Lung Cancer Leading the Way in Personalized Medicine
Mark Kris, MD: Hello. I'm Mark Kris, Chief of the Thoracic Oncology Service at the Memorial Sloan Kettering Cancer Center in New York. This is Medscape Oncology Insights on lung cancer. Today, we'll look at some of the important studies presented on lung cancer at the ASCO meeting in 2001 here in Chicago. Joining me is Dr. Jyoti Patel, Associate Professor at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois. Welcome, Jyoti.
Jyoti Patel, MD: Thank you.
Dr. Kris: I know that today you went over the highlights of lung cancer studies done at the meeting. Could you share some of those with our viewers?
Dr. Patel: Absolutely. We had a great bunch of studies that were presented early on Friday in a clinical science symposium and in the oral abstract session yesterday. Most of the studies, in aggregate, break into 2 big groups. One is truly personalization of care and finding the molecular underpinnings and really targeting those with rationally designed drugs.
The other set of studies dealt with how we give chemotherapy, and how we can give prolonged chemotherapy to patients and keep them living without cancer symptoms for longer periods of time.
One of the most important presentations that came out was Rafael Rosell's presentation of the EURTAC [European Randomised Trial of Tarceva vs Chemotherapy] trial.
The EURTAC trial. EURTAC was a Spanish trial that is singular in the fact that it was in a Caucasian population of patients with EGFR [epidermal growth factor receptor] mutations. So, these patients had activating EGFR mutations and were randomly assigned to receive an EGFR tyrosine kinase inhibitor (erlotinib) or chemotherapy. This was a huge effort because the Spaniards had already shown that they could do wide-scale screening. They had previously shown that; it's been published. But in this effort they looked at more than 1200 patients and found a mutation rate of almost 20%. Then, 140 or so patients were randomly assigned to standard chemotherapy or to erlotinib. Interestingly, the Spaniards were able to do DNA sequencing and then to do confirmatory tests, and there was 100% concordance. But most impressively, they did it in less than 5 days. The average turnaround time was 4.5 days. So, the primary endpoint was progression-free survival, and it was met nicely. Patients who had activating mutations had improved response rates (55%) when they received erlotinib, vs 11% with chemotherapy.
The study is still immature, and we don't have overall survival. Rosell and colleagues said they have less than 50% of events, but it looks like the lines will be pretty similar, and that's expected. It's a European population. There was a high rate of crossover to getting the other drug, so patients did end up getting erlotinib. The study is important because when you look at the past 2 years in which there have been several EGFR mutation studies, this is the only one done in a Caucasian population. There have been several done in Asian populations, and although those have been impressive, what really is striking is that the rates of patients with mutations are much higher, and the undertaking may be a little bit easier. Their countries are smaller, and so we now finally have data that really give credence to the fact that all patients should have mutation testing if you're considering therapy with an EGFR inhibitor. Patients with adenocarcinoma should likely have EGFR testing because you can really improve response rates, progression-free survival, and give these patients the best quality of life they can have.
Dr. Kris: Yes, I think that's a key message. I put it in just a few words, "Test, don't guess." Also, there is that complementary information from last year at ASCO. The trial by Vince Miller and Pasi Janneis not an exact kind of trial. They compared erlotinib alone with erlotinib plus chemotherapy. They also had a group of what I call "Euro-Americans," European heritage Americans, and I was amazed how the data were, at least for response rate, identical to IPASS [IRESSA Pan-Asian Study]. The progression-free survival was 16 months on the mutated patients, and the overall survival was more than 30 months. So there is still this idea that somehow gefitinib or erlotinib works better or differently in folks from Japan than in folks from Toledo, but I don't think that's true. I think that it's all about the mutation.
Dr. Patel: Right, it's the biology that drives the cancer. It's not where you happen to be born.
Dr. Kris: All the abstracts here said "test," and they showed you can do it. We can do it here in the United States, too. There are so many private companies that can do testing, and people should do it.
NCI's Lung Cancer Mutation Consortium
Dr. Patel: Another effort that was really noteworthy was something that you were part of and that you presented, and that was the Lung Cancer Mutation Consortium. That is an effort by 14 institutions around the country that are support by an National Cancer Institute grant.
