GRACE :: Lung Cancer




Maintenance Therapy for Advanced NSCLC




Dr. Jack West, Swedish Cancer Institute, defines maintenance therapy in advanced NSCLC and discusses maintenance treatment strategies.

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For patients with advanced non-small cell lung cancer, our typical approach, if we have someone who does not have a driver mutation that we typically treat with a pill-based targeted therapy, is to give chemotherapy. That chemotherapy is typically given in a cycle of three weeks or sometimes a four week period of time where the blood counts go down and then recover. That treatment is typically given once every three weeks, sometimes once or twice on a weekly basis in that three week interval, but we typically give that therapy for about four to six cycles of therapy — that’s about three to five months of treatment. By that time, by four to six cycles in, the two drug combination that includes a drug called platinum is usually creating some cumulative side effects: fatigue, low blood counts, and other complicating issues that make it increasingly challenging to administer more of the same potentially intensive therapy, and by four to six cycles you really tend to reach a point of diminishing returns.

At that point we often favor a maintenance therapy approach. That is, dropping the carboplatin or stopping all of the agents that have been given previously and either continuing one or more of the agents from the first line setting, or using what’s called switch maintenance to give a completely different treatment. These maintenance therapies are designed to do what their name suggests — to maintain a response after we’ve seen the most shrinkage that we’re likely to get from the more intensive first line therapy.

When we do a continuous maintenance approach, it’s typically taking a drug like cisplatin or carboplatin in combination with one or two partner drugs, usually a second chemotherapy agent and sometimes Avastin which blocks a tumor’s blood supply, and then after four to six cycles we drop the platinum and we will typically continue a drug like Alimta if that’s been given in the first line setting, and if a drug like Avastin has also been given we might continue that and give Alimta and Avastin together until the cancer progresses.

If a combination like carboplatin and Taxol were given with Avastin, the maintenance therapy is often just the Avastin because Taxol tends to have some cumulative neuropathy issues — numbness and tingling that can lead to a real limitation in how much of that therapy you can give. We might also consider a switch maintenance approach — instead of continuing some of the agents, come in with Alimta as a single agent if a patient has non-squamous histology. Another agent that is approved as a switch maintenance therapy is Tarceva (erlotinib) — this doesn’t tend to be as favored as a switch maintenance because the efficacy of Tarceva in patients who don’t have an EGFR mutation tends to be on the lower side.

What do these maintenance therapies have in common? Well they’re all agents that can be given on a longitudinal basis without a lot of cumulative side effects and they tend to be the agents that have good activity in patients who have already been on prior therapy. So any of these is a reasonable choice, the most common being a continuation maintenance of dropping the platinum and continuing one or two partner drugs that were given with it, or sometimes switching to an agent like Alimta (pemetrexed) or Tarceva (erlotinib). It’s also reasonable to not pursue maintenance therapy if a patient has cumulative side effects and really needs a break from therapy. That is certainly something to discuss with the patient; it’s not as if maintenance therapy is a mandate for all patients, but it is something that is a strong consideration if a patient is motivated and can continue to tolerate ongoing therapy after four to six cycles.


The Role of Targeted Therapy Post-Resection

GRACE Cancer Video Library - Lung



Dr. Heather Wakelee, Stanford University Medical Center, evaluates the lack of evidence for the use of targeted therapies after surgery, and describes ongoing trials attempting to resolve that issue.


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Since the mid-2000s we’ve known that many patients who have non-small cell lung cancer, particularly the adenocarcinoma type, have particular gene mutations that we can identify and when we find them, treat with specific new drugs. We know this data from patients with metastatic lung cancer — the first to be discovered was EGFR or epidermal growth factor receptor, then ALK or anaplastic lymphoma kinase. Now there’s a very long list of gene mutations that we can identify when we look in patients with advanced stage lung cancer, and when we find them, offer specific targeted therapy that can have a very high likelihood of shrinking the tumor. This has really changed the way we think about and treat advanced stage lung cancer. However we haven’t figured out how to best use those treatments for patients who have earlier stages of lung cancer.

So in the setting of an early stage lung cancer that’s been removed with surgery, patients are theoretically cured at that point. Chemotherapy has been proven to lower the chance of the cancer coming back, but when you find one of these mutations in the tumor, the temptation is to give one of these targeted drugs. That strategy has been looked at in multiple clinical trials and we still don’t have a straightforward answer.

