Benjamin Levy, MD: Let’s talk about CNS [central nervous system] disease, ALK-rearranged lung cancer does have a proclivity to go to the brain. This is not an uncommon event like we see in the EGFR-mutated lung cancer patients. Josh, some comments on how you manage CNS disease for ALK-positive patients, trust the drugs, hold off on whole brain. Is there a particular agent, and Ross, maybe you can comment as well, on which drugs may have better activity in the brain?

Joshua Bauml, MD: This is a similar story to what we were talking about before with osimertinib. Both brigatinib and alectinib have fantastic CNS penetration, and we saw in the trials that were presented there were CNS responses, there was control of disease. Also, like the osimertinib story, changing from erlotinib/gefitinib, which don’t have great CNS penetration, and crizotinib, which doesn’t have CNS penetration, to newer drugs that do. I do tend to trust in the drugs, and I’ll say if a patient has brain metastases, I will start them on the TKI [tyrosine kinase inhibitor]. We’ll work closely with the neurosurgeons, the radiation oncologists as needed, for monitoring closely, but avoiding whole brain radiation therapy at all costs, and seeing what we can do with the drug and maybe some SRS [stereotactic radiosurgery].

Benjamin Levy, MD: Ross, you presented the data at World Conference on Lung Cancer and subsequently published. Is there a hint that brigatinib may have better CNS activity than alectinib, or we just don’t know?

D. Ross Camidge, MD: Again, it’s hard to compare. But with the caveat again that you’re expecting the data to look slightly worse because it’s more immature. And yet, the hazard ratio among those with brain metastases was already better than alectinib. Alectinib was 0.4 at the same time, and this was 0.2. They’re just amazing numbers. Although I have to say, I don’t think either of them is the best drug in the brain. I actually think lorlatinib is the best drug in the brain. It’s quite phenomenal how much of it gets in. And I’ve had patients who, although they’ve done fabulously on alectinib or brigatinib when they progress in the brain, lorlatinib can salvage them in the brain, that is its real strength.

Benjamin Levy, MD: I have interestingly not used brigatinib that often. I’ve stuck to alectinib. I’m curious to see what brigatinib would do in a treatment-naïve patient, compared to what I see with alectinib. You obviously have a little more experience. But we’ll see. It would be interesting to see how these data shake out and how the mature data come out with the brigatinib.

Zofia Piotrowska, MD: Or even if lorlatinib moves to the first line.

Benjamin Levy, MD: A crowded space. Let’s talk about different drugs and sequencing and how we do that. Patients obviously, they’re on alectinib as standard of care. What do we do next? Do we biopsy all patients post-alectinib, or brigatinib? Do we do plasma genotyping on these patients? What’s your common practice? What’s the message to the community?

D. Ross Camidge, MD: If you’re…like the vast majority of people who are ALK-positive and they start now, and they’re going to start on alectinib and then they progress. And sure, there are going to be some situations where it’s oligoprogression, you’re going zap with radiotherapy and keep them on the drug. Because why move away from a good thing if it’s just a tiny little bit that’s growing?

The only licensed drug post a next-generation inhibitor is lorlatinib, where it probably has about a 40% response rate. The FDA label is actually somewhat misleading. It quotes a 48% response rate, which includes people who’ve only had crizotinib, which is actually not in the label and they do better so they float up that number.

But I actually don’t rebiopsy. For research purposes we’ll rebiopsy and we’ll send them to Bob’s laboratory. But we don’t need to because what’s your choice? I’m going to go on lorlatinib or chemotherapy, and so I’m just going to try the lorlatinib.

Robert Doebele, MD, PhD: One of the exciting trials that’s now just being activated is ALK Master Protocol to try and really formally look at this. Because none of the labels mandate that you biopsy or have a particular resistance mutation. I think we think we understand a lot about how to match these drugs and which ones are resistant to which. But the ALK Master Protocol I think is going to help us answer I think a lot of intriguing questions.

Like what happens if you don’t have a mutation? Is lorlatinib the best option, or is chemotherapy? What happens if you have MET and some of these other options? Also, it’s going to answer the question of tumor versus ctDNA [circulating tumor DNA], we’re going to look at correlations in them. I think that might help us. But I think right now it’s very reasonable to just proceed to another ALK TKI in the absence of a biopsy. I think we’re learning a lot from this and it’s ultimately going to help us treat our patients better, but right now you don’t have to do it.

