New Biological Insights and Recent Therapeutic Advances in the Management of Lung Cancer: A Clinical Investigator Think Tank
Activity and tolerability of AZD9291 in EGFR inhibitor-resistant, advanced NSCLC with the T790M mutation
4:07 minutes.
TRANSCRIPTION:
DR OXNARD: I think it’s important to realize that these new EGFR inhibitors are not T790M inhibitors specifically. They are good mutant EGFR inhibitors, and they are intended to be not good wild-type EGFR inhibitors. And so they’re meant to have less toxicity than our first class of agents like erlotinib and afatinib and greater effect, because they also inhibit the resistance mutations. So it’s a really smart drug. And I think what’s nice about this trial is it was well designed. They took patients with EGFR mutations who’d had resistance and, in the first dosing cohort of 20 mg, they saw responses. I mean, when you can do a first in man trial and see dramatic responses in the first dose of the pill, that’s pretty impressive. And I think it highlights how good our science has become and how it’s informing our trial design. It was an international study. It became quite large quite quickly. They accrued dosing cohorts in T790M-positive and -negative resistance at multiple doses, from 20 to 240. And at all these doses, they did not see significant toxicities. They started to see a little bit more Grade 2 toxicity as they got up to 160 to 240 mg. And they said, “It’s not being tolerated as well.” It never reached an MTD, but it was causing dramatic responses. And so they picked 80 mg as that sweet spot where you had effect without significant toxicity. Remember, patients are on these drugs for a long time, and so even Grade 2 toxicity adds up and can be uncomfortable. DR LOVE: What kind of toxicities were seen at the higher dose? DR OXNARD: They show here a 5%, looks like a 5% incidence of — no. I think 5 patients — I’m sorry — with Grade 3 diarrhea, 5 patients with Grade 3 rash. And so out of 20 patients treated, that’s getting up there. It’s still not enough to achieve an MTD, but some of it. And the patients I’ve treated, yes, there are occasional cutaneous or diarrhea side effects, but certainly nothing like we see with our experience with erlotinib and afatinib. And the response rate in T790M-positive cancer was 64% in 107 patients, and so a really dramatic waterfall plot. The response rate in T790M-negative here was 22% in 50 patients, so clearly lower. And if you look at that even more closely, some of those patients maybe were re-responding because they’d had a break. If you look at patients who came immediately off TKI, it’s an 11% response rate in 28 patients who did not have T790M. Even a subset of those might have a hidden T790M clone, perhaps, but we think this is really a drug for one type of resistance and not for the other. DR LOVE: And what kind of trials are being done right now with this agent? DR OXNARD: The single-arm trials have completed. There are now randomized trials in the acquired resistance setting versus chemotherapy, first-line trials versus erlotinib, again, toward the idea that maybe this will be better tolerated. Right? Even if it doesn’t necessarily dramatically beat PFS, if it’s a drug that’s tolerated better than erlotinib and patients enjoy being on it more, that might be an advantage. And then there are combination studies adding this drug to other targeted therapies like MET inhibitor, MEK inhibitor, PD-1 inhibitor. DR LOVE: Right now, indirectly, how would you compare rociletinib to AZD9291, both in efficacy and tolerability, or can you really not do that? DR OXNARD: I don’t think we can do it much. I mean, the trials are so immature even with their follow-up. Both cause dramatic responses. I think there’s this — hyperglycemia is a unique characteristic of the CO-1686, which we don’t see with 9291, but otherwise, the uncommon side effects like QTc or pneumonitis, I’ve seen it with both drugs. I think we need the greater “n” to assess whether that’s really any different between them. DR LANGER: There were 5 cases of interstitial lung disease, the pneumonitis, and those can be showstoppers. So I’m far more concerned about that. It’s relatively rare, but I’m far more concerned about that in the long run than QTc prolongation. DR OXNARD: But some of those are asymptomatic, not requiring any change in therapy. The harder you look for it, the more you see it. It’s like the more EKGs you do, the more QTc changes you see. DR LOVE: So were any of those 5 cases clinically evident? DR LANGER: I’m not aware of that. DR OXNARD: A couple of them were. I mean, there definitely has been clinical pneumonitis with both of these drugs. |