Available Choices in ALK+ Therapy and Rationale for Selection


David Spigel, MD: Lorlatinib is another modern ALK inhibitor, an interesting compound that, like many next-generation compounds, was designed to be better in terms of getting into the CNS [central nervous system] and to have greater ALK inhibition than the earlier-generation therapeutics. We now know that lorlatinib is an active drug and has an approved indication in a second-line setting. Its role beyond that is unknown. This is just like all the drugs. At 1 point we didn’t know their value in the first-line setting. A randomized phase III trial versus crizotinib has already been completed, and we await those results. And I’d expect that to look like the ALEX trial in terms of being better than crizotinib, or brigatinib being better than crizotinib.

Lorlatinib may have a little bit of a different toxicity profile. It has the same toxicities we expect with ALK inhibitors, and 1 I left off before is transaminitis. That can be another challenge for similar patients. This 1 can have a rare kind of mood-effect change for patients, and that can range from something that approaches confusion or delirium to just not being themselves, or not acting right. It’s not a common toxicity, and it was seen certainly at a higher-dose level in earlier studies. But I do think it’s going to be a unique toxicity, albeit rare that clinicians will have to kind of adjust and understand, something they aren’t used to seeing with, say, alectinib or brigatinib. But I think if it’s an active drug and the data continue to look good in the CNS, especially, I think it’s going to be another weapon in our armamentarium for fighting ALK lung cancer.

Lorlatinib right now competes with only brigatinib, in my view, as a drug to do after you’ve done something first line, and often it’s alectinib. Lorlatinib is a drug we’ve had as part of a clinical trial, and so we have some experience with it. But I’d say brigatinib for most of the community is going to be the choice because that’s the 1 that’s been around long enough for doctors to be more experienced with. Lorlatinib is a new drug, a new kid on the block, and it’s going to take some time to get adjusted to that. But I think like with anything, there will be folks who try it.

My guess is lorlatinib is going to be a third-line drug for most patients, and that doctors will follow the ABL sequence with it. And until we have data to show that lorlatinib should be used first line, I think that will be the likely sequence. And I think there will be some doctors who choose brigatinib, followed by alectinib, followed by lorlatinib. But we’ll see. I think it’s like anything. Anything we’ve ever done in oncology you’ve got to get comfortable with; these drugs can surprise you sometimes. You have to be comfortable giving medications that can help people but also hurt them, which none of us [wants] to do.

Robert C. Doebele, MD, PhD: When we’re considering second-line options for patients who’ve first been treated with a next-generation ALK inhibitor as a frontline option, so thinking about ALK-positive patients who received ceritinib or alectinib as their first-line ALK TKI [tyrosine kinase inhibitor], what are their second-line options upon progression? According to our FDA labels, the only 1 that has an FDA approval is lorlatinib. That’s FDA approved for patients who had either crizotinib and a next-generation inhibitor or a next-generation inhibitor. So we’re looking at on-label indications; that’s our best option.

Do we have any data with other drugs following next-generation inhibitors? Yes. There are emerging data from brigatinib that the response rates are in the range of 20% to 40% following alectinib or ceritinib. I think that those could become options, although technically they’re not FDA approved for that option.

If ALK-positive patients are first treated with the next-generation inhibitors—for example, alectinib or ceritinib—and they’re progressing only in the brain, we obviously want to use a next-generation inhibitor that has good CNS penetration. I think we have the most data to date with both brigatinib and lorlatinib, and it’s important to keep in mind that lorlatinib is the only FDA-approved option. But I think both of those would be reasonable options to consider in a patient who’s, for example, progressing on alectinib or ceritinib only in the brain. We know that both alectinib and ceritinib have good CNS penetration, so the progression that we’re likely observing is true resistance and not lack of CNS penetration like originally seen with crizotinib.

In terms of choosing drugs based on adverse-effect profile as a next-generation inhibitor following a frontline next-generation inhibitor, you may want to consider adverse effects. For example, both alectinib and brigatinib can cause creatine kinase elevation in the blood. If patients have that with alectinib, you may not want to choose brigatinib as your next drug because they may run into similar issues. I think keeping the unique adverse effect profiles in mind when moving to a new agent is important.

When choosing a second-line ALK TKI for a patient who’s started on a next-generation inhibitor—for example, alectinib or ceritinib—we can also think about using the resistance patterns as a way to choose the next line of therapy. If a patient is on alectinib and generates a G1202R-resistance mutation, lorlatinib may be the best choice. If you generate resistance via I1171 mutation on alectinib, you could use ceritinib, although brigatinib and lorlatinib also have activity against these, and so those would be reasonable.

If we have a clearly defined bypass signaling mechanism, it may be that 1 of these next-generation inhibitors will not work in the second-line setting. I still think it’s reasonable to try again with close surveillance and understanding that there’s perhaps a lower chance of seeing a response or long-term benefit in those patients.

Transcript Edited for Clarity

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