Joshua Bauml, MD: I would say that lorlatinib is different from alectinib and brigatinib in that the toxicity is greater. I mean, the adverse effect profile is worse. If I had a biopsy that showed that there was a resistance mutation, which at least in vitro is sensitive to brigatinib, I would be tempted to, rather than switching them to lorlatinib, to give them brigatinib.

Benjamin Levy, MD: What adverse effect profile are you concerned with, with lorlatinib?

Joshua Bauml, MD: Lorlatinib is associated with CNS effects, confusion, there have been reports of altered mental status situation, as well as elevated lipid panels. That doesn’t worry me as much, but the confusion and altered mental status is, as we discussed, our patients were living with these adverse effects for a very long time, and if I can avoid having to expose someone to that toxicity profile, I would like to.

Benjamin Levy, MD: Yes.

Zofia Piotrowska, MD: I agree. I think it’s something that can be problematic for patients, usually managed with dose interruptions and sometimes dose reduction. But it’s a unique adverse effect I think among the drugs that we’re used to seeing and something that requires counseling and close communication with patients. It’s not so much the patient who comes in and complains about it, but it’s the family members who say, “They’re just not quite themselves.” And it’s something that patients don’t always attribute to drug until you say, this really is drug related. They say, well….

D. Ross Camidge, MD: It’s kind of mood and personality, but even the speech slowing. I’ve never had a drug where I can tell what drug someone is on just by talking to them. Because there’s a very distinctive speech pattern they have.

Zofia Piotrowska, MD: But generally, manageable for most patients I think with dose interruptions and dose adjustments. I think it’s something to watch for, but not prohibitive in the majority of the patients.

Benjamin Levy, MD: If patients are started on alectinib, this is backing it up a little bit and high level clinical overview, the next drug to treat them with, everyone’s in agreement the data are most with lorlatinib would you say?

D. Ross Camidge, MD: At this ASCO [American Society of Clinical Oncology meeting] we saw a 104 patient study from France that showed a 50% response rate with brigatinib, post next-generation inhibitors. We saw a smaller study that Bob and I were associated with that had a 40% response rate post next-generation inhibitors. Last World Conference on Lung Cancer, we had a poster that showed a 70% response rate with brigatinib. And then there’s a smaller study that showed a 17% response rate. So clearly there’s heterogeneity.

Benjamin Levy, MD: Right.

D. Ross Camidge, MD: But at least the nice thing is that as these small datasets start to move, it’s moving more toward the middle, a sort of 40% to 50% response rate.

Zofia Piotrowska, MD: It probably depends on some, that spectrum of resistance mutations, right? I mean that’s where the biopsies would probably help you figure out.

D. Ross Camidge, MD: Yes, if you put all the wrong patients on, you have a 0% response rate.

Joshua Bauml, MD: But I feel like the way that the ALK trials have been structured has been independent of the resistance mutation. I think that was probably driven by the fact that in crizotinib, because many patients who progressed on crizotinib did not have a resistance mutation because the affinity for ALK wasn’t very high, so you weren’t really pushing on that, you weren’t developing resistance. Everyone was responding to the next one, so we didn’t need to limit. And now, as a result we have these indications, and I feel like we’re flying blind. What I see when we see 17% and 70%, it’s more like what Zofia was describing. I have no idea who these people are, and I think that it implies to me that having that biopsy and resistance data would be critical to gather.

D. Ross Camidge, MD: What I think most of that is, if you look at the data that came out with lorlatinib, that if you could find a mutation, you had a 60% response rate, and if you couldn’t, you had a 20% response rate. Now 20% tells me we’re not as good at finding mutations as we think we are, but clearly that’s part of who determines....

Joshua Bauml, MD: Yes.

Robert Doebele, MD, PhD: That gets back to the question of what’s the best therapy? Because if it’s really 20%, then chemotherapy might be a better option and that’s something that this new trial, the ALK Master Protocol, will answer.

Benjamin Levy, MD: So many questions to answer seeking-wise, and this genotype.

Zofia Piotrowska, MD: So much to talk to for 2 years.

D. Ross Camidge, MD: We’ve got another 3 hours to talk.

Transcript Edited for Clarity