ALK-Rearranged NSCLC: Updates From ASCO

Benjamin Levy, MD: Let’s move on to ALK which is yet another gene fusion, perhaps the first gene fusion in lung cancer that was actionable and targetable. Ed, we’ve come a long way. It’s a crowded space with multiple different drugs, and we’re trying to learn about how to sequence these drugs. And, if we can sequence these drugs, there’s a retrospective analysis from JTO [Journal of Thoracic Oncology] saying the median overall survival for stage IV ALK-positive patients is roughly 81 months which is incredible, speaks to the importance of the discovery of the gene and targeting it with the right therapy. You want to just bring us up to speed with where we are with ALEX, ALTA-1, and CROWN and how you interpret this data and how you use ALK TKIs [tyrosine kinase inhibitors] in the ALK space?

Edward Kim, MD, MBA: It’s a complicated area, especially when you start considering secondary mutations and what Dr Christine Lovly [Christine Lovly, MD,] has published on some of this where you’re looking for those secondary mutations and what may match up. It’s great. Again, I’m a more the merrier type of person, so ALEX was a great study that established alectinib in the first-line setting. It was alectinib vs crizotinib. This is another case where sometimes getting lucky is better. I’m talking about the field as crizotinib was the first standard. There were even discussions, you probably remember them. I guess I’m just talking to Dr Alex Spira [Alex Spira, MD, PhD, FACP]. Alex, remember when ALK was rare, it’s too small, and ROS1, why would we ever even want to target ROS1? It’s only 1% and it’s awesome that we have all this. The updated PFS [progression free survival] was .43, the median PFS was 35 vs 11, overall survival just killed it. It’s just a new standard. It has high CNS [central nervous system] potency. It’s easy to take. It was similar to the FLAURA data when it came out, we had 2 of these super drugs that had high penetration, high responses, and low adverse effects. And it’s still on the study. Thirty-five percent of patients are still on the study. It’s just unbelievable.

ALTA-1 was brigatinib. I was involved with some of this development. Again, going against crizotinib, PFS was 24 vs 11, with a hazard ratio of .43, very similar hazard ratio and a median follow up of 24.9 months. Again, another drug that’s out there being looked at. There were some dosing and toxicity issues early on, but they’ve gotten through those and it’s becoming more well used.

The CROWN data, now most recently, again approved earlier this year with lorlatinib, going against crizo [crizotinib]. Response rate is 76%, 12 months PFS of 78%, with no disease progression. They had ctDNA [circulating tumor DNA] looking at screening week 4, week 24 in the study and saw that maybe a reduction in this overall shedding of DNA by the tumors early on may associate with better response or PFS. Again, that’s the questions we have to be asking and then about resistance. And there’s a debate out there. What do you use first? What do you use second? I’m going to beat you to the punch, Ben, because I know you’re going to ask this question. I’m a traditionalist still. I’d still use alectinib first, but that’s not saying that the other choices are wrong. It’s just familiarity and trying to, we’re all trying to worry about what’s next, what’s the resistance pattern, and then what can we give to these patients.

Benjamin Levy, MD: Nice summary, Ed.

TRANSCRIPT EDITED FOR CLARITY