The largest trial to look at this so far was called the RADIANT trial and in that trial, after getting chemotherapy if that was the right thing for them, patients either received the EGFR drug called erlotinib, or a placebo. Now most of those patients in that trial actually did not have a specific mutation in EGFR because the study was designed before we knew about how important those mutations were. In the subset of patients who did have the EGFR mutation, those getting erlotinib seemed to have more time before the cancer came back, but if you looked at their overall survival, it wasn’t any different than the patients who had been on the placebo arm. The theory is that those who were on the placebo arm who had the cancer come back, when it came back they were then able to get erlotinib or a similar drug and have the same benefit. So it’s not clear that starting the erlotinib right at the time of surgery actually helps people live longer, though it might slow down the time to recurrence.

That’s obviously not a complete answer so there are more studies happening now trying to get a better sense of what we should do in that setting. There are a couple of trials in China, actually several trials in China, a study in Japan, and now a big study in the United States, all with the same general idea that a patient who has a tumor resected or removed by surgery, who is shown to have an EGFR mutation in that tumor, is randomized to either get an EGFR drug or to get placebo. Some of the studies have chemotherapy before or after, some compare it to chemotherapy, so there are some differences, but the general idea is whether or not giving the EGFR targeted drug will actually help people be cured or live longer versus waiting, and then for those who do have recurrence, giving it at that time. So those are really important trials that are ongoing and we’ll hope to know the answers in the next few years.

For the patients with the ALK translocation in the United States, the big trial called ALCHEMIST is open not just to EGFR but also to ALK patients. What that trial is about is asking that any patient who has a surgery at a site that’s participating in ALCHEMIST have part of their tissue from the tumor sent in to a central laboratory to be tested for EGFR or ALK. Those patients who have EGFR are then randomized to either get the EGFR drug erlotinib, or to get a placebo pill, and those who have ALK to get the ALK drug crizotinib versus a placebo pill. Over time people will be followed to see — does this change when the cancer comes back, and does it ultimately change overall survival for the patients where the cancer does come back?

So this is a really critical trial and it’s going to help us know what the best way is to use these targeted drugs for patients in this setting. Until we have those trial results back, I do not recommend that patients get the EGFR or ALK targeted drugs after surgery because we just don’t know if that’s going to help them live longer.


Local Therapy for Limited Acquired Resistance

GRACE Cancer Video Library - Lung



Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, describes the types of situations in which local therapy is appropriate for treating limited acquired resistance.

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It’s my privilege to speak to you today about a favorite topic of mine, local therapy for limited acquired resistance.


So just five years ago, we were celebrating the curves that I’m showing you here. This is great — we have a targeted therapy, it works better than chemotherapy, it’s less toxic, it’s more convenient, demedicalizes the patient’s life, and this is a legitimate victory and I don’t want to take that celebration away, but I think only five years later, I guess now six years later, I think the perspective is a little bit different as our drugs get more effective and the bar goes up.


We say these drugs are lasting less than a year on average — now what? We’re trying to find something other than chemotherapy. There are multiple promising approaches, including next generation drugs aimed at the targeted therapy, but I’m going to talk to you today about a slightly different approach. Before doing so, I want to just share that this story is very analogous for crizotinib and ALK and ROS1, it’s the exact same story.


The approach I colloquially call “weeding the garden.”  This approach is what it sounds like — using some kind of local ablation or surgery to take out areas of progression, areas that are growing despite the targeted therapy, the areas that perhaps have a resistance mutation of some kind, and then using the original therapy for the rest of the cancer that’s still well controlled.


So when might this make sense, and when might it not? Well the situation  where it surely does not make sense is classical progression. Prior to the advent of targeted therapies and immunotherapies, there was really only one pattern of progression that we mostly saw: when the cancer was going to grow, it grew everywhere and it grew in multiple new spots — not a time when weeding the garden makes good common sense.

We have two new patterns of progression where it does make more common sense. One is oligoprogression — that is what it sounds like, you have progression in just one or two spots, those spots maybe have T790m or some other resistance change, where the rest of the cancer is beautifully controlled still on the targeted therapy. The other situation is when the progression is in an area that the drug doesn’t get to so well. So there’s this filter between the rest of the body and the brain called the blood-brain barrier. Its job is to keep poisons out of the brain and it appropriately sees most of our anti-cancer therapies as poisons and keeps them out of the brain. You can have cancer growing in the brain not because there’s some resistance gene, some secondary mutation or amplification of some gene, but just because the drugs aren’t getting there well. I think that’s another area where it conceptually makes sense to consider weeding the garden.


