GRACE :: Lung Cancer

Should Avastin be Added to EGFR TKI Therapy for EGFR Mutation-Positive NSCLC?

GRACE Cancer Video Library - Lung



Dr. Jack West, medical oncologist, reviews evidence in favor of adding Avastin (bevacizumab) to the EGFR inhibitor Tarceva (erlotinib) for patients with lung cancer that harbors an activating EGFR mutation.

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The historical standard of care over the last several years for patients with advanced non-small cell lung cancer, whose tumor has an activating EGFR mutation, has been single-agent oral EGFR tyrosine-kinase inhibitor therapy. That is a pill like Iressa (gefitinib), or Tarceva (erlotinib), or Gilotrif (afatinib), and these agents are associated with long responses that typically will last 9, or 12, or sometimes more months, but unfortunately, in almost every case, will demonstrate progression after some period of time — and we would always like that to be longer.

One of the big questions that we’ve wanted to know is, if we could add something to this therapy and do better than that — and one of the key questions has been about adding an anti-angiogenic agent, something that blocks the tumor’s blood supply, which is a drug like Avastin (bevacizumab), which is used in other cancer settings, and in some cases, for lung cancer, in combination with chemotherapy. In lab-based studies there is evidence that adding a blood supply blocker, an anti-angiogenic agent, to one of these EGFR inhibitors can more effectively suppress cancer cells, and for longer, but we haven’t seen clear evidence that this is beneficial for patients in the real world. In fact, there have been a couple of large studies that have asked the question about adding Avastin to a drug like Tarceva — these trials, however, have only been in broad populations that are called molecularly unselected, not looking specifically at patients with an EGFR mutation or any other feature, but just really taking all comers.

One of the key studies is called BeTa, and this was a study where all the patients had receive first-line chemotherapy, and were getting, now, a second-line treatment, after progression, and they were either getting Tarceva alone, or the combination of Tarceva with Avastin.


The study, overall, did not show a significant improvement in survival, but when they looked at the different subgroups of patients, based on various clinical characteristics, you can see that a couple of subgroups of patients did particularly well with the combination.


Specifically, when they looked at patients who were Asian or Pacific Islander, or never-smokers — those patients really seemed to skew more toward greater benefit with the combination of Avastin and Tarceva.


They also looked at a small subgroup of patients, whom they had tumor tissue on and were known to have an EGFR mutation, and those patients also trended clearly toward a better effect with the combination of Avastin and Tarceva.

So, that’s provocative, but that’s just one study. What’s interesting as well, though, is that a remarkably similar study was done where patients received either Tarceva alone, or Tarceva and Avastin, as a maintenance therapy. So, they had not progressed, but they had already received first-line therapy, and then went on to get Tarceva, or Tarceva and Avastin.


This study also showed no significant improvement in the overall population — this was, again, a molecularly unselected population, but when they looked at the different subgroups, based on their clinical characteristics, it was the same subgroups who got the benefit, in terms of overall survival, from the combination.


So, again, it is the Asian and Pacific Islander patients, and the never-smokers — the two groups who we know are most enriched for having an EGFR mutation. So, this is really a bit more compelling evidence that, maybe, there’s really something there.

The question was asked more directly in a study done in Japan and just published in Lancet Oncology not too long ago.


This trial had about 150 patients, all with an activating EGFR mutation, who were randomized to receive Tarceva, or Tarceva and Avastin, as a first-line therapy. The study was designed to look for a significant improvement in progression-free survival, the time before at least half the patients had demonstrated significant progression of their cancer, on this combination that they started with, or the single agent.


What they found was a significant improvement in progression-free survival in the patients who received the combination. In fact, the difference in median time to progression, the time when half the patients in each group had progressed, was over six months longer in the patients who got the combination.


When we look at overall survival — most of the patients are still alive, so it’s too early to really say much, but the trend is in the direction of favoring the patients who received the combination.

The other side of the coin, beyond efficacy, is tolerability, and the combination was associated with more side effects, as you’d expect — although, there were no treatment-related deaths with the combination. In the Japanese experience, there were more patients who had significant problems and needed to come off of the drugs, specifically Avastin, than we’ve typically seen with this combination in other studies. 40% or so of the patients had to discontinue the Avastin because of side effects, usually high blood pressure, or leaking protein into the urine, something called proteinuria; whether that is because these patients just had been on these agents for longer than they usually are in other studies, or there is something about the Japanese patients, or EGFR patients, who were more susceptible, we don’t know. But, at the end of the day, it was still a tolerable regimen, and more of the patients did well and did not progress for much longer when they received the combination.

