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alectinib

Dr West

New FDA Approval for Zykadia (ceritinib) for ALK-Positive NSCLC: Why I Think It’s a Poor Choice for Initial Treatment

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The FDA just approved a new therapy for the approximately 4% of patients with NSCLC who have the molecular marker known as an ALK rearrangement. The agent Zykadia (ceritinib), a “second generation” ALK inhibitor that is more effective than Xalkori (crizotinib) in lab models of ALK-positive NSCLC, and the new approval was for Zykadia as first line treatment for ALK-positive lung cancer, a setting where we have historically favored Xalkori since it was approved in 2011. . Despite the FDA approval for ceritinib, I don’t believe it should be favored as a first line therapy for ALK-positive patients. Why would I not favor it?

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Dr West

Should Alecensa (Alectinib) be the new first line ALK inhibitor for ALK-positive NSCLC?

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Probably the most immediate potentially practice-changing presentation from ASCO was the Japanese J-ALEX study in the subset of about 4-5% of patients with non-small cell lung cancer (NSCLC) who have the molecular driver known as an anaplastic lymphoma kinase (ALK) rearrangement, which we now routinely test for from the tumor tissue of patients with a non-squamous metastatic NSCLC.   The current historical standard of care as first line treatment is Xalkori (crizotinib), which is an ALK inhibitor that happened to be readily available when the ALK rearrangement was first being studied in NSCLC about 5-7 years ago. Though it was granted an accelerated FDA approval back in 2011 based on early very promising activity and has since been confirmed to be superior to chemotherapy as first line treatment in ALK-positive patients, it is a less active ALK inhibitor than many other “second-generation” ALK inhibitors such as Zykadia (ceritinib) and Alecensa (alectinib), both now FDA-approved for patients who have developed progression after Xalkori or who are not able to tolerate it, as well as other agents still in development, including brigatinib (likely to become approved soon), and a few others further behind in development but also very active against ALK-positive NSCLC.

A question that logically follows is whether it is better to give one of these more active second generation ALK inhibitors as first line therapy, where they are likely to be more active for longer than if given for “acquired resistance” after Xalkori, or whether it’s better to start with Xalkori and have other powerful ALK inhibitors left for later.  Should we use our best drug up front or only the most effective drug required to do the job for now, saving something in the tank as we think more about advanced lung cancer as a distance race than a sprint? How much do we prioritize control now vs. options later?

There are several trials that have been initiated that all test a second generation ALK inhibitor vs. Xalkori.  Two of the first to be completed compare Alecensa to Xalkori, a large, global trial known as ALEX, and a smaller trial done in Japan only, known as J-ALEX, which reported early and remarkably interesting results at ASCO 2016.

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GRACE Video

Timing of Second Generation ALK Inhibitors: First Line vs. Treatment after Acquired Resistance

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GRACE Cancer Video Library - Lung

GCVL_LU-FC02b_Second_Gen_ALK_Timing_First_Line_Acquired_Resistance

 

Dr. Ross Camidge, University of Colorado, addresses the question of whether to use a second generation ALK inhibitor as first line therapy or only after acquired resistance to crizotinib.

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One of the long-standing philosophies in oncology is you use your best drugs first. To be honest that goes back to a mindset that maybe people weren’t going to survive for you to try a treatment in a second line or third line setting, so you were just trying to get in your best drug in whilst you had a chance. Now we’ve seen with the next generation ALK inhibitors, they have better activity in the brain, they have activity after crizotinib has stopped working, so the logical question is, what if you come in with these drugs first instead of crizotinib? Could they displace the recently crowned king of ALK crizotinib by being the new pretender? Well, maybe.

The only direct head to head study is with alectinib and that’s the so-called ALEX study — alectinib, ALE, compared to crizotinib which is also called Xalkori and that’s where the X comes from — ALEX. There’s a very similar study run in Japan which is called the J-ALEX study. Both of those have finished accrual, so we should see those results in the near future.

Now, when we get that data it’s going to be very interesting to look at. Does the alectinib just have to be better that the crizotinib? Well, sure, it probably has to be and it probably will be. The real question is, how much better? If it’s just a little bit better, sure that’s a positive study, they’ll get a license for the drug, but you could still use crizotinib followed by alectinib, or followed by any other second generation ALK inhibitor, and maybe that sequential benefit may be more than if you use your best card up first.

What if it’s the same as the sequential therapy? Well that might change peoples’ prescribing if the drug is better tolerated, more convenient, or cheaper, and new drugs tend not to be cheaper. Perhaps what we’re hoping for is that by suppressing some of the dominant mechanisms of resistance from the get go, we’ll actually change the natural history of the disease. Every time resistance occurs, more cells divide, they grow up, and they’re generating the next and the next mechanism of resistance.

So the more you can suppress cell turnover from the get go, the more maybe you can extend out the overall duration of control — but we have to wait for those results to come out and until they come out, I wouldn’t start using second generation inhibitors in the first line setting without that data.


GRACE Video

Ceritinib and Other Second Generation ALK Inhibitors for Acquired Resistance in ALK-Positive NSCLC

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Camidge_Ceritinib_Second_Generation_ALK_Inhibitors_Acquired_Resistance_ALK-Positive_NSCLC

 

Dr. Ross Camidge, University of Colorado, describes the second generation ALK-inhibitors which provide good options for ALK-positive NSCLC patients who have developed acquired resistance to crizotinib.

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One of the exciting things about the ALK field is that in a relatively short space of time, we’ve gone from defining a molecular subtype of lung cancer that responds very nicely to a first generation drug, crizotinib, that we’ve actually not got more choices. More specific, more potent ALK inhibitors have been developed: ceritinib, alectinib, brigatinib to name a few. Ceritinib is already licensed — the other two drugs have got what’s called FDA breakthrough approval. That means the FDA is very keep to look at the results, and hopefully if they’re good, will license the drug fairly quickly.

What they’re showing is, one: because they tend to be slightly cleaner drugs, they have a different side effect profile from crizotinib. For example they tend to not have the swelling of the ankles and other areas of swelling which is associated with an off target effect of crizotinib called anti-MET activity. However they’re not completely free from side effects. Ceritinib for example has a lot of gastrointestinal side effects — a lot of nausea, a lot of vomiting and diarrhea, and nearly 60% of people need a dose reduction. The alectinib and brigatinib are looking relatively cleaner in terms of the side effects.

In terms of whether they work: after the crizotinib has stopped working, people have progressed in one of two ways. Either their cancer is growing in their brain because crizotinib doesn’t penetrate into the brain very well, or the cancer has evolved and changed its biology in the presence of the crizotinib.

The good news is these next generation drugs work on both of those mechanisms. Either more is getting into the brain or the drug is just more potent, and therefore we’re seeing responses in the brain, and also they work on some of the known resistance mechanisms to crizotinib. We’re seeing 50-70% of people responding in their body after initially progressing on crizotinib.

So very rapidly we now have a clearly defined next line of therapy for ALK-positive patients progressing on crizotinib.


GRACE Video

Local Therapy for Limited Acquired Resistance

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GRACE Cancer Video Library - Lung

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.

GCVL_LU-FB06_Local_Therapy_Limited_AR_03 

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.

GCVL_LU-FB06_Local_Therapy_Limited_AR_08 

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.


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