Dr. Kris: This was an American Recovery and Reinvestment Act grant, by the way.
Dr. Patel: So, that's impressive because it's getting all the people on board. So, how long did you have?
Dr. Kris: It was a matter of weeks, over Memorial Day weekend, too.
Dr. Patel: To get all the players to come to the table and to agree. But you looked at about 1000 adenocarcinomas, tested for 10 mutations, and found mutations present in 54% of patients. The best part of that study, to me, was that many of these are "druggable" targets, and clinical trials exist for these patients. You can direct them rationally to the right patient. What was the Memorial Day experience?
Dr. Kris: Very comparable. Our group of patients had a 60% rate of mutation. A lot of people have said, "well, gee, the mutation occurs in 14% or 3%," but the truth is, when you put all the mutations together it occurs in the majority of patients.
I think another important point, now that we have to make that decision whether to use erlotinib up front or not, you need that mutation result to guide the care of a patient even if they don't get erlotinib. To me, the message from my past was you have to give chemotherapy.
Actually, there was another trial here at the meeting, the Thomas trial, where patients without any mutation testing were randomly assigned to get (in this case) erlotinib and bevacizumab vs a combination chemotherapy and, again, inferior survival to unselected patients that got erlotinib up front. To me the message is clear that you just don't do the best job you can by treating people without testing. Again, "Test, don't guess."
Dr. Patel: It has really changed the natural history of the disease, right? You keep patients well and asymptomatic for a long time, so up front therapy does matter even if you catch up out back.
Dr. Kris: Yes, absolutely.
Dr. Patel: The fact that you keep patients well for that initial period is so important.
Dr. Kris: This idea of "let's try the erlotinib, and what have we got to lose?" Well, you have a lot to lose. You have inferior survival for people in whom you do that, and that's pretty sobering. What else did you find interesting?
Dr. Patel: Another trial that I liked was a trial by Dave Spiegel looking at the MetMAb antibody. This was a randomized phase 2 trial of erlotinib and placebo vs erlotinib and MetMAb in previously treated patients. MetMAb is a 1-arm antibody that targets Met. It prevents the only known ligand of Met from binding hepatic growth factor. Usually, Met is overexpressed. It's correlated with worse prognosis in non-small cell lung cancer, so it seems to be a rational target. When it does dimerize, you have downstream signaling.
So, in the study, patients who had previously been treated actually had to provide tissue. The investigators were staining for Met with immunohistochemistry, and they developed a companion diagnosis that quantifies how much positivity they had. There were high Met expressers and low Met expressers. High Met expressers were Met-positive patients and low expressers were Met-negative. The study was nice because it incorporated that correlative as a primary endpoint, so the 2 endpoints were the intent-to-treat analysis in progression-free survival, and the second was looking at this enriched population of Met-positive patients and to see what their progression-free survival was.
So, interestingly, if you look at the intent to treat analysis there was absolutely no difference. It was ineffective. It was a negative trial. But if you look at the group of Met-positive patients, patients who received antibody and erlotinib had a 2-fold higher progression-free survival and a 3-fold improvement in overall survival. These are small numbers, and you certainly have to take it with caution but certainly thought-provoking and worthy of further study, because Met is a rational target with this antibody.
Dr. Kris: Yes, everybody who sees those data says that it's there, it needs to be confirmed, and we're all looking forward to seeing the study move ahead as quickly as possible to see if, indeed, it is a good target.
Dr. Patel: The most practice-changing study that was presented was with chemotherapy. That was the Paz-Ares study of maintenance pemetrexed in patients. Remember, we have talked about maintenance for the past 3 or 4 years at ASCO. We have tried to define what maintenance is. We know it's extension of therapy, but there is continuation maintenance, which is prolongation of whatever drug you're using and the doublet past the 4-6 cycles of platin-based therapy.
Then there is switch maintenance. Switch maintenance is the idea that they use a drug that targets noncross resistance and use it immediately after first-line therapy. Some people even call it "early second-line therapy." We have seen in recent years that pemetrexed and erlotinib have shown improvements in progression-free survival and in overall survival with that strategy.