So where does this leave us? We have a more than six month improvement in the median time to progression with the combination, but this is only one study, done in Japan, and sometimes we see differences in studies done in one part of the world, versus another. Overall, I would say that, to me, these data are quite compelling, and it’s enough to lead me to favor the combination for my patients if an insurer will cover the Avastin, which is not, at this point, a clear standard of care. To many investigators and general oncologists, the combination is not yet their preferred regimen — they would like to see more evidence, larger studies, and ideally, work from other parts of the world to corroborate what we saw out of Japan. In fact, there are studies being done, one in Europe and one in North America, that are asking the same question, so we’ll hope to get more information soon, but this is certainly a very promising lead, and enough to lead me to favor the combination for my patients who have an EGFR mutation.

What is Maintenance Therapy for Advanced NSCLC?

GRACE Cancer Video Library - Lung



The concept of maintenance therapy for advanced lung cancer has emerged over the past few years. Dr. Jack West, medical oncologist, reviews the concepts behind it and treatment options for patients.

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One of the core ideas in treating advanced non-small cell lung cancer is that we try to treat is aggressively, early on, to induce the greatest shrinkage we can, which tends to be associated with a longer survival for patients. This specifically means that we typically treat with a two, or sometimes three-drug combination as first-line therapy, and most of the time, when we see tumor shrinkage, it tends to be front-loaded, and we see that early on, in the first one or two scans done. Most commonly, we’ll give four to six cycles of treatment for patients with this multi-drug combination, and then think about stopping treatment or downshifting. This idea of downshifting to a less intensive therapy, but still keeping something going, is the idea of maintenance therapy.


So what is maintenance? It is essentially to maintain the tumor shrinkage that we achieved early on, with first-line therapy, but by using a more tolerable, less intensive regimen after that, that can be continued longitudinally, without too many cumulative side effects.

There are two main ways of approaching this — one is by doing what’s called continuation maintenance. You start with a two-drug or three-drug combination, and then you drop one or two of the agents off, and keep some of the first-line therapy going, but not all of it, and this makes it less intensive, and potentially able to be given for a much longer period of time to maintain the response that was achieved early on. An alternative approach is called switch maintenance, and that is starting with four to six cycles of a combination, then stopping all of those agents and switching to one or more agents after that, that have not been given before. Again, the idea is to come up with a regimen that is not too intensive, but that can maintain the momentum that was already achieved — basically keeping the tumor shrunk for longer.

Now, what do we hope to achieve by maintenance therapy? Several studies have demonstrated that there is a very consistent improvement in progression-free survival, the time before the cancer will progress, in patients who receive effective maintenance therapy. In just about all of the cases of what we call effective maintenance therapy, this is a treatment that is essentially a standard second-line treatment, but we give it earlier than second-line, which is when the patient has actually demonstrated progression of their cancer; instead, we’re giving it more proactively — immediately after first-line, and these agents that have been shown to improve survival when given second-line, after progression, are also associated with improvement in progression-free survival, and in some cases, significant improvement in overall survival when given earlier on, as a maintenance therapy.

However, there are some potential issues and questions about how necessary maintenance therapy really is, and although it is certainly a widely practiced approach and a standard of care, it is not a mandate at this point. This is because — the fact is that, the studies that give maintenance therapy do have an imbalance, where more of the patients on randomized maintenance therapy received more intensive therapy than the patients who are randomized to receive supportive care, or no treatment, just placebo perhaps, instead, at the time of completing first-line therapy. So, what we actually see is, sometimes it may just be that more treatment is associated with better outcomes, and longer survival, than less treatment. But, one thing we can say is that maintenance therapy assures us that the patients who have achieved tumor shrinkage, or at least stable disease, and are therefore the patients most likely to benefit from later treatment, definitely get that later therapy that can help them.

One of the challenges and issues about taking breaks from treatment is that some patients will decline and not be well enough to receive additional treatment that would have otherwise helped them if they had just gotten it earlier. So, with some patients potentially falling off the curve, missing that opportunity, there is a tendency to try to push effective treatment to earlier, and minimize time off of therapy where we might have patients miss that opportunity if they decline quickly.

