Second-Line Therapy in ALK+ NSCLC

Mark A. Socinksi, MD:I wanted to get your perspective on brigatinib as a drug. One of the exercises that we recently went through, realizing that many patients diagnosed withALKmay still be on crizotinib, was determining what the best drug was to use after crizotinib. When you look at individual phase II trials, at the ceritinibs, the alectinibs, and brigatinibs that are out there, you get the sense that brigatinib has the best PFS [progression-free survival]. You could make an argument that it’s not even close, and that brigatinib seems to be the most active in that setting. Do you have thoughts on that? I know you can use any one of these after crizotinib. Do you have a preferred one after crizotinib?

Thomas E. Stinchcombe, MD:I don’t really have a preferred one. I have to admit that this patient population is pretty rare in my clinic now. I’d probably sit down in this situation and talk about alectinib or brigatinib with the higher PFS, but the unique toxicities versus alectinib, which are fairly well tolerated. I think it’s really a dealer’s choice depending on patient and physician preference at this point.

Mark A. Socinksi, MD:So at ASCO [American Society of Clinical Oncology annual meeting] 2019, you had some preliminary data on brigatinib after other ALK inhibitors. Can you walk us through that, because that’s an interesting comment about sequencing?

Thomas E. Stinchcombe, MD:I think when this trial was designed, we knew that alectinib was soon going to be adopted as the first-line therapy. And the inevitable question was, what do you do after alectinib? Brigatinib, preclinically, has activity against a lot of these ALK resistance mutations and has very promising second-line data. So we developed an investigator-initiated trial along with the group at Colorado. It investigated brigatinib after any next-generation ALK inhibitor, and we deliberately kept the eligibility criteria very loose, no line on the number of lines of therapies. It was really designed as a single finding study. We had completed the first stage and we presented the data at ASCO. The median number of lines of ALK-directed therapies was 3, with a range of 1 to 6.

Mark A. Socinksi, MD:I’m surprised at that. I didn’t think it would be 3, but it is what it is.

Thomas E. Stinchcombe, MD:It is what it is. I think a lot of these patients had been heavily pretreated in the community and they were coming in to look for a novel therapy. It was a 2-stage design, so this is the first 20 patients. So preliminary data, but 11 of the patients had brain metastases. Importantly, we saw 8 confirmed responses out of the 20, so a response rate of around 40%. The median progression-free survival is 7 months now, but the number of events is relatively small. So that PFS median may adjust over time with longer follow-up. We have not seen any significant toxicity beyond other trials at this point.

Mark A. Socinksi, MD:Brain activity? You mentioned how many patients had brain metastases? Do you remember?

Thomas E. Stinchcombe, MD:Eleven of 20.

Mark A. Socinksi, MD:That underscores the problem with brain metastases, right?

Thomas E. Stinchcombe, MD:Yes, especially in this heavily pretreated population. And I think preliminarily, when we look at the PFS in the brain metastases population and those without brain metastases, it is very similar at this point. But the numbers are relatively small. You divide 20 by 11 in subsets. But the concept is that it’s shown some activity and some promise in this setting.

Mark A. Socinksi, MD:I think that this is an incredibly important trial. How many patients do you plan to enroll?

Thomas E. Stinchcombe, MD:In this cohort, we’re going to enroll a total of 40. We’re already moving to the second stage. And then, as we were doing the trial, we realized that we might go into a more homogeneous patient population. So there’s a cohort B, as we call it, that looks at 40 patients who just had alectinib in the first-line setting.

Mark A. Socinksi, MD:And nothing else?

Thomas E. Stinchcombe, MD:Nothing else. The thought is that the ones in cohort A had multiple mechanisms of resistance or heterogeneous mechanisms of resistance, and we needed to get a more homogeneous patient population and one that reflects clinical practice more clearly. Then we’ve added a cohort C, and this is interesting because patients will be on brigatinib, 180 mg. Then, if they experience disease progression, CNS [central nervous system] or extra-CNS, they’ll get an escalated dose of 240 mg of brigatinib to see if better CNS penetration can induce responses or disease control.

Mark A. Socinksi, MD:Is that specifically for brain metastases or any progression?

Thomas E. Stinchcombe, MD:Any progression. They can come from the community, be on brigatinib, and then come in to see us for the 240 mg cohort.

Mark A. Socinksi, MD:If I remember from the original phase I data, there were not necessarily any adverse effect or toxicity concerns at 240 mg with brigatinib?

Thomas E. Stinchcombe, MD:No, there were not. I think this is what allowed us to safely escalate. And this patient population was preselected for the people who tolerated the 180 mg dose, so I think that hopefully we won’t see any additional toxicities in that select group of patients.

Mark A. Socinksi, MD:It’s interesting. As you say, we established alectinib as the standard of care. The question is what to do next. We didn’t have a lot of data purely after alectinib. But one of the more recent ALK inhibitors, and we’ve had a number of them, obviously, approved in a relatively short period of time, is lorlatinib. And lorlatinib did have some interesting data after 1, 2, or 3 previous ALK inhibitors. What’s lorlatinib’s place in every dayALKlife nowadays?

Thomas E. Stinchcombe, MD:I think it’s a valuable addition because it was studied in a patient population that reflects clinical practice, where people are going through multiple ALK TKIs [tyrosine kinase inhibitors]. The response rate was around 40%. The median progression-free survival was around 7 to 8 months. I think the CNS response rate was very similar to the extra-CNS response rate, so it clearly has CNS activity. I think it has some unique toxicities. Some patients may have some neurocognitive problems when they initiate the therapy. That is the most prominent. It can cause some high cholesterol, so you have to make sure you check the cholesterol levels as well. Occasional neuropathy.

Mark A. Socinksi, MD:Those new drugs are making us into internists again.

Thomas E. Stinchcombe, MD:I know. The rash, the hypercholesterolemia. I thought I left that. I’ve used lorlatinib, and I think it is an interesting agent that will have a place because these patients are really cycling through multiple therapies over a period of years.

Mark A. Socinksi, MD:With now at least 5 drugs approved in this space, if we agree that the second-generation drugs have supplanted crizotinib, is there a role for crizotinib at any point in treatment moving forward?

Thomas E. Stinchcombe, MD:Crizotinib may have a role in patients who haveMETamplification as the primary mechanism of resistance. I think the problem withMETamplification is that you don’t know if it’s the passenger or the driver many times. Then the rare mutations, that might be the unique role. So I think it will still have a role, but it would be….

Mark A. Socinksi, MD:Very limited.

Thomas E. Stinchcombe, MD:In theALKspace, I don’t see it being used in the frontline anymore.

Mark A. Socinksi, MD:We talk about 5% to 10% ofEGFR-mutated patients progressing with histologic transformation, typically to small cell. Have we seen that inALK-positive disease?

Thomas E. Stinchcombe, MD:We’ve seen it in case reports. I think Dr Ignatius Ou published on this, and I think, interestingly, it seems to be lower. But I’m not sure if that’s just that we’re not looking or maybe….

Mark A. Socinksi, MD:Not rebiopsying.

Thomas E. Stinchcombe, MD:Yes. The other problem is we used crizotinib, which was less potent. So maybe as we have these patients on these more potent ALK inhibitors for years, mechanisms of resistance may change as we learn more.

Transcript edited for clarity.