We saw a nice study last year, the IFCT study, that looked at gemcitabine with platinum as maintenance in different randomized arms.
Dr. Kris: That was continuation maintenance too, and it showed a progression-free survival benefit by continuing the gemcitabine.
Dr. Patel: Exactly. Many of us have been waiting for this study because there are a lot of people who have, by default, done pemetrexed maintenance. So the study was 4 cycles of cisplatin/pemetrexed. Patients were randomly assigned in a 2-to-1 fashion to pemetrexed vs placebo, once every 3 weeks. Response assessment was every 6 weeks, and the primary endpoint was progression-free survival. The study did show an improvement, and the hazard ratio was intriguing at 0.62, and a survival progression-free survival improvement a little shy of 2 months.
The most interesting part was the Forest plot that was presented, showing that almost all patients benefited. But, really, the patients who seemed to garner the most benefit were those who had at least partial response or complete response to treatment. Although that sounds earth shattering, we have to realize that, for example, erlotinib switch maintenance is only approved in Europe for patients who have stable disease. But it seems to make sense. If it's working, don't stop.
Dr. Kris: Absolutely. It never makes sense to me to stop. Maintenance is not a new thing for me. What have you done in your practice before these kinds of things happened?
Dr. Patel: I was one of those people to whom continuation maintenance has made sense. Now it's nice to actually have some phase 3 data to back me up. But I have to say there are a couple of studies, such as the study that we talked about last year from IFCT. There is an older study that was not statistically significant, but there was a 2-month improvement in survival with continuation gemcitabine. So, we have a lot of good options. I'm not sure it's right for everyone, but if a patient is responding I think it's a very good option to consider continuation if you and the patient agree that they are tolerating it.
Dr. Kris: It's a no-brainer because you are only making that consideration in people who have evidence of benefit and also evidence of tolerability. The oncologist says that it's okay, and the patient says it's okay.
Dr. Patel: Right.
Dr. Kris: Obviously, you shouldn't be continuing it at all if those 2 criteria aren't met.
Dr. Patel: Right. They did, in fact, do a quality of life analysis and there was no statistical difference between the arms, of placebo or pemetrexed, which also makes you feel a little bit better.
Dr. Kris: Yes, but I would say that has always been my experience, and I think patients are very eager to accept, to continue therapy because they feel the benefit. They know the benefit in ways that we can't know, and it really makes sense to them. So, I take that to the bank.
I have to say that I am amazed that each year here at ASCO we get some new piece of information that really helps us take care of patients, and that's one piece. I'm also amazed at how lung cancer is leading the field all of a sudden. I can't tell you how many people came up to me and said that we hope to do the same thing we're doing in lung cancer now in our patients. The most amazing thing about that lung cancer mutation consortium project is that we could do this, and we use that information to care for that patient. A lot of people have done research. They have done retrospective analyses. But this is all about getting the information, taking care of that patient, using that to direct folks to clinical trials, and then whatever is left over you can use for research as well. But that's a tertiary goal, and the other one is more important.
Dr. Patel: Today, Larry Einhorn had a presentation about 40 years of progress in lung cancer, and he showed us the long list of phase 3 trials that have been negative with chemotherapy and biologic agents in unselected populations. I think from this year and last year we can say that human biology has given us a whole host of targets. We have drugs that work against the targets. The onus is on us to get the right patient and the right mutations to that drug, 2 fold. One, exactly as you said, immediately delivers benefits to the patient. But the other part of it is that there are likely drugs that we have tested in these past 40 years that have activity in some patients, and unfortunately, by using unselected populations, dampen signals and kill the development of a potentially significant drug in our arsenal.
Dr. Kris: This gives us a chance to do that. I'm also amazed by the number of compounds we have to study, and that's another message of ASCO.
Dr. Patel: Absolutely.
Dr. Kris: So, it's been a great discussion, both at the meeting and here today. Thanks, Jyoti, and thank you, our audience, for joining for this edition of Medscape Oncology Insights. This is Mark Kris signing off from ASCO 2011 in Chicago.
