two ways to do that. One would be to develop better agents. Perhaps an agent that targets multiple pathways at the same time, just as if you were fighting a war you might want to attack in two directions at the same time, and there, thereby have a better affect against the enemy. The other, of course, would be to select your patients more carefully, to understand who is going to benefit most from any of these therapies, that would be the development of predictive factors that could tell us which drugs to use in which patients. I think both approaches are important, and perhaps we can discuss them both today.

 

Kim:

 

Now you have quite a bit of experience in, in this type of co-targeting. Last year you reported some data from a study that you can share with us that showed some promise of integrating both targeting the epidermal growth factor receptor and the vascular endothelial growth factor.

 

Herpst:

 

Right! Over the last five years now we have looked at combinations of targets and it makes sense, because if we know that these tumors are dependant on their vascular supply, and they're also dependant on the epidermal growth factor receptor, why not target both at the same time? And we've actually gone from phase one all the way through to a phase three study that have shown some affect of, of giving both the drug Bevacisumab, it's IV, it's an antibody, and the drug Erlotinib, it's the pill, together. Those are, are data we've presented at ASCO in the past. But this year we actually have a different agent, known as Vandetanib. The thing that's nice is that's everything in one pill. So it's completely oral. In that pill we have activity against the epidermal growth factor receptor and against the blood vessels. And here we have a study where we actually used the drug with Docetaxel. With, with a common chemotherapy that's used in patients who have failed at least one chemotherapy for lung cancer.

 

Kim:

 

So this was the study that was presented at the ASCO press program, clearly a very large study that builds on the experience and correct me if I'm wrong, but that early combination therapy of Erlotinib and Bevacisumab was something born out of here at M.D. Anderson through your guidance. And now if you could talk about the trial you're presenting this year with the combination of the pills and detanib with Docetaxel, and how a, it's importance and now relates to other lung cancer findings.

 

Herpst:

 

Right! So the idea of co-targeting the two pathways is a, is one that came out of work in the laboratory here at M.D. Anderson. It then went to early phase trials. The agent we're taking about today, Vandetanib, the early phase studies were done by ourselves at M.D. Anderson. Actually Dana Farber and other sites, actually the principle investigators there, Bruce Johnson and John Haymac, close colleagues on several of our grant funded programs, and we're very involved in those early studies. In fact Doctor Haymac since has come to M.D. Anderson where he's now a member of our group. And the idea is that this drug Vandetanib, in a pilot study when it was used with Docetaxel, it appeared in that small study with only 120 patients, that there was a benefit. Meaning when you gave the drug Vandetanib, the dual inhibitor, with the Docetaxel, it appeared that there was an increased time to progression. Meaning it took longer for the tumor to grow when you gave it two drugs versus the one drug, Docetaxel, to standard therapy alone, and that was a manuscript published last year by Doctor Haymac as the first author and several of us in the group, of course, we're involved as well, including myself. So then we launched, and actually we launched this several years ago, because we knew the results, as is often the case, the results are known before they're actually in final form and published. Two or three years ago, we organized a large multi-national trial, almost 1,400 patients worldwide; this included the United State, of course, Europe, Asia, Latin America, South America. We really accrued these patients from over 100 sites around the globe. And it was a trial that basically asked a very simple question, can we verify that when you use Docetaxel with Vandetanib it performs better than Docetaxel alone. How do you prove such a thing? You use a placebo. So the patients and the physicians alike did not know who was getting which combination. And this trail was, was performed in a rigorous way with very careful safety management, of course. Now I'm presenting the results for the multi-national group that, that lead it. I'm very honored to be the chair of the steering committee of this study.

 

Kim:

 

 So clearly this is a study that could change the way we practice in second line lung cancer in the future.

 

Herpst:

 

Um, one would think so. Let me tell you the results and, and you can judge for yourself. So basically in this study the first important point is that it was safe. You could give this drug Vandetanib with the Docetaxel therapy. While there was some increased rash and some increased diarrhea, some loose stools, which are often seen with these small molecule type agents, there really was very little else that, that strikes the eye that, that made that combination therapy worse. One thing we were very concerned about was pulmonary bleeding. Because this is something you see often see with agents that target angiogenesis, that target blood vessels and we did not see this in the trial, in 1,400 patients or so around the world. Now we did see that the therapy appeared to be better. We met our primary endpoint. We were looking to see if we can improve the progression free survival, and in fact we did that in a significant way. Patients had close to a month improvement in the time it took for their tumors to get worse. We usually portray that with a term known as the hazard ratio, and that hazard ratio was 0.79, which in my opinion is a reasonable benefit for this combination therapy, especially in light of the symptom benefits that were seen as well. One of the slides that I'll show at my presentation actually looks at patients and asks them through the questions to see how they are feeling and to see what their symptoms are from their lung cancer. And we actually were able to show that not only did the patients tumor progress more slowly, but their symptoms progressed more slowly as well. Now the ultimate endpoint for any trial in lung cancer is overall survival. Unfortunately this trial did not show a survival benefit within statistical significance. There was, in fact a nice trend. But that doesn't completely surprise me, because now a days, as we talked about earlier, with many of the advances that we've seen in lung cancer, we now have other therapies patients can get once they're off of the trial. So it's quite likely that what's happened is many of these patients after they completed therapy, either with the treatment arm or the placebo arm, went on to get other therapies, which would confound the ultimate results. But nonetheless we have what I believe is the first trial of an oral agent targeting either epidermal growth factor or vascular endothelial growth factor, and that's the thing, we don't know which activity if, or perhaps both, are important for this affect, that was, was safe and affective in this disease. So we're quite excited to be bringing these data to the community now for their peer review, and for, for their input. And whether or not this becomes a standard of care will, there, there are many steps before that can happen. But the first is here at this ASCO meeting where investigators from a large multi-national team led by ourselves at M.D. Anderson are, are presenting these data for review.

