**Transcript of Cyberseminar**

**Spotlight on Evidence-based Synthesis Program**

**Treatment of Metastatic Non-Small Cell Lung Cancer: A Systematic Review of Comparative Effectiveness and Cost-Effectiveness**

**Presenters: Paul Shekelle, MD; Michael Kelley, MD**

**January 15, 2013**

**Treatment of Metastatic Non-Small Cell Lung Cancer: A Systematic Review of Comparative Effectiveness and Cost-Effectiveness**

**January 15, 2013**

Heidi:Our first presenter today is Paul Shekelle. He is director of the Southern California Evidence Based Practice Center site at the RAND Corporation; a consultant in health services at RAND; a professor of Medicine at the UCLA School of Medicine; and a staff physician at the VA Medical Center in West Los Angeles. 

We also have Dr. Michael Kelley, the National Program Director for Oncology; the Chief of Hematology and Oncology at the Durham VAMC; and associate professor of Medicine at Duke University. Paul, can I turn things over to you?

Paul Shekelle:You sure can. Thank you so much, Heidi. I hit show my screen, right?  Alright, is that – is it showing up?

Heidi:It is, yes.

Paul Shekelle:Perfect, ok.

Heidi:We are seeing your slides.

Paul Shekelle:Yes, alright, excellent. Thanks so much for the introduction. As Heidi indicated, I am Paul Shekelle. I am a general internist here at the VA in West Los Angeles. I direct the Evidence Synthesis program site at, here at West L.A. On this particular review, I was assisted by Alicia Maher who is one of our experienced systematic reviewers; and two research associates, Isomi Miake-Lye, and Jessica Beroes. Jessica is with me right now. This review also had input from two clinical content experts, one of which is on with us, Michael Kelley, who has already been introduced. The other one is Apara Ganti who contributed a lot, but is not on the phone with us today. 

We were assigned the topic of treatment of metastatic non-small cell lung cancer systematic review and comparative effectiveness and cost effectiveness. I will not spend a lot of time. Let me just give the – what we are going to do. I am going to give all of the slides. Then, Michael or I will be able to answer questions and elaborate as questions or comments come in from people who are listening, depending on whether it is about the methods or about the clinical interpretation of these data. 

In terms of the – I am not going to spend a lot of time on the opening slide. Anybody that has worked in the VA knows that lung cancer is a big problem in the VA. It is leading; and in America, it is the leading cause of cancer death in both men, and unfortunately in women. A lot of people when they show up are already too far advanced for any kind of curative attempt at therapy. That small cell is different than non-small cell. 

This is going to be focusing on non-small cell. This is an area, which because of its health impact, there is a ton of new literature published on this every year. In just a moment you are going to see that when we started to do the literature search on this, we only had to go back two years to find something like 60 systematic reviews of other literature that went back. There was a tremendous amount of literature that gets published about lung cancer every year. This review was requested to evaluate the current evidence. What has been published in terms of cost effectiveness about treatments for advanced non-small cell lung cancer? 

Alright, so all of the evidence synthesis program projects are guided by what we call key questions. For this one, the key questions were these. For patients with metastatic non-small cell lung cancer what is the comparative effectiveness of the different recommended?  Then they gave us a reference to some guidelines of first line chemotherapy regimens. What is...?   That is a key for number two for patients with metastatic non-small cell lung cancer what is the comparative effectiveness of the different recommended second line chemotherapy regimens?  Then key question number three; for patients with metastatic non-small cell lung cancer what is the benefit of maintenance therapy?  Then, what is the relative cost effectiveness of the different approaches in key questions one through three?

I can tell you that in the literature search since we do not have a way of restricting it easily to just – so, recommended drugs. We ended up looking at sort of almost anything that could be prescribed for this. There are a lot of non-recommended therapies that they looked through as well. Then in the cost and cost effectiveness, we ultimately ended up focusing that on a just few particular comparisons of interest. We will go through that when we get to that time period. 

Ok. I am not going to spend a long time on the methods. Suffice it to say, we looked for doing an early search. We already identified that there were going to be a lot of reviews in addition to a lot of the original trials. We did not want to reinvent the wheel too many times here. We looked for existing systematic reviews. If we identified the high quality systematic reviews, we took them at face value and then moved forward from that. We summarized these all here narratively. There is no pooling that we did, no meta-analysis per se.

