Transcript:Mark Socinski, MD: The AURA3 data were very impressive, and they were the icing on the cake of the story of osimertinib from phase I all the way to phase III. Jared, we mostly think that if drugs work better in the second-line setting, they’re going to work better in the first-line setting. We do have some data on osimertinib in the first-line setting. What’s your perspective there?

Jared Weiss, MD: Well, I think there’s a lot of wind-to-the-sails of that idea from the J-ALEX data, which asked the same question with crizotinib, where I think we were surprised at just how much better the next-generation ALK agent was than the first-generation; it exceeded the preceding data. So, we do have some actual data here. We have expansion phase I data from osimertinib in the frontline setting that gave us a median PFS over 19 months and excellent safety data. That led to a randomized phase III trial of first-generation versus third-generation treatment, which I think is a very appropriate and ethical trial not only for the hopes of preventing resistance, but in contrast to a lot of our other next-generation drugs. Historically, our next-generation has been rougher than our first-generation. In contrast, osimertinib is a very specific and very well-tolerated agent compared to the first- and second-generation TKIs. This trial offers the hope not only of preventing or delaying the emergence of resistance and maybe getting a longer PFS—a lot like what we saw in J-ALEX for ALK—but perhaps also reducing toxicity along the way. These are not patients on treatment for a few weeks or a few months, like we’re used to thinking with chemotherapy. These are patients who we may well be counting in years. And so, that reduction in toxicity, particularly around diarrhea, could be rather relevant to quality of life.

Mark Socinski, MD: It’s the FLAURA trial. I think it completed its accrual. I think it’s an important trial. But getting back to actually a slightly different point. Jared mentioned the median PFS in the first about 19 months and a change. How much?

Tracey Evans, MD: Right. We got about 10 months from the first-generation, followed by the third-generation.

Mark Socinski, MD: Are we ready to dismiss that sequencing? It brings up a lot of sequencing issues.

Jared Weiss, MD: We don’t know. In ALK, if you had added up the numbers, you would have expected, from J-ALEX, a hazard ratio of roughly 0.5, but we didn’t. We got a whole lot better than that. And so, I think the key point for thinking about this trial is we just don’t know. It could be better, a lot like we saw with ALK. It could be the same. It could just be additive or, for all we know, we could be very wrong and it could be worse.

Tracey Evans, MD: But we’re looking at PFS, right? I’m a little worried about the effect on overall survival because it means we have less. What is the resistance pattern going to be when people become resistant and are we going to have fewer overall options? And will our overall availability of treatment not lead to as good an overall survival if we start with our best stuff?

Alexander Drilon, MD: Just to add another layer to this, to me: an additional advantage of doing osimertinib in the first-line setting is its CNS coverage. And even at the 80-mg dose, you can see significant intracranial disease control with osimertinib. So, you have the additional element of preventing relapse in the brain or preventing the appearance of brain metastases, which is valuable.

Mark Socinski, MD: That’s actually what I was going to come back to Tracey with, with the next issue.

Tracey Evans, MD: Yes, I’m glad you brought that up. The BLOOM trial that was presented at ASCO this past year, there were 2 phases to that. One was the demonstration of efficacy on brain metastases of a new drug, an EGFR TKI from AstraZeneca, that’s designed to have better blood—brain penetration. But they also presented data on osimertinib dosed at twice the usual dose, 160 mg, in patients who usually we consider the worst of the worst. These were patients with CSF (cerebrospinal fluid)-established leptomeningeal disease, a patient population that historically has only survived a couple of weeks. The treatments we have for these patients are terrible: either intrathecal chemotherapy or craniospinal radiation, neither of which work very well. And you’re perfectly within your rights to not treat these patients that way and to refer them for comfort care. They took 20 of these patients and they gave them 160 mg of osimertinib. Twelve patients were around and doing well 12 weeks later, and 7 of those patients were symptomatic and 3 of them had improvement in their symptoms. There was demonstrated efficacy. All these patients were positive for T790, so it looks very promising for the blood–brain penetration for this agent and that we can salvage patients that we previously thought not salvageable. I had a patient who is actually just on standard-dose osimertinib and who has had her leptomeningeal disease controlled now for 1 year on this agent. So, that’s very impressive.

Mark Socinski, MD: Yes. It’s certainly a huge unmet need in a very frustrating clinical situation, which patients are in.

Tracey Evans, MD: Right. And I think the first-line agents do have some efficacy in the brain. I’ve treated patients with first-generation agents who had asymptomatic subcentimeter brain metastases. I put them on erlotinib and saw responses. And then when people progress in the CNS, we’ve tried pulse dosing, where people take 10 pills once a week to try to get the blood levels for better blood-brain penetration. But, yes, these agents are effective within the brain, which is exciting.

Mark Socinski, MD: And then, Vali, I’d like you to comment on the story with icotinib. We have actually some randomized data with the old standard whole brain, which no one likes.

Vali Papadimitrakopoulou, MD: This is to augment the point that Tracey just made that all these agents, even the first-generation agents, have activity in the brain. And the study was comparing a standard approach to treatment of brain metastases. Actually, out of these patients that were treated in this trial from China, about 16% to 20% had symptomatic brain metastases with the standard approach, which is radiation therapy and standard chemotherapy versus icotinib, a first-generation EGFR TKI. And the end result of this trial, bottom line is that icotinib was better at every parameter that was looked at, including intracranial progression-free survival, overall progression-free survival, and response rate of these lesions. The only thing that wasn’t different was overall survival, which we didn’t really expect. So, this confirms what we have known, but never had done a study for here in the United States or in other countries: that these drugs work better than standard therapy.

Mark Socinski, MD: Yes. It’s an important study. And we really need to engage our radiation colleagues because so often we see them, the knee jerk reflexes, to do whole brain radiotherapy. And this is a population that tends to have much longer survival, so the potential toxicity of [the] whole brain is more pertinent in that population. I think it’s important. This has been great. We’re 13 years into EGFR mutations and look where we’ve come in just a relatively short period of time.

Transcript Edited for Clarity