GRACE :: Lung Cancer



Dr West

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


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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ALK Inhibitors for Acquired Resistance: Zykadia and Alectinib

GRACE Cancer Video Library - Lung



Dr. Nathan Pennell, Cleveland Clinic, discusses acquired resistance to Xalkori in ALK-positive patients, and second generation inhibitors designed to overcome that resistance, such as Zykadia and alectinib.

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I’d like to talk now about next-generation anaplastic lymphoma kinase, or ALK, inhibitors. So, we know for patients with ALK-positive non-small cell lung cancer, that targeted treatment with ALK inhibitors like Xalkori, or crizotinib, are now the standard of care for patients with advanced disease, based on head to head trials showing that they work better than chemotherapy in inducing major tumor responses and delaying the progression of the disease, and potentially even improving survival. While responses can sometimes last a long time with Xalkori, unfortunately a majority of patients will eventually go on to develop what is known as acquired resistance where the cancer begins to grow despite continued treatment with the drug that worked so well initially. Something has changed in the cancer that’s caused the drug to no longer work to inhibit it, and when we biopsy these cancers, we find that there are a lot of different changes.

So unlike epidermal growth factor receptor mutation-positive lung cancer, there is no one dominant mutation that’s leading to resistance in ALK- positive lung cancer. There are lots of different mechanisms, but fortunately there are a wide array of new ALK inhibitors out there which have shown to be effective in this setting.

The first one that was farthest along and, in fact, is already approved for patients in this setting, is called Zykadia, or ceritinib. This was approved last year based on a large trial in patients who had progressed on the Xalkori, and about 50-70% of patients will have a major response to the Zykadia, with a duration of disease control that’s, on average, probably in the eight to ten month range. This drug is a little bit tougher than the Xalkori, so many patients have some nausea or vomiting, diarrhea or upset stomach, but these are things that oncologists are used to dealing with and with dose reductions and management of side effects, patients can tolerate this and it can work quite well.

There are also a number of other ALK inhibitors that are still in clinical trials that are likely to be approved soon. Probably the one that’s farthest along is known as alectinib. So we’ve just recently seen trials, again, showing that between 50-70% of patients with acquired resistance to the Xalkori will respond to alectinib, and the vast majority will have disease control for a fairly good period of time — again, the average is somewhere in the eight to ten month range, but many patients longer than that, and at least in published results, alectinib may be easier to tolerate than the Zykadia.

So this is just the tip of the iceberg. At last count, I think there were six or seven other next-generation ALK inhibitors in development — I don’t have time to list all of them, and none of them have been compared to one another to know which one is best, but all of them, at least preliminarily, appear to be effective in the setting of acquired resistance to crizotinib.

What I would recommend in 2015 is, if patients develop an acquired resistance to the Xalkori, that they preferentially enroll on a clinical trial of one of the new next-generation ALK inhibitors because I think this is the only way we’ll ever learn which of them is best and which one works the longest. But, if you don’t have a clinical trial available to you, or you’re not eligible for a clinical trial, your doctor can prescribe Zykadia right now and we know that’s an effective treatment.

The other thing that’s nice about these drugs is that they all seem to have some activity in brain metastases. We know that ALK-positive patients develop brain metastases at an extremely high rate, and this can be a real problem, sometimes even while the rest of the cancer remains under control. Both alectinib and Zykadia have been shown to have efficacy in brain metastases, in addition to the rest of the body — so, good news for ALK-positive lung cancer patients.


New Ideas and New Treatment Options for Acquired Resistance for ALK/ROS1




Xalkori (critzotinib) was the first approved treatment for ALK+ and ROS1 lung cancer. Since then, other drugs have been approved or are currently undergoing scientific review. In this video, Dr. Owonikoko outlines these options for patients.

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Can or Will Specific Molecular Characteristics Help Determine Which ALK Inhibitor to Choose?




Drs. Leora Horn, Ben Solomon, & Jack West review whether there are specific factors that should make one second generation ALK inhibitor more ideal than other competing options for a specific patient with an ALK rearrangement.

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Dr. West:  Where does this leave crizotinib — a drug that still has activity that can be long-lasting for many patients, tends to be less active, though, than any or all of these second generation ALK inhibitors, and with less activity, but not none, in the brain. So, does your view change, that you would be inclined to move these second generation inhibitors up front, if they’re paid for, or would you still favor giving crizotinib until progression, and then getting whatever you can get from a second generation inhibitor; Leora?

Dr. Horn:  So, we have trials that are going to answer that question, and it’s similar to with the EGFR front line trials, where I think the combined survival, when you’re on crizotinib, and then you get a second generation inhibitor, should be combined, compared to getting that second generation inhibitor up front. And, so, I heard this meeting, that the ALEX trial is closed, the 396 phase three trial is going to be opening, and so, we have studies that are going to answer these questions for us.

Dr. West:  But it would have to be, when we’re looking at progression-free survival, a statistically significant difference of four months, maybe enough to declare a winner as first line therapy, but that’s not the same thing as showing it’s the better strategy, compared with sequential first line crizotinib, followed by second line, second generation ALK inhibitors.

Dr. Horn:  Correct, or can we see that, you know, 50% of patients on the second generation inhibitors do not get brain metastasis? You know, that will be something that will be meaningful.

Dr. West:  And for you?