 

Kim:

 

Now you mentioned the biomarkers and other aspects, and really personalizing therapy is becoming the forefront. What are we gonna see at ASCO? Or what have we moved in that direction?

 

Herpst:

 

Well you know it is funny Ed, you know, the theme of ASCO is personalized therapy for cancer, and that's been our theme in our lung program now for more than five years, and of course, you know as well as I, as we are very closely involved in the development of our Battle program, the battle against lung cancer. Where, we actually now since 2005 we've been treating patients with advanced lung cancer,  who fail therapy with fresh tissue biopsies. Because we realize and, you know, I as much as anyone having conducted a large number of trials over the years that to really make the next step you don't, not only need the active agents and the safe agents. No doubt we have those now. But what we need is we need to match those agents to the right patients. And through studies like our Battle Program where we're actually learning which tissue predictive markers will lead to the, the best results in any given patient. That's how we're going to make the next step. And Battle 1 is now moving towards Battle 2, where we're looking at new agents, new combination of agents. So I was thinking we're seeing at this meeting so many posters and presentations talking about different markets that can identify a subset of patients who might do better than others. That's the striking thing, if you see a, a trial like ours or, or several other trials presented here this year last year, where it's clear that probably about 10, 15% of the patients are really benefiting, and the rest, and some probably are just doing a little bit better. And some might even be doing worse with that new therapy. If we could pull that 10% off the top and make them our target, then we can start to subset patients with lung cancer that truly have more affective therapy for this disease. So, we're getting there. Plus, I'd like to ask you, you know your thoughts as someone who's been so involved with this as well.

 

Kim:

 

Well yes, as you mentioned, you know I am presenting Battle this year at the ASCO. It's our initial finding that is going to be sort of the initial results of what we have. We, we plan to; of course, you know finish this study by the end of the summer. But it's really been ground breaking in the sense that the collaborative department and, and clearly this is the Department of Defense grant that Ke Hong has secured and allowed us to conduct studies like this. In that we are really getting these real time tissues on patients using biomarkers to randomize them to, what we felt several years ago, including the drug you mentioned, Vandetanib, to be realistic treatments for lung cancer patients. I think we guessed correctly on those treatments years ago. It really does change the approach that I think many researchers have to take toward designing studies for lung cancer, in that it's not an excuse anymore, not to get biopsies, not to get biomarkers real time. We can't just go with these archive tissues. So I'm going to be sharing the results, we did that this year at ASCO. We'll hopefully finish the, the enrollment to 200 evaluable patients by the end of the summer, and it'll be exciting to report that data. I think, as you know, we've been working on this Battle program very closely for several years. It's really helped us build on a really changing paradigm in the department, now moving to the Battle 2 program. If you could just briefly give us a little hint on what's coming with Battle 2.

 

Herpst:

 

Well Battle 2, the ground war, as we like to call it. Battle 2 is basically building on Battle 1. So we've shown that we are able to do these biopsies safely. We don't have the final results yet, but our hope is that we're treating patients more effectively as we're learning how to treat them even better in the future, There is a large amount of discovery from this discovery, and some of the keen expression profiles, we realize that there are patterns of gene expression, and there are pathways that tumors can express to allow them to get away from the drugs we're using. In fact, it makes sense. Under Darwinian pressure, any tumor is going to learn to become resistant. These tumors are going to find ways to pump out the drugs we give them, to grow in, in the presence of these agents that are inhibiting certain receptors and pathways. So in Battle 2 where we're trying to learn from this, we're trying to use not single agents, but more combinations of agents. We've picked agents that are specifically involved in overcoming resistance to the epidermal growth factor receptor pathway. And building on, on where we've been, we're hoping to, to then treat even more patients effectively by using these new combinations. And, and again using the Battle 1 data base to help us design the markers that we'll use in the Battle 2 trial. So we're quite excited about that. There's a key, as you know, is, is our team. We're both so fortunate to be part of this, this group at M.D. Anderson of nurses, and radiologists, and statisticians, and it's really, it's, there's no place really like, like our center with the, the resources to do these trials to take good care of our patients while learning how to treat the next patient even better than those that we have here now. And that's the goal. We have to continue to raise the bar in this deadly disease.

 

Kim:

 

So I think you really emphasized that, that it really does truly take a team approach. I think at M.D. Anderson here we have this, sort of multidisciplinary approach. Thanks so much for having this discussion with me today. I think we've really found some significant findings that our listeners will be interested in. If you have any questions about anything you've heard today on Cancer New Line, contact Ask M.D. Anderson at 1-877-MDA-6789 or online at www.mdanderson.org/ask. Thank you for listening to this episode of Cancer Newsline. Tune in next week for the next podcast in our series.

 

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