Precision Medicine in Advanced Non-Small Cell Lung Cancer - Episode 11

Managing Resistance to ALK Inhibitors in NSCLC


Benjamin P. Levy, MD: We’ve talked a lot about different data points for different drugs: crizotinib, alectinib, brigatinib, ceritinib, lorlatinib. It really hammers home, again, how we’re struggling with what goes first and why, and what the scientific rationale is in terms of how we sequence. Alex, what do we know about resistance mechanisms and ALK? How does that kind of feed into what we sequence with?

Alexander Drilon, MD: In some ways, it’s similar to EGFR. And in some ways, it is different. It’s similar in the sense that when cancers with ALK fusions are treated with these pills, a proportion of them can acquire mutations that might affect drug binding. But at the end of the day, these fusions are still dependent on the ALK pathway. If you have a situation like that, where you have an earlier-generation drug and you acquire one of these mutations—the difference from an EGFR is that there’s no 50%, 60% that will acquire a gatekeeper—you see a smattering of different types of mutations across the board. But if you then get on to a better agent like lorlatinib or brigatinib that has activity against these mutations, there’s a reasonable chance that you respond—40%, as you mentioned. There are also cases that may lose dependence on ALK. As we’re moving these better agents into the first-line setting, we need to understand what the mechanisms of resistance are. As doctors, we probably need to be a little bit more careful, because there is a chance that you’ll have a higher proportion of patients who may not respond to another pill, especially if you don’t have the next best thing. In those cases, you would look into things like chemotherapy.

Benjamin P. Levy, MD: Are we in an era where we need to routinely biopsy these patients, through either plasma or tissue, to gain the insight? How do we do this?

Alexander Drilon, MD: I absolutely believe that on an academic level, we should be learning about resistance. However, I don’t think that we have enough data out there to say that it should be done routinely in the community, especially since the lorlatinib data reveal that there’s a 40% chance that patients will respond regardless of what the resistance was at that point in time. But the onus is on us [the investigators] to identify what these mechanisms of resistance are.

Benjamin P. Levy, MD: Yes. We’re just beginning to learn how to use this information to make subsequent decisions.

Transcript Edited for Clarity