Alright, searches were limited to peer reviewed English language literature. Alright, our clinical content people also gave us a bunch of articles to start with as a beginning. Then also reviewed the results of our search and identified anything that we might have overlooked. It is specific, some abstracts that came through after the search date that they thought were important to add. The exclusion criteria were pretty minimal. It was duplicate publications. If it was not about small cell, or non-small cell lung cancer; or, if it was only stage one, two, or threeA non-small cell lung cancer. To be included in trials, it has to be – or systematic reviews had to address first, second line, or maintenance therapies. 

There are some other slightly third line or other kinds of things that not very many things like that. But we did not deal with those. Alright, we summarized the strength of evidence using a system that is called GRADE’s. GRADE is an acronym for something that I cannot even remember. I am going to skip over that. Because everybody just called it GRADE’s. Here is basically how GRADE works. You start with the study design. Randomized trials start at a strength of evidence of high whereas observational studies start at a strength of evidence of low. But then, a variety of factors can make it go up or down. 

Alright, so you can – you knock down the GRADE’s some as if there is a risk of bias. Meaning that there is a lot of quality problems with the studies. Or, if it is - the data are inconsistent. Or, if it is indirect, meaning that it is measuring proxy outcomes. Or, maybe not in the population of interest; or, if the data, there is a lot of imprecision. Or, if you suspect or strongly suspect publication biases. Alternatively, you can go higher if effects are very large. If there is evidence of a dose response gradient. In observational studies, if there is a – if a plausible residual confoundings would only tend to increase the expected effect. Ultimately, these get graded into high, moderate, low, or very low. Since everything that we are starting with in this is...

[Audio Gap]

Ok. Since everything here starts with randomized trials; everything starts with high. We only knock it down if we have one of these concerns here around risk of bias, inconsistency, and direct [inaudible] imprecision. Alright, so as I indicated, we screened a lot of titles. Alright, we went back only two years to find 88 systematic reviews they have to look at in cost effectiveness analysis. 

We ultimately looked through 55 systematic reviews across these, most of them in key question one and key question four. We looked through 120 trial citations; and added some additional ones to key question one, two, and three. As you can see, most of the data here are around initial treatment, first line therapy. There is way less data around second line therapy or maintenance. 

Alright, and as I indicated before, a few articles showed up as a result of peer review, and from our – and from our clinical content experts. We identified an initial pretty high quality review that was done by colleagues up in Canada whose, the end date of their search was 2007. It was only about first line therapy. They divided their first line therapy review into a number of subquestions. That made a good organizing structure for us to follow as well. We followed their structure. 

This next series of slides is going to be subquestions about first line therapy. Each of them is going to start by saying that we identified this existing review in the report. We then actually tell you exactly what that existing review is. We then looked at new studies since that existing review had been done. Then we come up with what we think is sort of the net sum of those things is. 

The first of the subquestions was does doublet chemotherapy...? Doublet chemotherapy meaning giving two drugs, ok, consisting of a platinum agent. Ok, plus a new agent to improve outcomes compared with doublets using older agents? This new versus old has to do with things that were used ten years, or so ago, or more versus things that are newer. I cannot give you the exact list. I mean, it is in the – it is in the report, but about what counts as new or as older. If you take a look at...  

The initial – the review by the Canadian folks itself included a meta-analysis of six randomized trials. They had five new randomized trials at their time. We identified seven more randomized trials. Now, we are talking about six, plus five, plus seven. Alright, and the cumulative evidence across all of these, ok, is that any differences in survival between platinum-based doublets, a platinum drug plus something else, are modest. They may be there, but they – and they may even be statistically significant. But, in terms of – in terms of survival, or in terms of progression-free survival, or response status, the numbers are small in terms of their differences. That is high grade evidence because it is consistent and it is coming from multiple randomized trials.

Alright, the next key question was does doublet therapy, so two drugs consisting of a platinum agent plus a new agent, improve outcomes compared with a new single agent, or to a platinum agent alone?   Are two drugs better than one?  At the time of the 2007 review by the Canadians, they themselves relied on an already published meta-analysis, which had eight trials with 2,300 patients in it. Since that time, we have only identified one new trial. Because I think that – and then there was an additional abstract in the – that we were referred to during peer review. That is probably because this question seems to be pretty much settled. Is that the cumulative evidence indicates that doublet therapy including a platinum agent has a higher survival rate than single agents. Doublets are probably considered the standard of care compared to single agents.

