Iressa for Treatment of Lung Cancer

M. D. Anderson Cancer Center
Cancer Newsline Audio Podcast Series
Date: November 21, 2008
Duration: 0 / 17:17

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Lisa Garvin:

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 all the news on cancer research, diagnosis, treatment and prevention, providing the latest information on reducing your family’s cancer risk. I’m your host Lisa Garvin.

Today we’ll talk with Dr. Edward Kim, Assistant professor in M. D. Anderson’s department of Thoracic Head and Neck Medical Oncology. Groundbreaking study results released just this week suggest that the drug Iresa has proven to be just as effective as chemotherapy for lung cancer. These findings represent the first time an oral cancer therapy has been tested head-to-head against standard therapy and has helped investigators learn more about two genetic mutations or biomarkers associated with Non-small cell lung cancer.

Thank you Dr. Kim for joining us today. Your study indicates that taking Iressa in pill form works just as well as systemic chemotherapy in certain lung cancer patients. What are the implications of that?

Edward Kim, M.D.:

Well, we don’t have much research especially in patients who have been pretreated with chemotherapy comparing head-to-head these oral biologic agents. Right now Iressa is the drug we studied in our trial. There is a companion drug that is approved in the United States and other places called Tarceva or Erlotinib. When we powered the study to look head-to-head against intravenous chemotherapy, and that is docetaxol or Taxotere, we were pleasantly surprised to see that we did not see any decrement or decrease in effectiveness that both study arms – whether you receive the oral chemotherapy or the oral biologic therapy Iressa – or the intravenous chemotherapy docetaxol those patients did very similar as far as their outcomes. They had similar survivals, similar response rates, all of the major clinical factors.

What we were happy to see was that the side effect profile was less, patients tolerated the therapy very well, and so where have we been trying to move forward as far as achievements in refractory lung cancer? Well, the drugs we have have not been able to extend survival as much as we’d like, frankly. But, we have additional drugs now that patients can take that are clearly as effective as our chemotherapies but offer better quality of life and better side effects so that they can tolerate these therapies more and try and live a more normal life while they are taking them.

Garvin:

Now as far as Iresa, it showed a lot of promise for lung cancer back in 2005, then the FDA didn’t allow it to be used in the United States. What happened back then?

Kim:

It was quite unfortunate the way everything worked out with this drug and it serves as a historical sort of benchmark on maybe what we should and shouldn’t do. There was a lot of excitement when this drug was first being tested and throughout the world thousands of people were being treated with this drug. The first time an oral drug for lung cancer! And the more astonishing part was there were certain people who had very, very dramatic responses in their tumors in which we saw things shrink in front of us, patients feeling better even within a three week period of time. We’d never seen this with chemotherapy before. So based on that and a couple of phase II studies the FDA did fast track this drug and it was made available, deservedly so, to patients throughout the country.

At that point, two phase III studies were then launched. One of them was called ISEL this was Iressa Survival Evaluation and Lung Cancer Study and the other one is a study we are reporting this week, INTEREST.

ISEL was Iressa vs. placebo, and so you would think that if a drug shows so much activity on its own, that it should have no problem beating a placebo or sugar pill. In fact, the results were quite disappointing. There was a trend in favor of the Iressa, but it was not statistically significant - it missed literally by two weeks. One of the blame was that the patient population that was studied was a much more refractory population. These folks had not had very good responses to prior therapy and so you were really looking at a patient population that was more sick, that their disease was less responsive and really any drug you tested in that setting may have a difficult time.

This was very much in contrast to the other studies that had been testing these biologic agents in chemo refractory patients. And so, in our study interest where we did test a more sort of uniform population of folks in this setting, we saw the results that we desired and I think validates that Iressa is a good treatment for lung cancer. Now, that being said, are we going to be able to prescribe this drug in the United States anytime soon? And the answer is no, not at this time. However, they are reviewing this drug again and seeing if it is a possibility. The good news is that this data not only helps people in the United States, but it also helps people worldwide. And so, there are many counties that have Iressa available as well as these EGFR small molecules again, like Tarceva. And I think the concept is that people know they can give these to folks with confidence knowing that you are not sacrificing any effectiveness in their therapy.