Introduction
Mark Kris, MD: Hello. I'm Mark Kris, Chief of the Thoracic Oncology Service at the Memorial Sloan Kettering Cancer Center in New York. This is Medscape Oncology Insights on lung cancer. Today, we'll look at some of the important studies presented on lung cancer at the ASCO meeting in 2001 here in Chicago. Joining me is Dr. Jyoti Patel, Associate Professor at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois. Welcome, Jyoti.
Jyoti Patel, MD: Thank you.
Dr. Kris: I know that today you went over the highlights of lung cancer studies done at the meeting. Could you share some of those with our viewers?
Dr. Patel: Absolutely. We had a great bunch of studies that were presented early on Friday in a clinical science symposium and in the oral abstract session yesterday. Most of the studies, in aggregate, break into 2 big groups. One is truly personalization of care and finding the molecular underpinnings and really targeting those with rationally designed drugs.
The other set of studies dealt with how we give chemotherapy, and how we can give prolonged chemotherapy to patients and keep them living without cancer symptoms for longer periods of time.
Don't Guess Test for Mutations and Targets
One of the most important presentations that came out was Rafael Rosell's presentation of the EURTAC [European Randomised Trial of Tarceva vs Chemotherapy] trial.
The EURTAC trial. EURTAC was a Spanish trial that is singular in the fact that it was in a Caucasian population of patients with EGFR [epidermal growth factor receptor] mutations. So, these patients had activating EGFR mutations and were randomly assigned to receive an EGFR tyrosine kinase inhibitor (erlotinib) or chemotherapy. This was a huge effort because the Spaniards had already shown that they could do wide-scale screening. They had previously shown that; it's been published. But in this effort they looked at more than 1200 patients and found a mutation rate of almost 20%. Then, 140 or so patients were randomly assigned to standard chemotherapy or to erlotinib. Interestingly, the Spaniards were able to do DNA sequencing and then to do confirmatory tests, and there was 100% concordance. But most impressively, they did it in less than 5 days. The average turnaround time was 4.5 days. So, the primary endpoint was progression-free survival, and it was met nicely. Patients who had activating mutations had improved response rates (55%) when they received erlotinib, vs 11% with chemotherapy.
The study is still immature, and we don't have overall survival. Rosell and colleagues said they have less than 50% of events, but it looks like the lines will be pretty similar, and that's expected. It's a European population. There was a high rate of crossover to getting the other drug, so patients did end up getting erlotinib. The study is important because when you look at the past 2 years in which there have been several EGFR mutation studies, this is the only one done in a Caucasian population. There have been several done in Asian populations, and although those have been impressive, what really is striking is that the rates of patients with mutations are much higher, and the undertaking may be a little bit easier. Their countries are smaller, and so we now finally have data that really give credence to the fact that all patients should have mutation testing if you're considering therapy with an EGFR inhibitor. Patients with adenocarcinoma should likely have EGFR testing because you can really improve response rates, progression-free survival, and give these patients the best quality of life they can have.
Dr. Kris: Yes, I think that's a key message. I put it in just a few words, "Test, don't guess." Also, there is that complementary information from last year at ASCO. The trial by Vince Miller and Pasi Janneis not an exact kind of trial. They compared erlotinib alone with erlotinib plus chemotherapy. They also had a group of what I call "Euro-Americans," European heritage Americans, and I was amazed how the data were, at least for response rate, identical to IPASS [IRESSA Pan-Asian Study]. The progression-free survival was 16 months on the mutated patients, and the overall survival was more than 30 months. So there is still this idea that somehow gefitinib or erlotinib works better or differently in folks from Japan than in folks from Toledo, but I don't think that's true. I think that it's all about the mutation.
Dr. Patel: Right, it's the biology that drives the cancer. It's not where you happen to be born.
Dr. Kris: All the abstracts here said "test," and they showed you can do it. We can do it here in the United States, too. There are so many private companies that can do testing, and people should do it.
NCI's Lung Cancer Mutation Consortium
Dr. Patel: Another effort that was really noteworthy was something that you were part of and that you presented, and that was the Lung Cancer Mutation Consortium. That is an effort by 14 institutions around the country that are support by an National Cancer Institute grant.