Alright, the next key question was does doublet chemotherapy regimen consisting of a platinum agent plus a new agent?  Or, I mean, pardon me; which doublet chemotherapy regimen consisting of a platinum agent plus a new agent is most effective in improving clinical outcomes? By the time in 2007, the Canadian review, there had already been two meta-analyses and nine additional studies; three of which were all – actually incorporated one of the meta-analyses. 

Then since 2007, there were at least nine new studies and two more meta-analyses that have looked at this question. Then we also found another doublet versus doublet. But neither was a platinum agent. Our cumulative evidence is consistent with the conclusion of the 2007 Canadian review. Again, that is any differences in outcomes between past platinum based agents are modest. There may be statistical differences, but the clinical differences are small. 

The next key subquestion was does doublet chemotherapy consisting of a platinum agent plus a new agent improve outcomes compared with non-platinum combination chemotherapy, including  a new agent?  This would be a platinum plus something else versus a doublet, neither of which is a platinum agent. At the time of the 2007 Canadian review, they relied on two meta-analyses and four additional relevant RCTs.  We found three additional RCTs, none of which showed any statistical differences between agents when tested. But the cumulative – adding those to the meta, the existing meta-analyses, and the reviews that were in the 2007 indicates that doublets with a platinum agent probably have a – or, have a statistically significant and slightly clinically important survival advantage over non-platinum doublets. But, that comes at the price of increased toxicity with the platinum agent. 

Alright, the next key subquestion. Are new doublets containing cisplatin more effective than doublets containing carboplatin. These are the two main platinum agents. At the time of the 2007 review there were already three meta-analyses about that topic. Since 2007, we found another trial. But the non-platinum agents differed too much to be able to draw a conclusion. We relied pretty much on the 2007 Canadian review was just that cisplatin combinations again may have a slight advantage over carboplatin combinations in terms of survival and response rate. However, again that comes at a price. This carboplatin is generally somewhat milder in its toxicity than cisplatinum [sic]. That GRADE is listed as moderate, ok, and mostly due to some inconsistencies in the results.

Alright, the next key subquestion concerns triplet chemotherapy. Does triplet chemotherapy with a platinum agent plus a new agent improve clinical outcomes compared with doublet chemotherapy, one of which is a platinum agent? Are three drugs better than two?  Alright, so at the time of the 2007 Canadian review, alright, they looked at some ACCP guidelines and the evidence that had been published in association with those ACCP guidelines. There was a meta-analysis that had 28 trials. There were 12 new RCTs; so, where the addition of a third chemotherapeutic agent failed to show superiority over conventional doublets. 

One of our clinical content experts identified for us in another systematic review and meta-analysis that actually had not been included in the 2007 one. That was the one by Azim. Ok, and then we found in addition four new trials, one of which was already in Azim. Ok. Then we also found another trial that compared a platinum based triplet versus a non-platinum doublet. It does not quite fit in this key question, but in our report we talk about it some. The cumulative evidence across all of these is that it is triplet cytotoxic therapy with a platinum agent might have some statistically significant advantage of it in terms of its response rate. But, definitely increases the toxicity compared to two agents. That was high GRADE evidence. 

Alright, now we move into targeted therapies. Now, we move into some of the newer things. Key questions, subquestion 1.7 was does the addition of targeted therapy to doublet chemotherapy consisting of a platinum agent plus a new agent improve outcomes compared with doublet chemotherapy consisting of a platinum agent and a new agent?  This is kind of a moving field here. These next couple of slides, there’s lots of new information that comes out. Sort of the conclusions are continually being improved over time. The 2007 Canadian review found eight trials of adding targeted therapy to conventional chemotherapy. This is in addition to conventional chemotherapy and not in place of. 

Ok, we additionally found ten other trials. I am sure Michael may want to comment on this in the question, and answer, and comment section because he and I have exchanged a lot of e-mails on this. There have been a ton of different things that have been tested as targeted agents in addition to conventional chemotherapy. Mostly, they have not panned out. The only exceptions were the addition of erlotinib, Tarceva, in early studies where it was an addition to conventional chemotherapy. Later sub group analyses of those studies shows that it is pretty much restricted to the patients that have epithelial growth factor mutations, receptor mutations. 

Then in one study and one study only adding, I will call it Avastin. Because I do not how to pronounce the generic name. Ok, in an Asian population, improved survival. We call that a GRADE of moderate. Outside of reproducible results with erlotinib; ok, and a single study with Avastin, the adding targeted agents has so far not proven to be an improvement as an addition to cytotoxic chemotherapy. 

