Benjamin Levy, MD: We all talked about this, and I’ll just throw it out there: to biopsy or not biopsy? If biopsying, do we use plasma or tissue? I’m probably the outlier here, but I’m a lorlatinib user, postalectinib. The data we have in the resistance setting indicate that patients who develop secondary mutations may respond better to lorlatinib than if they don’t. But even if they don’t, lorlatinib elicits response rates similar to chemotherapy. I have not been, off a trial, routinely biopsying patients. My experience is that the younger patients I have on alectinib have progression that’s a little different, and it’s a little more critical that we get going on a second-line therapy. We don’t have time to do the biopsy. What are people’s practices? I heard this peppered throughout this conversation, but does everyone on the panel routinely biopsy patients at progression? If so, is it tissue or plasma biopsy? Lyuda, I’ll start with you.

Lyudmila Bazhenova, MD: I do. I routinely biopsy them for 2 reasons. No. 1 is that small cell transformation has been described as an ALK resistance. I haven’t seen one, but there is a patient in our group who was found to have a small cell transformation. We did suspect it because the progression was very quick, so you do have some clinical factors. But 1 of the reasons to rebiopsy is to allow small cell transformation. If you have some acquired alternative pathways, that might sway me toward using a different drug. If I find a MEK amplification as a mechanism of resistance, could I go back and use crizotinib, for example, which has dual ALK and MEK activity?

Also, in the lorlatinib data, the efficacy of lorlatinib depends on whether you have a secondary ALK-resistant mutation. If you have an actual ALK-resistant mutation, then your response is 70%. To your point, if you don’t have an ALK resistance, the response rate is still 30%. You can still make an argument that we shouldn’t do the biopsy. I’m also 1 of the NRG-LU003 sites for the NCI [National Cancer Institute]–NRG Oncology ALK master protocol. It’s covered by the trial, so I’m not putting my patients at any financial risk by doing it.

Benjamin Levy, MD: Briefly, Josh first and then Becca, what are your thoughts on routine biopsy in this setting?

Joshua Bauml, MD: I view doing repeat biopsy at the time of progression on TKI [tyrosine kinase inhibitors] as the standard of care, regardless of which TKI I’m administering. Our data on mechanisms of resistance have been derived from seminal papers and fantastic work by single centers, but they are small series. What we see in those small series is a bunch of outliers. Each patient is unique. You look at something like RET fusion, which we’re seeing after resistance to osimertinib. We’re seeing these very rare alterations, and it’s critical to understand what is happening in the biology of the patient’s tumor because it can guide our care. It is very unlikely that we are ever going to have a phase 3 clinical trial evaluating patients who have received alectinib and then have RET fusion, and then they have this. We’re going to need to make some conclusions based on the biology that we’re seeing in front of us.

Benjamin Levy, MD: Becca, what is your parting shot here?

Rebecca Heist, MD: I agree. I am always surprised by what I find at biopsy, and that speaks to the fact that we can’t make assumptions about what’s happening at resistance. We actually need to look. Tumor biopsies, in my mind, are still the gold standard. We use more liquid, and if there’s not a safe biopsy option, that’s very reasonable. But for transformation to small cell, for multiple reasons, tumor biopsies are what I try to do as much as possible.

Benjamin Levy, MD: Those are all good points, and this is a very good discussion.

Transcript Edited for Clarity