Advances in Treatment for ALK-Positive NSCLC - Episode 8

Second-Line Treatment for ALK-Positive NSCLC


Robert C. Doebele, MD, PhD: Using brigatinib following progression on crizotinib has been a very meaningful improvement for our patients who were started on crizotinib. We know from multiple studies of ceritinib, alectinib, and brigatinib that brigatinib appears to have the greatest efficacy in patients who are ALK-positive who failed crizotinib, with a PFS [progression-free survival] of approximately 15 to 16 months, and also very good CNS [central nervous system] control. This is almost double of what we see with ceritinib and alectinib in terms of progression-free survival. In my opinion patients who were on crizotinib and progressed, brigatinib is the preferred option for my patients.

Thomas E. Stinchcombe, MD: Brigatinib is available in the second-line setting and this was investigated in the randomized phase II trial that looked at 2 different doses of brigatinib — 90 mg, or 90 mg for 7 days followed by 180 mg. And it showed a good response rate around 50%, 60%, and the progression-free survival on the 90 mg followed by 180 mg was around 16 months, which is longer than other second-line trials, although there might be differences in patient population. And I think this is really promising that it has shown very high activity at this point. Brigatinib was designed to hit many of the ALK resistance mutations and so it makes sense that after crizotinib that it would have high level of activity in the patients who progressed.

Brigatinib was approved in the second-line setting based on a randomized phase II trial. It investigated 90 mg daily or 90 mg followed by 180 mg daily. The response rate was around 50% or 60% in this setting, and the progression-free survival on the 90 mg followed by 180 mg was 16 months which was longer than previous second-line trials, understanding that there might be some differences in patient population enrolled with that figure. I think it’s showing promising efficacy at this point. They also looked at the CNS penetration. The response rate was very similar to the overall response rate, around 50%, 60%. ..... patients with a brain metastasis of 1 cm, who were asymptomatic could enroll. This was sort of a primary treatment of ..... brain metastasis. And the CNS progression-free survival is very promising, so I think that this demonstrates that the drug does have CNS penetration and more importantly, CNS activity.

Robert C. Doebele, MD, PhD: The data that are needed to understand how to treat patients post—second-generation inhibitors is, first, response rate, and second, duration of response, or progression free survival – how long does this benefit last?

I think the sub-analysis that we need to understand, related to resistance mechanisms, is, does it differ by the types of mutations that we’re seeing in ALK, or whether or not they have ALK secondary kinase domain mutations. I think we’ve started to see this now with some small trials of brigatinib post—next-generation inhibitors where we’re seeing response rates in the range of 20%to 40%.

With lorlatinib we’re seeing response rates in the range of about 40% post­­—next-generation TKIs. And there’s an example of where the response rate appeared to be higher in patients who had an ALK secondary kinase domain mutation than in those that did not. And that biologically makes sense based on what we know about resistance – those patients who have ALK kinase domain mutations are more likely to have tumors that are still dependent on ALK signaling. Those that don’t have ALK kinase domain mutations are much more likely to have bypass signaling and may not respond to an ALK inhibitor because their tumor may rely on other signaling pathways.

I think it’s still reasonable to treat ALK-positive patients who have received a second-generation inhibitor with lorlatinib based on the data that we have, although I think it’s important to be aware that if they don’t have a secondary kinase domain mutation, their chance of response may be lower. Probably not zero because of issues around detection and other things, but it’s likely to be lower.

Thomas E. Stinchcombe, MD: So, with the promising preclinical data with brigatinib having activity against many of the ALK resistance mutations, we were very interested in exploring it in the post-next-generation ALK TKI [tyrosine kinase inhibitor] setting. I’ve worked with my colleagues at Vanderbilt as well as University of Colorado and UT [University of Texas] Southwestern, and we developed an investigator-initiated trial. At the time we designed this trial, we were anticipating alectinib would become the preferred agent in the frontline setting, and clinically we were going to need to know if brigatinib had activity post-alectinib, or post any next-generation ALK TKI.

This was a prospective trial. Patients were eligible as long as they had received one next-generation ALK TKI. When we looked at the patients to date, the median number of lines of therapy are three ranges, 1 to 6. And the trial used a 2-stage design. We’ve completed the first stage of 20 patients, and 8 out of the 20 patients have had confirmed responses for response rate of 40%. We’re demonstrating activity as well. Many of these patients had a CNS progression before going on the trial or a brain metastasis, so it’s consistent with a very heavily pretreated population. I think it’s very interesting that it’s shown activity.

We’re looking at the progression-free survival right now, it’s around 7 months, but importantly the trial is very early, and so that progression-free survival is immature at this point. And so I think that this trial will complete accrual at this point, but we’ve made some modifications of the trial as well. We are now doing it just in a pure post-alectinib patient population because I think that will most likely reflect clinical practice. And then many of the patients we were enrolling had received multiple lines of therapies and probably had multiple mechanisms of resistance, some, ALK-dependent, ALK-independent. And we think if it’s a more homogeneous patient population in the post-alectinib setting, we might see more activity at this point.

Importantly, we are collecting tumor biopsies and ctDNA [circulating tumor DNA] on all these patients enrolled. The tumor biopsy has to be done prior to starting enrollment, so it will accurately reflect the ALK resistance mutations at the time we initiate the brigatinib. I think that we’re going to learn a lot about the molecular characteristics of the patients who are responding. And Dr Robert C. Doebele [,MD, PhD,] of University of Colorado is running those analyses.

Another aspect of the trial is adding a third cohort, and this is going to investigate brigatinib at 240 mg, and it’s going to enroll patients who tolerated a 180-mg dose of brigatinib and maybe had progression. And the hope is with escalating the dose, we might have some additional responses. I think this will be particularly intriguing in the patients who maybe have disease control outside of the brain, but then have CNS disease progression. If we can escalate the dose, improve the blood-brain barrier penetration, will we be able to get control of the brain metastasis? I think we’re very eager to enroll this, and patients can come from the community as well. If you get brigatinib in the community, you can come to us and we’ll enroll you in this dose escalation cohort.

I think what we’ve seen with the trial pending is that there’s a clear signal of activity. I think we’re all eager to do a couple things on the trial, 1) identify the patients who are most likely to respond, whether that be through molecular characteristics that predict response to brigatinib, or their certain clinical characteristics such as CNS disease progression versus non-CNS disease progression that are more likely to respond. We’re eager to get the duration of response, as well as the progression-free survival data because I think those analyses right now are immature. But we really would like to see a prolonged progression-free survival at this point.

Transcript Edited for Clarity