Alright, now the next question. This was not a question in the original Canadian review. Because this is all – this next bit is all data that has sort of developed since then. Does targeted monotherapy improve outcomes in selected patient populations?  This is certainly from my perspective, one of the – one of the big advances in metastatic non-small cell lung cancer treatment over the last few years is targeted monotherapy in the right populations. We identified seven publications from six trials that assessed use of targeted monotherapy compared to conventional chemotherapy primarily in the population of patients with the EGFR gene mutation. 

I am not an expert in this, but Michael can comment much more on it. They are very sophisticated in this in terms of how many copies and other kinds of things in terms of trying to identify who is most likely to benefit from them. There are also two meta-analyses of these targeted agents, which are all tyrosine kinase inhibitors, erlotinib being the first. But also gefitinib, and there are a few others. 

The results are pretty consistent. Ok, erlotinib, and gefitinib monotherapy is superior in terms of response rates, progression free survival, and toxicity. Ok, it is an oral agent. It does not have to be given IV. It generally has much milder toxicity effect. The difference as opposed to what we were looking at in the earlier slides where we might – where a lot of these things when they were being pooled might have differences of in survival of some, or of progression free survival of something like eight months versus seven months, ok, between some particular cytotoxic regimen and some other cytotoxic regimen. It might be statistically significant to the person involved, obviously, that month is a welcome benefit. But as a proportion of the overall time, it is not great. 

Here, these differences were big. These were measured in many additional months of progression free survival. These were, and consistent findings. In the meta-analyses overall survival favors treatment with these drugs. But it has not yet reached conventional levels of statistical significance. But if you look at the Kaplan–Meier curve, they are obviously very different.

Ok. Moving out of targeted therapy; another important subgroup to consider is the elderly, particularly around the toxicity around these drugs. One of the key subquestions in the Canadian review was is doublet regimen better than a single agent for the elderly population?  In 2007, the Canadians identified six trials as being relevant to this question, but nothing exactly answered the question just the way they wanted it. 

Since then, we identified four new trials including one that was right on target. The cumulative evidence indicates that taking the EGFR people out of the equation, ok, that doublet chemotherapy probably has a slight benefit in terms of survival compared to single chemotherapy – or singlet therapies. But again, it is causing more toxicity in the elderly population. That was a strength of evidence of moderate. 

That finishes up the first line therapy. We only have a few slides for second line and for cost effectiveness. Then we will open it up for questions and discussion. The – for the second line therapy, there were a bunch of existing systematic reviews, none of which were nearly as good or as comprehensive as the – as the Canadian review that existed on first line therapy. Sort of the summary and the conclusions of all those plus some of the new trials is that doublet second line cytotoxic therapy might offer slight benefits in progression free survival and response rate, but not overall survival; and again, at the cost of toxicity. That early on, erlotinib was given in sort of an unselected patient population as second line therapy and produced modest effects in overall survival. I think that the new data would indicate that this was really restricted to patients that have never smoked, or, the ones that have the EGFR mutation. That is really the treatment of choice for those people. Otherwise, it is probably is not. 

Some of the...  Here are the summaries from the additional trials that we found. Considering data from first line and maintenance therapies, so pulling data from a lot of different strands, ok, there is sufficient data to support that the histology type influences the effectiveness. [inaudible] is more effective in nonsquamous lung cancer. It should not be used in squamous cell lung cancer. Whether some of the other ones are more preferred in squamous cell is whether a docetaxel or something is more preferred is still a little bit up in the air. 

The tyrosine kinase one, we already talked about. When it is used in unselected patients, it produced survival similar to docetaxel. There were four studies that looked at that head to head. But those were unselected patient populations. It probably was a mix of people responding well who had the EGFR mutation and people who do not respond who had the wild type. Insufficient data to support the effectiveness of other drugs or drugs in combination. Then, the above second line studies are typically undertaken after evidence of these progressions should be distinguished from maintenance therapy, which is undertaken when a patient has had stable disease during treatment. This is second line therapy not maintenance therapy. 