For EGFR, I think radiation is a particularly promising approach to do this — at left you can see data preclinically in the lab on why EGFR mutated cells seem to be more sensitive to radiation than non-mutated cells, and at right some human data to back up that this actually happens in real people.


This approach has been tried retrospectively — the Memorial group here did a mostly surgical series where they got a median time until progression of another ten months after this approach, so they’ve mostly cut out the sites of progression and started TKI back up again.


Our colleagues at Colorado, where we happen to be taping today, have done this in a mixed series of EGFR and ALK patients; they show their data separately for whether the progression was primarily in the brain or elsewhere. When the brain was the primary site of progression, they got another 7.1 months out of targeted therapy. When it was outside of the brain, they got an additional four months.


I have the privilege to lead a study prospectively evaluating this approach for patients with oligoprogression on EGFR mutation. The design is very simple, you have to have gotten benefit out of an EGFR TKI, typically erlotinib in the first line in this country, but no prohibition against gefitinib or afatinib, but now one or two sites, up to five sites, are growing. We do stereotactic radiosurgery to those sites of progression, and then restart a TKI for the remainder of the sensitive disease. My collaborators are shown at right, including many GRACE contributors.


[In 2015] Pfizer agreed to fund a very similar study for patients who have previously received a benefit on crizotinib but are now  progressing. The design is rather similar here, where we do radiosurgery to the sites of progression, restart the crizotinib, and because which mutations are sensitive to crizotinib is evolving at the current time, we don’t define this on a molecular basis but on a practical basis — patients who have received benefit but now have growth in four or less spots.

You might reasonably ask me the question, “well we have all these exciting next generation tyrosine kinase inhibitors we’ve heard about on GRACE, we have the clovis compound and the AZ compound for EGFR, we have alectinib and ceritinib for ALK — why not just jump to one of those?” I actually think that would be a perfectly reasonable approach, perhaps the preferred approach when there’s poly progression, but I can show you graphically why you might consider the approach that I’m talking about.


So here’s the approach of starting with the first-gen TKI and moving straight to the next-gen TKI. Let’s imagine that my approach of eliminating oligoprogressive disease only has minimal efficacy, only gets you a few extra months on the first line therapy, you might look at this graphically this way: that you’ve inserted an additional therapy, you’ve squeezed a little more juice from the orange, in first line, before moving to that next line. But it’s entirely possible that in reality we get something better than that. So the first of these alternative hypotheses is that we get a longer duration of control — perhaps ten months or a year, replicating the original experience with the first line targeted therapy. Here we have a larger advantage to total cancer control before moving on to chemotherapy. Alternatively, if we’re radiating spots, we may be eliminating some of the spots that are eventually going to cause resistance on second line TKI, and so it’s entirely possible, I would call it my professional fantasy, that we’ll actually not only prolong the duration of benefit of the first line drug, but make the second line drug last longer when we get there. The possibility of that approach is shown at the very bottom — that fantasy phenomenon.

So I thank you for your kind attention.


Elderly Patients: Selecting Appropriate Systemic Treatment Agents

GRACE Cancer Video Library - Lung



Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, evaluates a variety of particular systemic treatment agents for possible use in elderly patients.

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It is my privilege to speak to you today about elderly patients; consideration of which chemotherapeutic agents might be best. So we’ve seen a lot on CancerGRACE about the advent of targeted therapy and this theme that when you combine a target with a targeted therapy, like a lock and key model, you as a theme get a treatment that has less side effects, is more convenient because they’re often oral, and tend to work better.


This of course has made lots of work for our medical students as we subdivide by histology, by driver mutations, and an even more complex systems view that probably starts to approach reality. But in the simplest way when thinking about targeted therapies such as erlotinib or gefitinib for EGFR mutants, or crizotinib for ALK or ROS1, and other emerging targeted therapies — as a theme these drugs are very effective and less toxic, and so to my mind, even though we don’t normally speak about them as geriatric drugs, to me they’re the epitome of geriatric drugs because of these themes.


In terms of traditional chemotherapy, there’s really only one agent that I would consider to have any data for superior efficacy in the elderly. You’re looking here at the design of a randomized phase III trial that randomized patients to carboplatin and regular cremophor solvent-dissolved paclitaxel, versus carboplatin and a newer nano albumin-bound formulation called Abraxane.


