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Should Third Generation EGFR Inhibitors Be Used Before First Generation EGFR TKIs or After Progression?
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Drs. Leora Horn, Ben Solomon, & Jack West consider whether third generation EGFR TKIs, so active in patients with acquired resistance, might be best used prior to development of acquired resistance.


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Dr. West:  So let’s turn to the question of — you have agents like these third-generation EGFR inhibitors that have impressive activity in patients with acquired resistance after a prior, say, first-generation EGFR inhibitor like Iressa (gefitinib), Tarceva (erlotinib), or the second-generation inhibitor Gilotrif (afatinib). Those agents really have activity that seems limited to the first line setting, not much activity in acquired resistance. There’s going to be a temptation to move these later agents into the first line setting with the thought that maybe you can postpone, for much longer, acquired resistance — there’s certainly trials looking at this, but before we have the result of those trials, is that going to be something that you’re going to be tempted to do or recommend?

Dr. Horn:  Not unless I have a patient who maybe has a germline T790m mutation, so T790m at the time of diagnosis. I think that those trials need to come out and we need to see what the combined progression-free survival is, just of third-generation on its own, compared to progression-free survival with a first, followed by a third, and without that data, I’m not tempted to change my practice at this time.

Dr. West:  Ben, what do you think?

Dr. Solomon:  Yeah, I’m with Leora. I think they’re really important trials, the trials with both compounds in the first line, compared with first-generation inhibitors — and I guess the rationale is that you might be able to prevent and delay the emergence of resistance by targeting T790 right from the beginning, but we know resistance develops to these third-generation inhibitors. As well, they’re new mutations that prevent the third-generation inhibitors from binding to the EGFR, and it might be that you may not be able to rescue and make the tumor re-respond to another EGFR inhibitor later on down the track, so I don’t think we can presuppose the answer to these trials, but I think they’re important, and certainly, if the time that you can control the disease by using a third-generation inhibitor first is longer than you can by using a first-generation inhibitor, followed by a third-generation inhibitor, it’s going to change the way we all practice.

Dr. West:  Well, that’s a good point though, that these are all looking at progression-free survival as the primary endpoint, but that’s not really the key issue — it’s not whether a first-generation agent is less than a third-generation agent, as much as first-generation, followed by the third-generation, versus starting with the third-generation, because your goal isn’t just to get them to this coming Christmas, but have patients live many Christmases in the future, and, so, I think that, to me, seeing if it changes overall survival, or really, looking further beyond just one line of therapy is an important issue.

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