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Osimertinib for EGFR T790M Resistance Mutations in NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Tracey L. Evans, MD, University of Pennsylvania; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; Vali A. Papadimitrakopoulou, MD, The University of Texas MD Anderson Cancer Center; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Published: Wednesday, Mar 08, 2017


Transcript:

Mark Socinski, MD:
I find EGFR so completely fascinating because it has taught us so much. I think the T790M was described in 2005, like a year after the original description, but it’s taken us quite a long time to get an effective drug. Now we have osimertinib, and I think the package insert response rate is 66%; durable responses and very impressive Waterfall plots. But until recently, we didn’t have randomized data. In the old days, we would resist going to chemotherapy as the next step. But now we have data. Vali, do you know something about that data?

Vali Papadimitrakopoulou, MD: The impressive thing about these data from AURA3—that I reported at the meeting in Vienna recently—is they are randomized data that pretty much recapitulate everything else we knew in AURA1 and AURA2, the first two studies where the drug was given without a control in a phase I and a phase II expanded cohort. That doesn’t happen very frequently in oncology where you see the same response rate and the same progression-free survival being recapitulated.

Mark Socinski, MD: Our history is that most positive phase II trials are negative in phase III.

Vali Papadimitrakopoulou, MD: That’s right. So, that speaks to the validity of the original data, but also speaks to how the drug is useful for the patients. It really proves the value of the drug as an addition to the armamentarium for the T790M patients. Of course, the rest of the patients that have other resistance mechanisms are still not being addressed with this. But the data were impressive. There was a high difference in progression-free survival favoring osimertinib, 10 to 11 months, depending on who was doing the review—central review or investigator review.

Mark Socinski, MD: And this was against standard platinum-based doublets.

Vali Papadimitrakopoulou, MD: Versus about 4.4 months for the platinum/pemetrexed standard chemotherapy.

Mark Socinski, MD: Which is the standard going rate.

Vali Papadimitrakopoulou, MD: That’s right. And the hazard ratio was just very impressive; it was 0.3. Response rate was 71% for osimertinib in this phase III data, which is really the same mirror image of all the other data that we have seen. And, of course, the side effect profile favors osimertinib in this population. It’s easier to take a pill, it’s much less toxic, and people don’t have to worry about the side effects related to chemotherapy. So, I think that really establishes the role of the drug. It opens the door now for more investigation of other resistance mechanisms and also opens the door for, and the question of, what happens after osimertinib, which will be the next generation of trials.

Mark Socinski, MD: Right. Do we understand, yet, enough about resistance mechanisms to osimertinib? There have been a few things around, but no T790M story yet, right?

Tracey Evans, MD: C797S.

Mark Socinski, MD: I don’t know how much we know about that yet.

Vali Papadimitrakopoulou, MD: We have some knowledge of the frequency of alterations that we can see, but not a large population. Actually, this clinical trial, AURA3, has systematic collection of data from patients that progress on the drug and that will represent maybe one of the largest databases.

Tracey Evans, MD: Right. Every biopsy is important because of the C797S mutation, at present, but you lose T790. They can re-respond to first-generation EGFR TKIs, so you want to know when they progress on osimertinib if there is something you can take an action on.

Transcript Edited for Clarity
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Transcript:

Mark Socinski, MD:
I find EGFR so completely fascinating because it has taught us so much. I think the T790M was described in 2005, like a year after the original description, but it’s taken us quite a long time to get an effective drug. Now we have osimertinib, and I think the package insert response rate is 66%; durable responses and very impressive Waterfall plots. But until recently, we didn’t have randomized data. In the old days, we would resist going to chemotherapy as the next step. But now we have data. Vali, do you know something about that data?

Vali Papadimitrakopoulou, MD: The impressive thing about these data from AURA3—that I reported at the meeting in Vienna recently—is they are randomized data that pretty much recapitulate everything else we knew in AURA1 and AURA2, the first two studies where the drug was given without a control in a phase I and a phase II expanded cohort. That doesn’t happen very frequently in oncology where you see the same response rate and the same progression-free survival being recapitulated.

Mark Socinski, MD: Our history is that most positive phase II trials are negative in phase III.

Vali Papadimitrakopoulou, MD: That’s right. So, that speaks to the validity of the original data, but also speaks to how the drug is useful for the patients. It really proves the value of the drug as an addition to the armamentarium for the T790M patients. Of course, the rest of the patients that have other resistance mechanisms are still not being addressed with this. But the data were impressive. There was a high difference in progression-free survival favoring osimertinib, 10 to 11 months, depending on who was doing the review—central review or investigator review.

Mark Socinski, MD: And this was against standard platinum-based doublets.

Vali Papadimitrakopoulou, MD: Versus about 4.4 months for the platinum/pemetrexed standard chemotherapy.

Mark Socinski, MD: Which is the standard going rate.

Vali Papadimitrakopoulou, MD: That’s right. And the hazard ratio was just very impressive; it was 0.3. Response rate was 71% for osimertinib in this phase III data, which is really the same mirror image of all the other data that we have seen. And, of course, the side effect profile favors osimertinib in this population. It’s easier to take a pill, it’s much less toxic, and people don’t have to worry about the side effects related to chemotherapy. So, I think that really establishes the role of the drug. It opens the door now for more investigation of other resistance mechanisms and also opens the door for, and the question of, what happens after osimertinib, which will be the next generation of trials.

Mark Socinski, MD: Right. Do we understand, yet, enough about resistance mechanisms to osimertinib? There have been a few things around, but no T790M story yet, right?

Tracey Evans, MD: C797S.

Mark Socinski, MD: I don’t know how much we know about that yet.

Vali Papadimitrakopoulou, MD: We have some knowledge of the frequency of alterations that we can see, but not a large population. Actually, this clinical trial, AURA3, has systematic collection of data from patients that progress on the drug and that will represent maybe one of the largest databases.

Tracey Evans, MD: Right. Every biopsy is important because of the C797S mutation, at present, but you lose T790. They can re-respond to first-generation EGFR TKIs, so you want to know when they progress on osimertinib if there is something you can take an action on.

Transcript Edited for Clarity
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