DR GOVINDAN: This study was targeting a group of patients who had prior EGFR TK inhibitors, and about 56 patients were enrolled at the time of presentation. But the bottom line is the focus on the group of patients who got the 900-mg dose twice a day. Remember, this is a Phase I study with a wide range of doses. So the real attention, eye-popping numbers came. When we look at those 9 patients who got the full dose, 900 milligrams twice a day, who had EGFR T790M mutation, 8 out of 9 actually had a nice response, again, this is too early. We have been here before, but these numbers are quite impressive. And I think only time will tell whether — first of all, we have to know what the right dose is. There’s a new formulation.
DR LOVE: Greg, of course afatinib is an irreversible inhibitor and dacomitinib is an irreversible inhibitor, but they clearly do cause EGFR on-target effects.
DR RIELY: Both these drugs were not developed against wild-type EGFR. We have to remember back to when people discovered gefitinib and erlotinib. They were working against the premise that epidermal growth factor receptor, EGFR, is overexpressed in cancer. And so we got a target, that overexpressed molecule. So let’s target wild-type EGFR. So that’s how those drugs were developed. They do a good job of hitting that target.
These drugs were actually developed against mutant forms of EGFR. So they’re refined to hit that target much better than wild-type EGFR. And that’s the key component, not the reversible or irreversible nature, but that these are mutant-specific EGFR inhibitors.
DR LOVE: But it seems like dose hasn’t been that much of an issue, even the idea that you can use a lower dose with mutants. But is there any reason to think that if you could go up higher on erlotinib or gefitinib that you might see greater activity?
DR RIELY: We’ve actually worked a lot in that area of giving higher doses of erlotinib, giving higher doses of erlotinib by itself, giving higher doses of erlotinib in combination with chemotherapy. And there are certain situations in which it makes some sense, maybe targeting brain metastases. But in the main treatment of non-small cell lung cancer with EGFR mutations, you don’t get significant benefit by simply giving high dose.