So, that is the general approach to maintenance therapy — it is not a mandate, but it is something that we tend to individualize for our patients, and discuss whether they feel up to tolerating more treatment after going through four to six cycles of a combination first-line therapy, and whether they need to have a break, whether they want to go on a family vacation, etc.; there’s always room for individualizing, but for many patients, continuing with maintenance therapy — either continuation, or sometimes switch maintenance to a new therapy, may be a very appropriate approach.

Optimal Systemic Therapy for Bronchioloalveolar Carcinoma (BAC)

GRACE Cancer Video Library - Lung



Bronchioloalveolar carcinoma (BAC) is an unusual subtype of lung cancer; medical oncologist Dr. Jack West reviews the evidence on the best systemic therapy to treat advanced, multifocal BAC.

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One of the unusual subtypes of lung cancer is known as bronchioloalveolar carcinoma, or BAC. That is a subgroup of adenocarcinoma, and many clinicians treat is as a special case. Because of that, it’s fair to ask the question of, “what is the best whole body, or systemic, therapy for that setting?” There are some clinicians who will tell patients that standard chemotherapy does not work and shouldn’t be tried at all. There are some people who feel that oral EGFR inhibitors, drugs like Iressa (gefitinib), or Tarceva (erlotinib), or Gilotrif (afatinib), might be the treatment of choice. But those are all oversimplifications based on prior information, and we now know better. In fact, as is often the case, we need to individualize for the particular patient, and their cancer.

The first main question to ask is whether it’s necessary to treat at all. Some patients will have an advanced or metastatic, cancer, but it is not growing at a pace that is really a threat, and for patients who don’t have symptoms, and who might have very slow-growing cancer, there shouldn’t be any rush to start treatment right away, just because they have what is technically called stage 4 cancer. There are patients who can go very long periods of times with no symptoms and feel well for months, or even years.

But, if patients demonstrate clinically significant progression of their disease, and especially if they have symptoms, it’s appropriate to think about what the best whole body, systemic therapy is. 


The trial that really changed our prospective on how to approach these patients was called IPASS. This was an Asian study of over 1,200 patients, from Asia, who had a never-smoking history, and an adenocarcinoma. And this group of Asian never-smokers with an adenocarcinoma are the kinds of patients who we have long recognized as being especially likely to respond well to oral EGFR inhibitors. Because of that, this trial directly tested Iressa to standard chemotherapy in a large number of patients who were enriched to likely respond well. However, it did not require that patients have an EGFR mutation, because the story about EGFR mutations was still being developed, and we didn’t know how important that really was — really not until this trial.

The study looked for a significant difference in progression-free survival — the time before the cancers began growing again, after an initial response or stable disease. When we look at the results for progression-free survival in the bottom left part of this slide, you can see that it’s an unusual pattern — it crisscrosses – it’s kind of like a figure eight, and when we see that, it suggests that there’s actually two different populations within the broad group here. The study was designed to look for EGFR mutations in patients where there was tissue available, and they looked at over 400 patients who did have tissue available, and found that 60% of the patients did have an EGFR mutation, which of course means that 40% did not, even though they were Asian never-smokers with an adenocarcinoma, and a group that we might reflexively want to give these oral therapies to. 

But, as you can see from the curves shown in the middle and the right side of the bottom portion of the slide, you got completely different results if patients did have an EGFR mutation, versus if they did not. If you did have an EGFR mutation, you did remarkably better getting the oral EGFR inhibitor. On the other hand, if you do not have an EGFR mutation, you did far, far better by getting standard chemotherapy, and we also see this when we look at the response rates. 


In fact, when you look at the patients with an EGFR mutation, Iressa was associated with a response rate of 71%; if you didn’t have that mutation, your response rate to Iressa was 1%. You were far better served by getting chemotherapy if you don’t have an EGFR mutation — you had a response rate of about 23-24%, which is, of course, much better than that 1% with Iressa.

So, this really changed our thinking about the field — we used to, perhaps, think that we could clinically separate patients and say, if you’re Asian, never-smoker, if you have an adenocarcinoma, we can just start by giving you an EGFR inhibitor, and expect that we were serving you well. In fact, this showed that if you guessed wrong, you could really do a disservice to the patient. That the patients who don’t have an EGFR mutation should get standard chemotherapy as their first-line treatment, and the same applies to advanced BAC — in patients who don’t have an EGFR mutation, they should go on to get standard chemotherapy, unless they have another driver mutation that we would standardly look for, such as an ALK rearrangement, or possibly a ROS1 rearrangement.

