Emerging Treatment Options for Patients with NSCLC with ALK Rearrangements

Transcript:

Martin Dietrich, MD, PhD: Shifting into a targeted therapy only space: ALK rearrangements, we’ve seen some updates for 2 of our first-line agents. Dr Brahmer, maybe you can start giving us an overview of what has been recently published by D. Ross Camidge, MD, PhD, about brigatinib, where this fits in, and how you choose.

Julie R. Brahmer, MD: Sure. This year at ASCO [American Society of Clinical Oncology Annual Meeting], Dr Camidge presented a poster on the ALTA-1 and the J-ALTA. And these were in TKI-naïve, ALK-positive patients. And it combined these 2 trials and gave us some nice 2-year data, intracranial data, and duration of response data across these 2 trials. And I think the median progression-free survival of nearly 3 years—it was 29 months, with a 2-year median progression-free survival of about 55%—and the response rate was nearly 80% and had approximately a 20% complete response rate and also showed activity in the brain as well with a 13% complete response rate in the brain. I think that really is helpful to know that we have long-term duration of response of just over 3 years and a 57% 2-year duration of response, and the overall survival at 2 years of these combined trials was approximately 79% with a 3-year overall survival at 74%, which in this patient population is amazing. I also think the median progression-free survival for those patients with intracranial disease was about 44 months. And in general, brigatinib remains easy to tolerate. Most of the adverse events were asymptomatic laboratory abnormalities. There was still, regardless of the differences in dosing, particularly when you first start brigatinib, about a 7% rate of interstitial lung disease here. So, I think brigatinib is another option in the first-line setting. I still use a lot of alectinib just because it’s so easy to use. And then obviously we’ll hear some lorlatinib data as well, because that’s a good option too.

Martin Dietrich, MD, PhD: Dr Sabari, maybe you can fill us in on lorlatinib in the long-term follow-up with some quite impressive information.

Joshua K. Sabari, MD: We saw an updated presentation and publication by Benjamin Solomon[, MD,] with lorlatinib, and this is in the CROWN trial. Very similar to how Dr Brahmer explained brigatinib vs crizotinib, this study is lorlatinib vs crizotinib, and I think it’s important to note that crizotinib was the standard of care many years ago and is not currently the standard of care. It’s very hard to interpret this data in the era where we are commonly using alectinib in the frontline setting. A couple of things really stood out to me in this update of lorlatinib. First off, patients received 100 mg daily of the medication of lorlatinib, and at a median follow-up, a duration of follow-up of over 36 months, they still had not reached median progression-free survival. That’s quite impressive. That’s over half of patients remain on therapy without progression at 3 years. That’s where we need to get with KRAS and all our other driver alterations. The median progression-free survival for crizotinib on the other end was 9.3 months, which has performed similarly in other clinical trials. One of the unique things about lorlatinib is that it has phenomenal CNS [central nervous system] penetration, probably best in class, and we saw an update from the Japanese cohort from Dr Hayashi showing an 100% response rate in the CNS as well as having long-term durable responses in the CNS. I think one issue with lorlatinib, and we’ve all experienced this in our clinical practice, is it has a unique toxicity profile: hypertriglyceridemia, hypercholesterolemia, weight gain, but most importantly, the mood and cognitive changes that not our patients are telling us but our patients’ families. And generally, when I start this agent, especially in older patients, I generally do dose reduce to 75 mg daily. And I think we need better guidance on these cognitive toxicities here. But clearly in a patient with CNS metastases up front, this is one of your best options for long-term durable CNS response.

Martin Dietrich, MD, PhD: We’ve seen some very compelling data for brigatinib and alectinib, and I think efficacy-wise, and if you look at the comparator arms, it seems like there [are] similar study populations based on the intrinsic crizotinib controls; they’re hard to compare. But now lorlatinib [is] coming in with this very impressive data and with this unique adverse effect profile.

Transcript is AI-generated and edited for clarity and readability.