The last, key question about maintenance therapy. There was – there is a pretty good quality meta-analysis and some new studies about this, but there are study design issues that limit drawing very strong conclusions. In particular, one of the issues is about whether maintenance therapy works at all, ok, and if it does work, whether maintenance therapy is best accomplished by continuing to give to you the same drugs as you got as first line therapy or whether you should switch to some other drug for maintenance therapy. Right now, there is not enough evidence to tell us which of those two strategies might be more effective. Obviously, again, as we have talked about earlier, patients that have EGFR mutations should be treated with the tyrosine kinase inhibitors. 

Alright, a few words about cost effectiveness. There are a lot of cost effectiveness studies out there, a lot. Almost the great majority of them are supported by the makers of the drugs. You can invariably, second bullet point; studies supported by the makers concluded that their drug was cost effective. OK, so you can find drugs, and cost effectiveness studies that compare docetaxel to something supported by the makers of docetaxel. They conclude that docetaxel is cost effective. You can find one supported by the makers of pemetrexed. They will conclude that pemetrexed is cost effective, et cetera, et cetera. 

Looking at the cost effectiveness studies that were not supported by the manufacturers, the following were reported. That adding Avastin to first line therapy was found to be not cost effective. That erlotinib in one study was marginally cost effective, ok, and differences between erlotinib and docetaxel maintenance therapy were slight in another study. We will discuss a couple of these in just a little more detail here. The strength of evidence of all of these are low. This is an area where much more high quality work needs to be done. Here is one of the non-drug company supported cost effectiveness analyses. 

This is the one about Avastin. Cost effectiveness analysis of adding Avastin to carboplatin and placitaxel. The comparison in here is b, for Avastin, plus carboplatin, plus placitaxel versus carboplatin and placitaxel alone. The data come – the outcome data come from a clinical trial, the ECOG 4599 trial. The discount rate is 3 percent per year. The details of the cost effectiveness analysis are obviously in the article. It is cited below. Then it is also summarized in the evidence report. But the incremental cost effectiveness ratio they found for adding Avastin was $560,000 for quality adjusted life year, or $390,000 per life year gained. 

Again, what the threshold is for calling something cost effective is obviously a somewhat arbitrary limit. Numbers anywhere between 50 or 60, up to $100,000 per quality adjusted life year are commonly used thresholds. I am not going to comment on which one is the right threshold other than to point out that these numbers are far higher than any threshold that has been suggested as to separate cost effective from non-cost effective therapies. 

Here is another of the cost effectiveness studies that was not supported by the manufacturer. This one takes a somewhat different approach. This one does not use any discounting. This is looking at erlotinib compared to placebo. Again, the incremental cost effectiveness ratio for the overall population was at $94,000 per life year, which is either somewhat above or at the threshold of what some people use for cost effectiveness ratios. But again, in subgroup analyses the numbers are much lower because the drug is much more effective. Never smoked was $39,000, the EGFR positive was $64,000, and the EGFR gene copy being high was $33,000. Those are all values that are well within the usual, even the lower limits of the usual thresholds for what counts as a cost effective therapy.

Now quickly just some limitations. Ok, a lot of the drugs here have not been compared head to head. Ok?  Meaning that you sort of have to make indirect comparisons. Indirect comparisons are always problematic, right. That if study a – if drug a beats drug b in one study, then in some other studies, drug b beats drug c, can you necessarily conclude that drug a beats drug c? Not necessarily, obviously it is the degree to which the differences are large makes it easier to make those comparisons, but these indirect methods are highly susceptible to bias. When the differences that we are looking at are small, it makes drawing any indirect conclusions very suspect. Then as we already indicated, there’s very little in the way of cost effectiveness analysis by someone other than the maker of the drug. 

Alright, so we came up with some VA research recommendations since cost effectiveness is an important thing for VA. Since VA can bear different costs and has a system of care, some of the patient populations are different than what might be seen in the general population. That something – a cost effectiveness analysis that takes all of these things into account are going to need to be done before we can make strong conclusions about what is going to be cost effective care within VA. 

Given the richness of the VA databases that using that combining with what is known from clinical trial data should be possible. That we would need to do a lot of sensitivity analysis like usual to assess the degree to which any of the assumptions that are made for a cost effectiveness analysis influence the outcome. That is the end of the – of the formal or the didactic presentation. I guess we give it back to you, Heidi for you to triage questions from people who are listening.

Heidi:I can definitely do that. We have not received any questions in so far. For our audience, this is a great opportunity to submit questions. The Q&A screen is located on the dashboard that is on the right-hand side of your screen. To open that up, if it has collapsed against the side of your monitor, there is an orange arrow at the upper right-hand corner of your screen. You can just click on that to open that screen up. Type your questions in. 

