Factors to Consider in Choosing ALK TKIs in Frontline Setting


Robert C. Doebele, MD, PhD: When patients are diagnosed with an ALK gene fusion, they have multiple options for frontline therapy. We know from multiple studies that receiving an ALK TKI [tyrosine kinase inhibitor] leads to better outcomes than receiving chemotherapy. The front-line therapy should be an ALK tyrosine kinase inhibitor, but we have multiple options. Crizotinib was the first ALK TKI approved. And while that was far superior to chemotherapy, we now know that there are several other agents that work much better.

Ceritinib has never been compared head-to-head with crizotinib, so we don’t really know truly if ceritinib is better than crizotinib, although I think most of us suspect that it is based on cross-trial comparisons between the 2 drugs. For example, the median progression-free survival for crizotinib when it was compared with chemotherapy was only in the range of 11 months, which seemed shorter than the 16 months that was observed in the ASCEND-4 trial.

Now with newer drugs, such as alectinib, we do have a direct comparison, and so I think we can clearly say that alectinib is far superior to crizotinib in terms of patient outcomes. While the response rates are slightly better for alectinib, the real meaningful benefit is how long patients can stay on therapy, the progression-free survival. There, again, dependent on which reporting you’re looking at, whether it’s investigator-reported or blinded review, the progression-free survival was in the range of 27 to 34 months. And so now we’re talking about progression-free survival in the 2- to 2½- to nearly 3-year range. And with crizotinib, it was far shorter than what we would expect in the 10- to 11-month range.

We know, now, that alectinib is really a superior frontline ALK TKI option for patients who are newly diagnosed with an ALK gene rearrangement. And although I think ceritinib is an option, because we don’t have that head-to-head comparison, alectinib seems like a more obvious choice given the data that we have.

Thomas E. Stinchcombe, MD: In the frontline setting, I think we really look at sort of the parameters of objective response rate, and those have been relatively similar in the first-line setting. Then we defer to, I think, 2 critical endpoints, the progression-free survival endpoint, as well as the CNS [central nervous system] penetration. Right now, I think alectinib serves the preferred agent because it has 2 phase III trials, and on these trials, they’ve shown a significant improvement in progression-free survival. On 1 of the trials the, long-term follow-up of median progression free survival is about 35 months, which is very impressive in solid tumors.

We know that with alectinib, the rate of brain metastases at 1 year is about 10%; with crizotinib, it’s around 40%. I think the ability to prevent brain metastases is one of the strengths.

I think that it also has a relatively favorable toxicity profile. I think that we’re going to see ceritinib is available. It has a reduced dose of 450 mg, which reduces some of the nausea and vomiting. We probably tend to use that less frequently. And looking forward, we think that brigatinib will probably be approved this year. And I think we’ll look at the median progression-free survival, the toxicity profile, and do sort of a dreaded cross-trial comparison between alectinib and brigatinib.

David Spigel, MD: When a patient comes in with an ALK-rearranged lung cancer, for me for now, the choice is alectinib. That’s a drug that I’m most comfortable with in terms of talking about its efficacy, its value to a patient, what I expect to happen with a patient. And if the safety is manageable. I’m still getting surprised every now and then with toxicity issues, and we were involved in the ALEX trial. And I still learn from that. It’s interesting because when I was getting into crizotinib use years ago I felt like there was an early learning period, and then you got comfortable and it got pretty vanilla.

Alectinib—I expected it to be just like crizotinib, but actually it’s been easy. But then later toxicities seem to present themselves: fatigue, myalgias, edema. And so that’s been a little bit of a challenge for me, but I’ve been able to manage it by adjusting the doses.

I don’t think about ceritinib because I have alectinib, but I think there was certainly a time we had people lining up around the block to get access to a drug like ceritinib on studies. You kind of feel bad for that drug that you turned to and was your favorite person to invite to the party at 1 time, because now we’ve left poor ceritinib by the wayside and have gone to alectinib.

But I think all these drugs probably will be in the toolbox, and that’s a great problem to have. We have brigatinib as well. We have lorlatinib as well. And at least for me, I can see going through that toolbox sequentially at different times for a patient might be of value before necessarily going to a systemic therapy like chemotherapy.

Everything seems to find its way into the standard of care in the refractory setting first and then moves in to the first-line setting. We have great data sets in the second line setting, specifically with drugs like brigatinib and even alectinib and ceritinib back in the day. Right now, I think, I think this question about how you sequence drugs for me is based on how the drugs are approved. We have alectinib first line, brigatinib second line. And so for me that’s a natural sequence to think about how to use these drugs. Even though we don’t really have data to tell us that that’s OK to do, there’s an ongoing actually phase II study we’re involved in looking at the role of brigatinib following alectinib.

When brigatinib finds its way into the first-line setting, and we all think it will soon, because brigatinib beat crizotinib pretty handily in an ALTA-1L trial, phase III study. I think, then, things get a little bit more interesting in terms of: Are there some patients we would give brigatinib first to? And then what do you do next? Is that lorlatinib? Is that alectinib? Or are we just going to stick with this paradigm of alectinib followed by brigatinib?

It’s really an interesting and a good problem to have, that we have choices like this. I don’t think we were so sure we would have this problem years ago when all these were being studied. I think we were just desperate to find the next-best drug. And it’s interesting that we have ended up in this situation with a lot of good drugs. I’m not sure how to sequence them and when to use them. We think maybe genomic testing, looking for resistant mutations, can guide us. But even there we’re struggling with understanding how you really apply that in real practice and make decisions based on a blood-test or a tissue-test result? But I think in the next few years, we’ll get closer to solving how to sequence these appropriately.

Transcript Edited for Clarity

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