Transcript
My name is Joshua Bauml. I'm an Assistant Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. We've recently seen the emergence of multiple small molecule tyrosine kinase inhibitors for the management of non–small-cell lung cancer (NSCLC) harboring a translocation in ALK.
The first one that came out was crizotinib. Then we had multiple second-generation ALK inhibitors that came out, notably alectinib, brigatinib, ceritinib, and now lorlatinib, a third-generation inhibitor.
We've seen in studies amongst patients who progressed on crizotinib or had progression on crizotinib that those patients can respond to these later-generation agents at a pretty good rate, regardless of mechanisms of resistance.
Initially, we thought, "Oh, this is great. We don't have to look for a mechanism of resistance." In truth, the reason that they were responding so well is that we know that most patients who experience progression while on crizotinib retain a wild-type ALK gene. That's likely because the degree of affinity for crizotinib to ALK is not very high.
In contrast, if we look at the other inhibitors, things like alectinib, brigatinib, and lorlatinib, they have a much higher affinity. At time of progression on one of these drugs, there's a much higher rate of resistance.
There have now been studies looking at moving these later-generation ALK inhibitors to the first line. There was some reason to believe that patients who were receiving brigatinib might do better than the other inhibitors because if you look at the later-line trials, brigatinib had one of the longest durations of response.
This year, at the ESMO Asia meeting, Dr. Camidge presented updated data on the ALTA-1L trial. This study compared outcomes of brigatinib versus crizotinib in the first-line management of NSCLC harboring an ALK translocation.
We'd already seen preliminary data at a prior meeting which revealed that brigatinib was, as expected and similar to what we've seen with alectinib, much better in terms of progression-free survival (PFS). At this updated data analysis, we continued to see a much better PFS with brigatinib than we saw with crizotinib on the trial.
The big question on everyone's mind when this study is presented is, how did these data square with the ALEX trial? The ALEX trial was a similar design, first-line management of patients with NSCLC harboring an ALK translocation of alectinib versus crizotinib.
These are 2 separate trials and different patient populations, but if you look at the PFS, outcomes are pretty similar. At this time, alectinib is the only drug that is FDA-approved for the first-line management of this sort of disease, but I imagine brigatinib will gain approval in the future.
How will we decide which drug to use? I think it's probably going to come down to toxicity. One of the major questions here, that remains unanswered, is "If the outcomes in later lines of therapy were so much better with brigatinib, why are the outcomes in first line not much better?"
I think probably that has to do with the heterogeneity inherent with later lines of treatment. When they've been exposed to crizotinib, for instance, in the first line, while most patients don't harbor a molecular mechanism of resistance, some could.
We didn't look in those second-line trials to evaluate for that. As a result, we don't know the contribution of those mechanisms of resistance to differential outcomes in the second-line trials.
At this point, I would say that alectinib remains the standard of care for the first-line management of non-small cell lung cancer harboring an ALK translocation, but if brigatinib were to gain FDA approval, I think it would be a very reasonable option to use in that setting.
