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Ross Camidge

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

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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

CNS Disease in ALK-Positive NSCLC: Monitoring and Systemic vs. Radiation Therapy

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GCVL_LU-FC05_CNS_Disease_ALK-Positive_NSCLC_Monitoring_Systemic_Radiation_Therapy

 

Dr. Ross Camidge, University of Colorado, discusses management of CNS progression for ALK-positive NSCLC including monitoring frequency and preferences between systemic and radiation therapy.

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As we started to treat ALK-positive patients with crizotinib, it became clear that the brain was somewhat of an Achilles heel. It was a common site for people, when their cancer started to grow, for that to be the site where their cancer was growing, and we know that in many of those cases that’s the only site where the cancer is growing. We know from a small number of studies where people have actually sampled blood levels and from the fluid around the brain that actually very little of the crizotinib is getting in, so it’s maybe just that you have a relatively under-treated part of you.

Now that plus the fact that people fortunately live a long time with ALK-positive lung cancer means that the brain can become this area that will crop up with disease. For me that means you should absolutely keep an eye on the brain. If you have no known disease in the brain I would do an MRI scan at least every six months. If you do have known disease in the brain, even if it’s treated, I would be looking more frequently, possibly as frequently as one scanning the body on treatment, or maybe half as often.

Now if you do have disease in the brain, because the activity of crizotinib is not zero, unless you have a lot of symptoms from the disease in your brain, many people will start on the crizotinib, but obviously keeping a close eye because if you do progress in the brain, then you may have to salvage it.

You can salvage it in a number of different ways. One would tend to stay on the crizotinib and either have local radiotherapy or occasionally surgery depending on the site of the deposits in the brain. For me though, there’s a difference between one type of radiotherapy and another. For example, you can either treat the whole brain, what’s called whole brain radiotherapy, or you can treat individual lesions with what’s called stereotactic radiosurgery or SRS. I very much prefer giving SRS, even to a reasonably large number of lesions, than whole brain radiotherapy for the simple reason that people with ALK-positive disease are now living long enough that they’re manifesting the side effects of whole brain radiotherapy and that can mean word finding difficulties, memory difficulties.

So I think for me if you’re just at the point where you can spot weld a few areas with stereotactic radiosurgery, that’s fine — stay on the crizotinib. But if someone is thinking about whole brain radiotherapy, I would probably switch to a next generation ALK inhibitor rather than do the whole brain radiotherapy because we know they have good activity in the brain.


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

Crizotinib for First Line Treatment of ALK or ROS1 Rearrangements

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GRACE Cancer Video Library - Lung

GCVL_LU-FC01_Crizotinib_First_Line_Treatment_ALK_ROS1_Rearrangements

 

Dr. Ross Camidge, University of Colorado, explains the preference for crizotinib rather than platinum doublet chemotherapy as first line treatment for patients with ALK or ROS1 rearrangements.

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Increasingly across many molecular subtypes of lung cancer, we’ve seen that giving a targeted drug first is better than going on chemotherapy. It doesn’t mean there’s no role for chemotherapy, but you’re going to start playing your best card first.

We’ve certainly seen within randomized studies that going on crizotinib compared to first line — what’s called platinum doublet, two drug chemotherapy — going on the targeted therapy was better. There was a higher response rate; there was a longer time before the cancer progressed.

For ROS-1, because it’s a much smaller population it’s hard to do those big randomized studies, but I think most people believe that, and I think that’s why ROS-1 probably should be in the panel of things that people look for from the get go to see if there’s a tablet that can treat your cancer more than just chemotherapy from the start.


GRACE Video

ROS-1 Rearrangements: What Are They?

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GCVL_LU-BA03_ROS-1_Rearrangements_Defined

 

Dr. Ross Camidge, University of Colorado, describes ROS-1 rearrangements and compares them to ALK rearrangements in frequency of occurrence and response to treatment.

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ROS-1 rearrangements are like the sister to ALK gene rearrangements. They’re also a gene which is silenced in most adult tissues, which is turned on again by a gene rearrangement creating what’s called a fusion protein which can drive the cancer cell. Structurally they’re very similar to ALK rearrangements and they respond to many of the same drugs. Particularly crizotinib, the first licensed ALK inhibitor, has also clearly shown good activity in ROS-1 driven cancers.

They’re rarer, maybe one quarter as common as ALK rearrangements or less. There are subtle differences. The benefit of crizotinib in ROS-1 gene rearranged lung cancer actually seems greater than it is in ALK, so the response rate is 70% as opposed to 60%. The median progression-free survival, the time it takes for the cancer to grow, on average is about 19 months as opposed to nine or ten months with ALK.

People are wondering about why the difference is, and there are various theories. Maybe crizotinib is actually a better ROS-1 inhibitor than it is an ALK inhibitor. Maybe the frequency of progression within the brain, which we know is somewhat of an Achilles heel for crizotinib and ALK-positive lung cancer — maybe that’s not such an issue with the ROS-1 rearranged patients simply because they have a lower frequency of deposits in the brain. Increasingly on a biological level, we’ve also seen a little bit of data that ROS-1 may be a more genetically simple cancer that ALK. It occurs in a part of the genome, part of the DNA of the cell, which is more structurally stable, so its ability to mutate and evolve in the presence of the drug and then progress later may be less. Either way, it’s a good thing to have if you have it.


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