Paul Shekelle:Well, let me take advantage of this time, then, and ask Michael to give us some of his reactions. Now, Michael does not have to be responsible for anything that we have just presented. He is free to disagree with it. But obviously, he is a clinical content expert. He can help give us the clinical interpretation of these data and how he might use these data in practice. Michael, do you want to say a few words?

Michael Kelley:I think I would start, Paul. First of all, thank you very much for that presentation and to your whole team for synthesizing it. It was really a large body of information. Obviously, some of which has been synthesized to some extent previously. But, updating six years’ worth of lung cancer data is a gargantuan feat. Just to place some context, this entire process, this kind of report. The reason that this was requested was really to try to clarify the question #4. 

I think a lot of the subject matter experts in oncology are pretty familiar with the, many of the studies that informed your conclusions from questions one, two, and three. But we do not necessarily think about the number – the cost effectiveness. We wanted to make sure that we had the up-to-date data on all of the randomized trials and any meta-analysis that has been performed for first line, second line, and maintenance for advanced non-small cell lung cancer. Then to interpret any of the cost effectiveness literature, which was out there; which I think was very helpful. 

I am not sure that oncologists are quite as attuned to critically reading that literature. It was very, I think, useful for me as a policy maker to have that. The reason that is going to become important more for us in oncology in the VA is that this year we are launching a new approach which is going to focus on clinical pathways. This is an approach which focuses on a selection of possible treatments from guidelines to reduce those to what is the practice for a particular organization, be that at the individual facility level or practice, VISN, or for the entire nation.

That those clinical pathway developments are done considering three factors; efficacy, toxicity, and cost. For information to make that selection for clinical pathways, it was very important for us to understand that question of before that you reviewed, Paul. It clearly, in terms of the actual practice in the clinic, a lot of this is very familiar to practicing oncologists. I am not sure that we have changed anyone’s opinions. But there clearly are areas for further research in questions one through three. Even the data that has been presented I think is open for some interpretation. I want to stop because I have blabbered on for a little bit here; and see if there are any questions before I go on with that next thought.

Heidi:We do have a couple of questions here. I want to apologize first because I am not a subject expert. I just want to apologize if I do butcher these while I am asking. But the first one we have here: Is it adequate to use monotherapy for NSLC with the ALK mutation or EGFR mutation?  If so, does everyone with NSLC require genotyping?

Paul Shekelle:Ok, why don’t we leave that one for Michael?

Michael Kelley:Alright. This is a question that we did not address specifically to Paul. We did not ask his group to look at that. This is something which he touched on briefly, because obviously when you start talking about first line treatment of non-small cell lung cancer, you come to that very quickly, especially in the current era. 

As I understand the question, is monotherapy adequate for patients who have mutation of ALK or familial translocation, or a activating mutation of EGFR?  I think that the data is pretty clear that first line treatment with a targeted therapy, either the currently approved crizotinib for ALK translocations, or erlotinib in the United States for EGFR mutations, is adequate in terms of producing equivalent survival. It has a better progression free survival and less toxicity. In my opinion it is the preferred approach. 

The second part of that question was should every patient have testing like we are testing of those mutations or genetic alterations. My approach currently is to do testing for every patient with advanced stage disease who is a possible candidate for systemic therapy for ALK and EGFR if they have adenocarcinoma histology; have been a never or light smoker, or have unknown histology in those three settings. I do not do it for every patient. I think there is some considerations for the VA, which perhaps are different from perhaps academic centers and private practice. 

In particular, the rate of discovering these mutations in the VA population is significantly lower. My estimate is for EGFR mutations on the order of about one percent. For ALK translocations is about a half of a percent or less. These are going to be relatively uncommon. As we get more experience with these, we may change our algorithms when we have a clearer understanding of how common the mutations are. That is the end of that question. 

Heidi:Great, thank you. The next question that we have here: How can we get EGFR data on fine needle aspiration biopsies, small sample?

Michael Kelley:How do I do this?  Alright, so again that is not a question that we asked Paul or his team. The answer is that you cannot do that testing from a small needle aspirate in general. Some, I think you can do it. But, it practically in practice, it is not done and cannot be done because there is not enough DNA in the sample. 