Patients were randomized one to one, you can see the basic results by age at the bottom of this slide. Why I’m showing this to you is that the only subgroup that had a major survival difference was the elderly. In patients of at least 70 years of age, there was a rather important improvement in survival, 19.9 versus 10.4 months — that is statistically significant. I would call that clinically meaningful but it is a retrospective subgroup analysis and so it requires confirmation in prospective studies. Two important studies are ongoing to look at this. One is looking at older patients with this regimen for their first treatment, and the other looking at such patients for their second treatment.


This was a randomized trial that compared for first treatment cisplatin and pemetrexed, versus cisplatin and gemcitabine. We’ve covered this trial a number of times on GRACE before in terms of looking at histology-specific differences in drugs and we’ve seen on GRACE before that pemetrexed is a particularly effective drug for patients with non-squamous histology, which mostly means adenocarcinoma, where it’s less effective in patients with squamous histology. We’ve also seen that it tends to be one of our better tolerated chemotherapy drugs, and these results held in this definitive trial both for younger patients and for older patients. While I don’t tend to use cisplatin in older patients (we’ll get to that) I do think that pemetrexed is a particularly geriatric-friendly drug for patients with non-squamous histology.


ECOG 4599, another trial we’ve covered multiple times over the years looked at the standard platinum doublet carboplatin and paclitaxel, with or without the addition of the VEGF inhibitor bevacizumab, otherwise known as Avastin.


We know that trial showed a small but real survival advantage in unselected patients, but why I show it to you today is that treatment advantage really seems to slim down when we look at older patients. So in my practice I don’t tend to use bevacizumab except for my really, really most fit older patients.

All the rage these days, of course, in thoracic oncology are the immunotherapeutic agents. These drugs as a theme are more effective in the second line than chemotherapy and less toxic — these make them good geriatric drugs so bear with me a moment.


Here’s the data on nivolumab in squamous cell carcinoma, second line of therapy, compared to my second least favorite geriatric drug docetaxel. We can see here a dramatic improvement in survival, and perhaps equally important, a better tail to the curve — more patients living a very long time on the nivolumab.


A similar effect shown here in non-squamous histology, and as far as to why this is making its way to a talk about geriatric oncology, here’s the toxicity.


It’s very rare in looking at thoracic oncology trials to ever have this favorable of a rate of grade 3-4 or high-grade toxicity, even for placebo. So these drugs are more effective and less toxic — these are very geriatric-friendly drugs.

Bringing it back to chemotherapy, which is what unfortunately still the majority of patients get — I think it’s worth taking a minute to talk about which of these drugs are particularly geriatric-friendly and which perhaps should be avoided for most older patients.


So cisplatin is my least favorite drug for older patients. Why? It’s our most nausea- and vomiting-inducing drug, perhaps of any we use in oncology. It has a high rate of harming hearing and there is already age-related hearing decline, it’s one of our worst drugs on the kidneys and kidney function does tend to naturally decline with age. There are plenty of other reasons to hate cisplatin as well, making it my least favorite geriatric drug.

In contrast, its little brother carboplatin I regard as a much more geriatric-friendly drug. It has much, much less for side effects, particularly on the kidneys and for patients who already have a little bit of age-related kidney decline, the dosing formula for carboplatin, it’s called the AUC formula, inherently accounts for this, so you just don’t have to worry about it — you get the right exposure to the drug sort of automatically even if there is some preexisting decline in kidney function.

Paclitaxel I would call a middle-of-the-road geriatric drug, particularly I would call it more favorable when used on a weekly schedule. Docetaxel, as I mentioned, is my second least favorite geriatric drug — there’s a lot of count suppression, a lot of fatigue. When I do use it for older patients, I tend to reduce the dose some from the standard dose. We’ve discussed nab-paclitaxel, otherwise known as Abraxane, because of the subgroup survival data suggesting it may be more effective in older patients. Pending the confirmatory ongoing studies, I think that this is a very geriatric-friendly drug. Gemcitabine I would call on the better side of geriatric drugs, it’s mostly excreted by the kidneys so you need to pay attention if there is kidney decline, but it’s a pretty geriatric-friendly drug — an effective drug with lower side effects. Pemetrexed or Alimta we’ve already talked about as a particularly geriatric-friendly drug, I would comment though that this drug is excreted mostly by the kidneys, and so if kidney function is not ideal, it’s a drug that needs to be used with extreme caution or perhaps not at all.

I thank you for your kind attention.


Emerging Options for T790M-Positive Acquired Resistance




Acquired resistance in EGFR patients is often driven by the T790M mutation. T790M-positive tumors respond differently to treatments than T790M-negative tumors. Dr. Greg Riely details how each status can predict patients’ responses to current treatments.

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