Garvin:

Now explain how Iressa works. It’s a targeted therapy as we know, but how does it work on lung cancer cells?

Kim:

Iressa, like several other drugs targets what we call the epidermal growth factor receptor pathway – or EGFR. There are both pills and intravenous drugs that are available that target this class. Some of the intravenous drugs, such as CETUXIMAB or ERBUTUX most recently showing effectiveness in lung cancer in combination with chemotherapy. Iressa is able to shut down this pathway, which seems to be very important in the growth and spread of cancers, namely lung cancer. By doing this, we see that the tumors shrink or they don’t spread as much. We call that disease control. So that’s a very simplistic way of looking at it. It is targeting one specific pathway in the cell. Scientifically we know that other pathways are probably affected as well, but this is the main pathway that drives the therapy when we treat cancer cells.

Garvin:

Now tell me about this Phase III study in itself. What was your goal, and what sort of results did you come up with?

Kim:

Well, this was an ambitious goal. We wanted to go head-to-head against chemotherapy. And, you have to test head-to-head to try and access a tie. Now it’s very hard to have a tie in anything, so you have to say it’s got to be close enough that it’s acceptable. And that’s something we call non-inferiority in lung cancer and in other clinical trials. This is the design that has been used multiple times for multiple drug approvals. So this was a study that has to be very high powered to look at Iressa head-to-head against docetaxol and there had to be enough patients to say with confidence that these are very similar drugs. We had to enroll over 1,400 patients worldwide in this study. This is the largest study of its kind in the setting of second line lung cancer where we had over 1,200 patients who had just one prior therapy. We knew that if we looked head-to-head we would probably see benefits with quality of life in favor of Iressa, we would probably see benefits in side effects, as drugs like Iressa do not effect your blood, they don’t effect you hair. The main side effects of a drug like Iressa is acne and a very mild diarrhea, so if you can tolerate those two things and that’s your choice of side effect for any type of therapy in a cancer, those aren’t bad choices to have.

We were very fortunate to be able to report the survivals were very similar in this study – between 7.6 and eight months that docetaxol performed as good as it ever has in this setting, and despite that, Iressa was able to show that it was clearly not inferior to the chemotherapy.

Garvin:

Ok – that kind of leads to my next question. What was the survival rate of the patients in this study?

Kim:

The patients who are treated with Iressa were 7.6 months and the patients who were treated with docetaxol were 8 months. The one year survivals were both 32 and 34 percent respectively. So, very similar outcomes between the two.

Garvin:

There were certain things you learned about genetic mutations, K-ras and EGFR. What did you learn about these tumor biomarkers, and can they be used as predictors or to select treatment?

Kim:

That is the real major frontier that is facing many different cancers and certainly in lung cancer we have many therapies available right now. What we do not know is which therapies are appropriate for which patients and that is something called personalizing therapy or trying to individualize therapy. The examples that are best described in cancer include the breast cancer patient who has over expression of a marker called HER2-NEW in which a drug trastuzumab or herceptin then works beautifully in. Also, patients who GI stromal tumors who have a mutation in c-kit when the are given a drug that targets this and that is going to be any of these IMATANIB or Gleevek type drugs. They work very well in targeting that tumor population.

We don’t know in lung cancer, so we obviously have to look down the family EGFR of what makes the most sense. There are several ways to measure EGFR. One of them is what we call staining for immunohistic chemistry. Another one is to find a mutation which has been described by the Boston Groups. Another is to look at gene amplification – or FISH. What we did in the study was used as a co-primary endpoint FISH. The reason why we used FISH was because there was, at the time the study was being conducted, a report from the Canadians on a very large study that FISH in a subset of patients predicted better outcome for TARCEVA. So, thinking that was extraplible to Iressa, that was incorporated as a major endpoint.