What I recommend is that you do a larger core needle. Talk to your interventional radiologist and the patient, of course, to discuss what the risks are of doing that procedure and get a bigger piece of tissue. There are discussions I have now with patients about what the incidence is of these mutations as I estimate them for their situations, what is involved in getting a biopsy for them, and decide whether or not it is worth doing that procedure or not. There are some patients for whom you cannot obtain a histology. You cannot do the EGFR testing or ALK translocation testing. Then you can make a clinical assessment as to whether to use one of the corresponding medications. I almost – I cannot remember a time when I have ever used crizotinib without having demonstrated the translocations in ALK. I think for EGFR, we have all used erlotinib in some situations where we were not sure whether it was present, because its FDA approved indication was arrived at prior to identification of the biomarker in 2004. 

I think if the approach going forward is to obtain larger biopsies, I think this is going to become increasingly important as additional relevant targetable mutations are identified. There’s already ROS1, which has been suggested to be targeted by crizotinib and several other squamous cell cancers. The practice of obtaining diagnosis by fine-needle aspirates I think is something that needs to go away for lung cancer. This also adds mention that it is very difficult to establish histology from a small needle aspirate as well. 

Heidi:Great, thank you. The next question that we have here: Are there any studies that demonstrate that EGFR testing should be mandated so that best clinical outcomes can be achieved?  What are the recommendations for second line therapy and EGFR?

Paul Shekelle:Well, the first one of those is kind of similar to what I think Michael already talked about in the first, in the response to the first question. Do you agree, Michael?

Michael Kelley:Yes, I am not sure I understand that question. Are there studies that mandated?  I mean, mandates come from policy and not from studies. But, I – other than that I think it is probably very similar.

Paul Shekelle:What was the second part again, Heidi?

Heidi:What are the recommendations for second line therapy in EGFR?

Paul Shekelle:Well, if you have it. I mean, I will let Michael. I will let Michael comment on what the recommendations are because that is not our purview. But, I can tell you from looking at these data and, of course, we are a systematic review group . We do systematic reviews on lots and lots of different things. Now, it is lung cancer. Some other time, it may be ear infections. Some other time it may be heart failure. As you look through these lung cancer data, in the cytotoxic therapies, you are looking at differences of between survival. Differences between treatment and no treatment is in survival on the matter of a couple of months. Then differences between drugs for survival on the order of a month. Something like eight to seven months comparing cytotoxic therapy a to cytotoxic therapy b. Then, all of a sudden we hit these tyrosine kinase inhibitors. In those populations and in the populations that respond, the EGFR populations, sll of a sudden, these are big differences. These are like you survive twice as long or three times as long. Things like that; I mean, with their five year survivors sitting here at our own VA.  

I know that if I had lung cancer, I would hope like hell I had EGFR positive mutation. Because that would give me the best chance to go as long as possible. I guess the question for you Michael is given a prevalence of one percent, which is I think what you said. How far down the path do you got to go to try to find whether or not somebody, I mean, it is not exactly like getting the golden ticket, getting lung cancer. But, if you had lung cancer, that is the kind that you would want to have.

Michael Kelley:Paul, I am pretty sure you do not smoke. You are – I think I met you at least once. You are probably older than 45. The chances of you having an EGFR mutant lung cancer would probably be much higher than one percent even though you are in the VA. Anyway, so clearly, I think that is one thing was not really emphasized in the slide. But it is in the report. That is the magnitude of the effect sizes. 

As I mentioned, for a first line EGFR inhibitor, the effect size on the progression free survival compared to chemotherapy is really significant. It is much greater than anything we have ever seen before. That said, there is no difference in terms of overall survival. I think the consensus around the explanation for that observation is the fact that overwhelming majority of patients who are not treated in first line with an EGFR tyrosine kinase inhibitor were treated with it in second line at the time of progression. 

That has resulted in a conclusion that I think is supported also by the maintenance data that it does not necessarily matter when in the course of your disease that you are treated with an EGFR inhibitor if you have a sensitive EGFR mutation. But that not getting treated would result in a much worse outcome. Then, the second part of that is that if you are going to be using a treatment algorithm, you are able to reduce initial toxicities by using the EGFR tyrosine kinase inhibitor first line, then that should be the order in which it is done. Anyway, so I wanted to come back to the question, which is...  

