GRACE :: Lung Cancer

ALK inhibitor

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

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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GRACE Cancer Video Library - Lung

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.


GRACE Video

ALK Rearrangements: What Are They, and Who Has Them?

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GRACE Cancer Video Library - Lung

GCVL_LU-BA02_ALK_Rearrangements_What_Who

 

Dr. Ross Camidge, University of Colorado, describes ALK rearrangements and the characteristics of patients who most often have them.

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ALK stands for anaplastic lymphoma kinase. This is a gene which is involved in the development when we’re a little tiny embryo, and then it gets turned off when we become an adult. As an embryo, it’s involved in the development of the gut and the nervous system and a few other things. It’s silenced in most adult tissues, but it can be turned on again by what’s called a gene rearrangement. What that means is it brings in the front part of another gene which drives the expression of the previously silenced ALK, then it actually functions as something so powerful that it can actually turn a normal cell into a cancer cell.

The absolute frequency is running somewhere between 3% and 7% of lung cancer. The people who tend to have these more often tend to be people with a kind of lung cancer called adenocarcinoma of the lung — that’s what it looks like in the microscope, comes from glandular tissue. It tends to be more common in never smokers, it’s slightly more common in people who are younger than the average age of people who develop lung cancer, maybe a decade or so.

You also need to understand that all of these factors which are associated with it are not exclusive. So you can be older, you can have a history of smoking, you can have non-adenocarcinoma and still have an ALK rearrangement that may respond very well to an ALK inhibitor. So you have to understand the difference between an enrichment factor, and an absolute — “you should never test”, or “always test.” For me, I test everybody unless they have a 0% chance, and that’s a very small group that has a 0% chance. Essentially I test everybody with non-small cell lung cancer.


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