Dr. Kris: This was an American Recovery and Reinvestment Act grant, by the way.
Dr. Patel: So, that's impressive because it's getting all the people on board. So, how long did you have?
Dr. Kris: It was a matter of weeks, over Memorial Day weekend, too.
Dr. Patel: To get all the players to come to the table and to agree. But you looked at about 1000 adenocarcinomas, tested for 10 mutations, and found mutations present in 54% of patients. The best part of that study, to me, was that many of these are "druggable" targets, and clinical trials exist for these patients. You can direct them rationally to the right patient. What was the Memorial Day experience?
Dr. Kris: Very comparable. Our group of patients had a 60% rate of mutation. A lot of people have said, "well, gee, the mutation occurs in 14% or 3%," but the truth is, when you put all the mutations together it occurs in the majority of patients.
I think another important point, now that we have to make that decision whether to use erlotinib up front or not, you need that mutation result to guide the care of a patient even if they don't get erlotinib. To me, the message from my past was you have to give chemotherapy.
Actually, there was another trial here at the meeting, the Thomas trial, where patients without any mutation testing were randomly assigned to get (in this case) erlotinib and bevacizumab vs a combination chemotherapy and, again, inferior survival to unselected patients that got erlotinib up front. To me the message is clear that you just don't do the best job you can by treating people without testing. Again, "Test, don't guess."
Dr. Patel: It has really changed the natural history of the disease, right? You keep patients well and asymptomatic for a long time, so up front therapy does matter even if you catch up out back.
Dr. Kris: Yes, absolutely.
Dr. Patel: The fact that you keep patients well for that initial period is so important.
Dr. Kris: This idea of "let's try the erlotinib, and what have we got to lose?" Well, you have a lot to lose. You have inferior survival for people in whom you do that, and that's pretty sobering. What else did you find interesting?
The MetMAb Antibody Study
Dr. Patel: Another trial that I liked was a trial by Dave Spiegel looking at the MetMAb antibody. This was a randomized phase 2 trial of erlotinib and placebo vs erlotinib and MetMAb in previously treated patients. MetMAb is a 1-arm antibody that targets Met. It prevents the only known ligand of Met from binding hepatic growth factor. Usually, Met is overexpressed. It's correlated with worse prognosis in non-small cell lung cancer, so it seems to be a rational target. When it does dimerize, you have downstream signaling.
So, in the study, patients who had previously been treated actually had to provide tissue. The investigators were staining for Met with immunohistochemistry, and they developed a companion diagnosis that quantifies how much positivity they had. There were high Met expressers and low Met expressers. High Met expressers were Met-positive patients and low expressers were Met-negative. The study was nice because it incorporated that correlative as a primary endpoint, so the 2 endpoints were the intent-to-treat analysis in progression-free survival, and the second was looking at this enriched population of Met-positive patients and to see what their progression-free survival was.
So, interestingly, if you look at the intent to treat analysis there was absolutely no difference. It was ineffective. It was a negative trial. But if you look at the group of Met-positive patients, patients who received antibody and erlotinib had a 2-fold higher progression-free survival and a 3-fold improvement in overall survival. These are small numbers, and you certainly have to take it with caution but certainly thought-provoking and worthy of further study, because Met is a rational target with this antibody.
Dr. Kris: Yes, everybody who sees those data says that it's there, it needs to be confirmed, and we're all looking forward to seeing the study move ahead as quickly as possible to see if, indeed, it is a good target.
Options in Maintenance Chemotherapy
Dr. Patel: The most practice-changing study that was presented was with chemotherapy. That was the Paz-Ares study of maintenance pemetrexed in patients. Remember, we have talked about maintenance for the past 3 or 4 years at ASCO. We have tried to define what maintenance is. We know it's extension of therapy, but there is continuation maintenance, which is prolongation of whatever drug you're using and the doublet past the 4-6 cycles of platin-based therapy.
Then there is switch maintenance. Switch maintenance is the idea that they use a drug that targets noncross resistance and use it immediately after first-line therapy. Some people even call it "early second-line therapy." We have seen in recent years that pemetrexed and erlotinib have shown improvements in progression-free survival and in overall survival with that strategy.