The question is what do you do when the patient progresses if you treat them in first line with the EGFR inhibitor?  My answer is that I treat them with chemotherapy. I treat them with first line chemotherapy just as I would a patient who has never been treated at all with a doublet, platinum containing doublet. Then, when they progress on that I go to the second line singlets. The data for that is really extrapolated from the rest of the data set in non-small cell lung cancer. 

There are a number of targeted agents, which are being developed for progression at that point. None of them are clinically approved. Some of them are available in certain parts of the country through clinical trials, but they are very limited. There are several mechanisms of action, which have been reported for EGFR mutations at the time of progression on an EGFR tyrosine kinase inhibitor. 

Those include a secondary mutation. There is a resistance mutation in the tyrosine kinase domain, an amplification of CNET. Then there is a fraction of patients where we do not really understand. Anyway, so those have been used to try to develop clinical trials to provide additional targeted agents for that group of patients. I hope that those come to the clinic very soon, because I think we all would like to be able to offer our patients additional therapies in that regard.

Heidi:Great, thank you. The next question that we have here: This is kind of a long one. Are there other areas you can identify besides cost effectiveness where data are lacking and further research would be recommended?  For example, is more research needed to determine what is the appropriate level of use of the newer agents since they are likely overused in some places and underused in others?  Also, in the area of palliative care would more research be useful because of wide variation and inadequate information about what really works?  Any other ideas?

Paul Shekelle:I mean, I think that Michael just sort of alluded to some other areas that would be useful research, that would feed into the kinds of cost effectiveness questions that VA has. One of them has to do with sequencing. The sequencing of giving some of these kinds of things as Michael talked about. Better data on the maintenance therapy. I mean, there are some systematic reviews that have concluded that it definitely works and it should be given to everybody. But, obviously that has not been – not everybody necessarily agrees with that. I think that – and the number of trials in maintenance therapy are relatively small, particularly compared to the number of first line therapies –  trials.

Moving to the palliative care area; which was not within the domain of this evidence review, but one that I have worked on before. I mean, there is no doubt that both based on the evidence that I have seen plus our own experience here in the VA with Ken Rosenfeld and Karl Lorenz’s work in palliative care, James Tulsky at the Palo Alto – I mean, at the Durham VA, as well, that palliative care is a really important part of the care of these folks because most of them are going to die. 

They are mostly going to die within a relatively short period of time. Improving the palliative care options of these people is definitely something that is a good thing. As the beneficiary in our VA of someone that has an absolutely first rate palliative care service, it can be a real help to everybody involved; the clinicians, the families, and the patients. I do not know if you want to comment at all, Michael as well about your observations on palliative care.

Michael Kelley:There is a randomized study, Tremmel, that showed that early palliative care resulted in an improved outcome, improved survival actually. They are not necessarily touting that as a way to prolong survival. But it clearly does not lead to a reduction in survival. There were some other benefits of that early palliative care intervention. Whether that is true in the VA, or in our setting, or, exactly what the effect of that intervention was – is not entirely clear to me. But, I do think there is some opportunity in terms of palliative care. Obviously, that was beyond what you said. I totally agree with all the rest of your comments, Paul.

Heidi:That is all of the pending questions that we currently have. Paul, Michael, do you either of you have any final remarks you would like to make before we close things out for today?

Paul Shekelle:No, I have nothing additional to add at this time, Heidi.

Michael Kelley:I would just like to thank everyone for joining us. I think this is an area that does deserve additional attention. That the fourth question, I think that is an area that a lot of us as practicing oncologists are not very familiar with not only in terms of quality of the data, or how to interpret it, but I am not sure that a lot of us even understand the cost of the drugs that we are using. I think we will be hearing more about that because that is going to play into our decisions when we are coming up with clinical pathways. Thank you again, everyone for joining. I hope you have a great rest of the week.

Heidi:Great, thank you. I also want to thank Dr. Shekelle and Dr. Kelley for taking the time to put things together and present for us today. We really appreciate that for our audience. Thank you very much for joining us today. As you leave today’s session, you will be prompted with a feedback survey. If you could take a few moments to fill that out, we would definitely appreciate it. 

We will also be sending you the link to the archive for the session. It will only be available on the VA intranet. It will – you will not be able to access it from outside the VA. But, for all of you inside the VA, we hope that you are able to pass this on to other people that you think would find value from this. Thank you for joining us for today’s HSR&D cyberseminar. We hope to see you at a future session. Thank you.

Paul Shekelle:Thanks.

Heidi:Thank you.

[END OF TAPE] 

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