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Local Therapy for Limited Acquired Resistance

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GCVL_LU-FB06_Local_Therapy_Limited_Acquired_Resistance

 

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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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[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.

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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.


Dr West

The Importance of the OLIGO in Oligometastatic or Oligoprogression

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There is a principle in management of lung cancer that some patients who have a very limited degree of metastatic disease or progression after a good response may do unusually well with local treatment, such as radiation or surgery, for the isolated area(s) of disease that are metastatic or growing. The idea for this stems from the concept of the “precocious metastasis”, which is essentially the idea of “the one that got away” — perhaps if there is just a very limited metastatic deposit of cancer or one area progressing and everything else is well contained, that area of escape can be obliterated without other areas of escape popping up elsewhere.

In the last few years, approaches like video assisted surgeries with wedge resections and focal radiation (stereotactic body radiation therapy, or SBRT) are now also making it more feasible to do additional local treatments with fewer side effects than in the past. This has led to a huge trend toward more and more surgeries or radiation treatments to areas of metastatic disease.  The question is whether this is really beneficial or whether it’s done largely because it’s easy to mislead patients and even ourselves as doctors that more is better, especially when it’s a profitable thing to do and someone else is paying for it. But I fear that these principles are being applied far beyond where they make good sense.

The term “oligometastatic” comes from the Greek root “oligo”, meaning few, along with metastases, and that fits when there is just one area of metastatic spread, or perhaps two. The problem is when local treatments are applied for 3 or 4 or more areas of disease. An isolated area of metastatic spread or progression may well represent a rogue area with its own biology, and there is an arugable reason to hope that we can resect or ablate that area and not have other areas of disease crop up. On the other hand, 5 areas of metastatic disease isn’t oligometastatic disease — it’s frankly metastatic disease, and it is unfathomably unlikely that the underlying cancer process can be controlled by just treating the areas you can see today. It would be like picking off a bunch of dandelions from the stems in your lawn and presuming your job is done. If you see 5 dandelions, you can be sure that eradicating those 5 won’t end the problem, and that plenty more will follow. Unfortunately, whether it’s a poor understanding of biology or an economic motivation to treat people in situations where it’s not oligometastatic at all, far too many practitioners of local therapies are all too eager to encourage patients to pursue treatments that cannot be reasonably expected to be helpful. 

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