We saw a nice study last year, the IFCT study, that looked at gemcitabine with platinum as maintenance in different randomized arms.
Dr. Kris: That was continuation maintenance too, and it showed a progression-free survival benefit by continuing the gemcitabine.
Dr. Patel: Exactly. Many of us have been waiting for this study because there are a lot of people who have, by default, done pemetrexed maintenance. So the study was 4 cycles of cisplatin/pemetrexed. Patients were randomly assigned in a 2-to-1 fashion to pemetrexed vs placebo, once every 3 weeks. Response assessment was every 6 weeks, and the primary endpoint was progression-free survival. The study did show an improvement, and the hazard ratio was intriguing at 0.62, and a survival progression-free survival improvement a little shy of 2 months.
The most interesting part was the Forest plot that was presented, showing that almost all patients benefited. But, really, the patients who seemed to garner the most benefit were those who had at least partial response or complete response to treatment. Although that sounds earth shattering, we have to realize that, for example, erlotinib switch maintenance is only approved in Europe for patients who have stable disease. But it seems to make sense. If it's working, don't stop.
Dr. Kris: Absolutely. It never makes sense to me to stop. Maintenance is not a new thing for me. What have you done in your practice before these kinds of things happened?
Dr. Patel: I was one of those people to whom continuation maintenance has made sense. Now it's nice to actually have some phase 3 data to back me up. But I have to say there are a couple of studies, such as the study that we talked about last year from IFCT. There is an older study that was not statistically significant, but there was a 2-month improvement in survival with continuation gemcitabine. So, we have a lot of good options. I'm not sure it's right for everyone, but if a patient is responding I think it's a very good option to consider continuation if you and the patient agree that they are tolerating it.
Dr. Kris: It's a no-brainer because you are only making that consideration in people who have evidence of benefit and also evidence of tolerability. The oncologist says that it's okay, and the patient says it's okay.
Dr. Patel: Right.
Dr. Kris: Obviously, you shouldn't be continuing it at all if those 2 criteria aren't met.
Dr. Patel: Right. They did, in fact, do a quality of life analysis and there was no statistical difference between the arms, of placebo or pemetrexed, which also makes you feel a little bit better.
Dr. Kris: Yes, but I would say that has always been my experience, and I think patients are very eager to accept, to continue therapy because they feel the benefit. They know the benefit in ways that we can't know, and it really makes sense to them. So, I take that to the bank.
Lung Cancer Leading the Field
I have to say that I am amazed that each year here at ASCO we get some new piece of information that really helps us take care of patients, and that's one piece. I'm also amazed at how lung cancer is leading the field all of a sudden. I can't tell you how many people came up to me and said that we hope to do the same thing we're doing in lung cancer now in our patients. The most amazing thing about that lung cancer mutation consortium project is that we could do this, and we use that information to care for that patient. A lot of people have done research. They have done retrospective analyses. But this is all about getting the information, taking care of that patient, using that to direct folks to clinical trials, and then whatever is left over you can use for research as well. But that's a tertiary goal, and the other one is more important.
Dr. Patel: Today, Larry Einhorn had a presentation about 40 years of progress in lung cancer, and he showed us the long list of phase 3 trials that have been negative with chemotherapy and biologic agents in unselected populations. I think from this year and last year we can say that human biology has given us a whole host of targets. We have drugs that work against the targets. The onus is on us to get the right patient and the right mutations to that drug, 2 fold. One, exactly as you said, immediately delivers benefits to the patient. But the other part of it is that there are likely drugs that we have tested in these past 40 years that have activity in some patients, and unfortunately, by using unselected populations, dampen signals and kill the development of a potentially significant drug in our arsenal.
Dr. Kris: This gives us a chance to do that. I'm also amazed by the number of compounds we have to study, and that's another message of ASCO.
Dr. Patel: Absolutely.
Closing Remarks
Dr. Kris: So, it's been a great discussion, both at the meeting and here today. Thanks, Jyoti, and thank you, our audience, for joining for this edition of Medscape Oncology Insights. This is Mark Kris signing off from ASCO 2011 in Chicago.