So this is how we now treat advanced BAC — it is individualized based on the molecular characteristics of their cancer. You look for a driver mutation, and if you find one for which we have an oral therapy that tends to work very well, that is your first-line treatment of choice. If you don’t find one of those driver mutations, your first-line treatment of choice is standard chemotherapy based, potentially adding the drug Avastin or bevacizumab, which is an anti-angiogenic agent.

Reirradiation of Tumor in a Previously Radiated Field

GRACE Cancer Video Library - Lung



Radiation oncologist Dr. Chris Loiselle reviews the possibility of re-treating with radiation for lung cancer, typically using stereotactic technique, in a previously irradiated field.

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Reirradiation of lung cancer is an area where we discuss a lot with patients, the risks and benefits, and think a lot about the unique situation that each patient is finding themselves in. I think it’s often an area too where many people are told by their physicians that once they’ve had radiation, they can’t have it again, and that is not true, generally. We often will consider doing reirradiation, or a second course of radiation; we’ll often do reirradiation with stereotactic techniques, like the CyberKnife, to really minimize any collateral damage, but it is a careful discussion of risks and benefits.

We think about doing reirradiation when we see patients who, typically, are in one of two circumstances. The first one being a patient who has an early stage disease treated with surgery or radiation, and they have a recurrence which, typically, is not operable. In this situation, we are treating with curative intent, and in the setting of curative intent, we may be willing to accept some increased risk depending on the certain circumstances in an effort to potentially cure a life-threatening lung cancer.

On the other side of reirradiation, the circumstance that we see most is a patient who has radiation, either to a primary site or perhaps to a metastatic site in the body, and they recur there, and it’s causing problems — it’s causing spinal cord compression, it is compressing an airway, and we think about this as a multidisciplinary team. We think about all options: we think about chemotherapy, targeted therapy, surgery, but sometimes when surgery or chemotherapy or systemic therapy are not a good option, and reirradiation, though it carries some risks, is an option, we move forward with a mutual understanding between ourselves and our patients about what we’re getting into, and we are looking toward doing the best that we can — again, sometimes thinking about understanding increased risks.

Cancer Growth Rate and Managing Slow-Growing Lung Cancers

GRACE Cancer Video Library - Lung



Dr. Jack West, medical oncologist/lung cancer specialist, describes special management considerations for indolent lung cancers that may not require treatment or are at risk for “over-treatment.”

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One of the core questions in managing patients with advanced non-small cell lung cancer is addressing the pace of the disease, because it can really vary a lot. In many cases, and in fact, in most cases of advanced non-small cell lung cancer, the cancer will be progressing at a rate at which you can see things getting worse if you don’t do treatment, over an interval of one or two months.

On the other hand, there are also some cancers that follow a more indolent or slow-growing pace, and in patients with a slow-growing cancer, especially if they don’t have symptoms clearly related to it, it might make sense to hold off on treatment for a longer period of time. So, it is worth asking a few central questions about how best to manage a patient with an indolent cancer, even if it is technically metastatic.

The first question is whether you see any progression at all over a period of, say, six or eight weeks, or maybe even longer, three or four months — because, if you’re not seeing progression over that period of time, it’s hard to have the real incentive to pursue a treatment that can have side effects. We don’t want the treatment to be worse than the disease. Again, if you do see progression at all, you need to ask whether it is clinically significant progression. Just being able to measure some degree of progression if you squint carefully — it is not necessarily enough to justify the side effects of treatment in somebody who is otherwise doing well, and may continue to feel well and do well for many months, or potentially many years, with a cancer that just happens to be quite slow-growing.

A second related question is: if you do see areas of clinically significant progression, is it really just one area that’s growing, or two, or is it multiple areas growing at once? Because, if you see just one or two areas growing, it might make sense to pursue a local therapy, something such as surgery or radiation. On the other hand, if you see multiple areas all growing together, it makes more sense to pursue a whole body, systemic therapy that can treat all these areas at once. But if you see just a single area growing, perhaps, even if it’s against a background of several other areas of known disease, if all of the other areas are growing at such a slow pace that you really don’t necessarily need to worry about them as a threat any time soon, it might make sense to just get the lead runner, to borrow a term in baseball, and address and neutralize the only area the really seems to be leading the charge as a threat.

And then, if we do see areas of multifocal progression, multiple areas growing at once, the leading consideration is going to be systemic therapy. If that’s the case, the leading question after that is: what is the best treatment to pursue — and that’s the subject of other videos here.

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