Dr. Solomon:  Yeah, no, so I think crizotinib is a great treatment, and I think there’s — we still have patients who are on the original phase one trial of crizotinib, continuing on crizotinib…

Dr. West:  You’ll retire before then!

Dr. Solomon:  That’s right, I hope! I think that is the current bar, and I think the standard first line treatment for patients with ALK rearranged lung cancer, at present, is crizotinib…

Dr. West:  Which is also, often, very well tolerated.

Dr. Horn:  Yes.

Dr. Solomon:  Yeah, and I do think the ALEX trial will be an important trial, because alectinib is another really well tolerated drug which does have better brain penetration, and I think that result will be an important result. But, again, I think we need to see how the data pans out, and I think we need to show that these drugs are better than crizotinib before moving them into first line.

Dr. West:  How would you approach a patient who is on Xalkori (crizotinib) in the first line setting, and develops two small brain metastasis that you can treat pretty readily with stereotactic radiosurgery, Gamma Knife, CyberKnife, and continue them on Xalkori, if they have no progression outside of the brain, or are you inclined to change them to a second generation ALK inhibitor with the thought that it has better penetration in the brain? Ben, why don’t I start with you?

Dr. Solomon:  Yes, so, in that particular instance, I think if the disease outside the brain was still really well controlled, and they were tolerating the crizotinib well, and my radiation oncology colleagues thought that those two lesions were suitable for stereotactic radiosurgery, I would go ahead with the stereotactic radiosurgery and continue the crizotinib. I think it would be a different situation, either if they had disease that was starting to progress outside the brain, or if they had multiple brain metastases that needed whole brain radiotherapy, and in that context, when we know that there are agents that can work in patients progressing on crizotinib, or that might work better in the brain, and therefore delay the time for them to need to have whole brain radiotherapy, that’s probably my trigger to switch.

Dr. West:  Your thoughts?

Dr. Horn:  I agree, I’d do the same.


Are There Clinically Significant Differences Among the Second Generation ALK Inhibitors?




Drs. Ben Solomon, Leora Horn, & Jack West evaluate the evidence and consider whether there are clinically significant differences among the second generation ALK inhibitors that would lead to a reason to prefer one over another for a particular patient.

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Dr. West:  Let’s talk about ALK rearrangements; they’re present in about 4 or 5% of the population, at least outside of Asia, and we’ve gone from, just a few years ago, having one agent, crizotinib (Xalkori), as the first line treatment, to now having a plethora of second generation ALK inhibitors. Are they clinically significantly different, and is there a reason to select one over another for an individual patient? Ben, what do you think?

Dr. Solomon:  So, we know that they’re different in terms of how they work in the lab. Some of the second generation compounds are more potent inhibitors of ALK itself, and can work against some of the mutations that make tumors resistant to crizotinib, and the other difference that’s emerging in the clinic is, some of the second generation inhibitors seem to have better activity in the brain than crizotinib does. So, I think there are some significant differences, and we know from trials that some of these drugs, so, ceritinib, alectinib, and brigatinib, can work in patients whose tumors have progressed on crizotinib, and do have pretty impressive activity in the brain.

Dr. West:  Leora, what do you think? Is there one second generation ALK inhibitor you’d favor, based on its therapeutic index, or unusually good activity in the brain, or is it what’s on hand?

Dr. Horn:  So, right now, the only thing on hand is ceritinib, but as more drugs become available, I think toxicity may, again, be an issue with ceritinib being a little more toxic in terms of GI side effects than what we’ve seen with alectinib. I’m obviously biased to X396 because we’ve been leading that development for a while, and, you know, we’ve seen that it’s well tolerated, and has CNS (central nervous system) penetrants.

Dr. Solomon:  Sorry Leora, I should have added that onto the list, too.

Dr. West:  I mean, the challenge is that it gets harder and harder to penetrate into a crowded market. Can a new drug, like X396 or brigatinib, after alectinib — can these drugs differentiate themselves when there are already various alternatives out there?

Dr. Horn:  Yeah, so I think what’s interesting and different about ALK, than we see with EGFR — with EGFR we do have multiple third generation inhibitors, but they’re all targeting T790m. When patients develop resistance to crizotinib, it’s a much messier story, and there are multiple reports coming out of patients getting a second generation inhibitor, and then progressing and subsequently responding to a different second generation inhibitor. I think that an inhibitor that has good CNS penetrants is going to be interesting, even upfront, because we know that 50% of patients on crizotinib will have CNS disease as their first site of progression, but I think time will tell if there’s one second generation inhibitor that’s really going to win out.

Dr. West:  So, are you optimistic that, in the relatively near-term future, we’ll be able to characterize the mutation in acquired resistance, and select one form of second generation inhibitor for one patient and a different one for another?

Dr. Solomon:  Yeah, so I think there are certain instances where you can define a mutation and then say that mutation is covered by, for example, ceritinib, but not alectinib, or vice versa, and make a choice based on that. But, for many patients who progress on crizotinib, we don’t find mutations, and these drugs are still active, so that won’t be the entire story. So, how to choose between the inhibitors, if they’re all available, will come down to toxicity, but we might have some clues based on mutation profile, as well. But I’m not sure that will be the sole way that we’ll be able to make a rational choice.

Dr. Horn:  And I think it will come down to cost, as well.

Dr. West:  But they’ll probably be priced comparably enough that there won’t be one that’s way more appealing for cost considerations.

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