We were disappointed to see that this did not separate patients. And so, regardless of whether you had a high level of FISH EGFR, it did not matter whether you were treated with the Iressa or the Docetaxol.

We also looked at subgroups of patients and this included EGFR mutations. EGFR mutations have gotten a lot of press about being treated with these types of drugs. What we were able to see again in a subset of patients in this study, and we had about 50 patients who had EGFR mutations, we saw that there was actually no difference regardless of treatment. In other words, if you treated a patient who had an EGFR mutation with Iressa, they lived quite long. If you treated a patient with DOCETAXOL, with an EGFR mutation, they also lived quite long. So, it seemed like the EGFR mutation helped you do better overall vs. those patients who only had wild-type or no EGFR mutation. But it did not seem to be predictive based on the treatment that you received.

So one of these things that we think about is prognosis vs. predictive. We know that if you are a woman you’re going to live longer than a man. That’s just life’s inequities and that’s what happens when we observe this. Well, I think that if you are a cancer patient and a lung cancer patient and you have an EGFR mutation, your treatment and longevity will be enhanced by having this mutation. It seems to be a favorable prognostic group. Similar to how when we look at never smokers or those patients who smoked a lot, the people who never smoked are going to do better pragmatically.

What we did observe which is now consistent with other reports is that despite no difference in survival, there is a difference in progression free survival and response rate. So, if you give Iressa or a drug like that to a patient with a mutation, they will have a longer period in which they will have disease controlled and also they will have a better response rate. There are some clinical factors that make this relevant in a patient population such as those with mutations.

Garvin:

Is the study a big leap forward in targeted therapy research or is it just a baby step at this point?

Kim:

I would say that any step we make is a baby step and the reason why I say that is because it’s still a very long journey to where we want to go. I think this study serves as a nice foundation to say now we have both treatment options for patients. You don’t have to feel bad about giving one or the other. We are saying to doctors, it’s ok to give a less toxic easier to administer treatment, an oral biologic therapy in lieu of chemotherapy. Now, is this type of drugs going to eliminate the need for chemotherapy? Absolutely not, we are going to need both Cytotoxics and biologic therapy. But one does not have to feel bad now about giving an oral biologic drug. In fact, if you think about breast cancer in the advanced breast cancer setting, we interchange chemotherapy and hormonal therapy, oral biologic therapy, very much so. I think in lung cancer we’re going to start seeing that sort of also permeate into our treatment decisions and hopefully again lead us back to we need to get tissue, we need to figure out what is unique about each patients different tumor and tailor a therapy that’s appropriate for them.

Garvin:

Now as far as Iressa’s future in the United States, do you think this study will help convince the FDA to re-approve Iressa in the United States?

Kim:

I can never make any predictions about the FDA as I respect them as an organization. I certainly hope that data such as this will allow them to consider such thoughts. I certainly would welcome Iressa back on the market here in the United States and I know many investigators across the country that still have patients from Iressa from several years ago so clearly there is some activity of this drug. And, my attitude is the more the merrier. I would love to have choices of agents in all settings so that we can sit down and talk with the patients and decide what’s most appropriate for them.

Garvin:

Great! Well, thank you for talking to us about your work. Are there any closing thoughts or anything we haven’t covered that you’d like to talk about?

Kim:

I think a message out there is I think patients with lung cancer should always try to remain optimistic. There are many, many studies being done, there are drugs being tested. Some of the patients that I have been treating for several years have witnessed multiple drugs approved during the time when they were diagnosed to when they are currently being treated. So I would say optimism is important, know that the science is trying to catch up to the therapy, but that we do have options out there and that I think patients need to educate themselves and find what therapies are available and ask their doctors about these therapies.

Garvin:

Thank you Dr. Kim. If you have questions about anything you’ve heard today on Cancer Newsline, contact ask M. D. Anderson at 1-877-MDA-6789 or online 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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