GRACE :: Lung Cancer

ALK Inhibitors

Crizotinib and other ALK inhibitors

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

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

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GRACE Cancer Video Library - Lung

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.


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