Transcript: Everett E. Vokes, MD: So, David, we’ve talked a lot about immuno-oncology and maybe we’ll transition briefly into the other major area of innovation in lung cancer over the last decade and a half, which is that of patients with a driver mutation. And you already earlier mentioned that for those patients immuno-oncology would not necessarily be the first thought, but targeted therapies are what are used [in] first-line [therapy]. And EGFR being the most common, certainly in a numerical sense as a driver mutation, where do you see the standard of care there now?
David R. Gandara, MD: Right. Well I think that’s a great question. Maybe I can start this off by actually just pointing out, since we just talked about immunotherapy, is that not only for EGFR and now ALK, but several other oncogene-driven subsets of lung cancer, it seems like immunotherapy is less effective. There’s recent data on patients with MET, exon-skipping mutations and some others. And I think that’s a cautionary tale because what it means is that unless we test upfront for those abnormalities, we won’t know that maybe immunotherapy isn’t their best option from day one. And we can include RET now among that. So that’s the first thing is that we the test, and we need the test with a broad enough test, maybe next-generation sequencing, so that we can pick up the abnormalities.
But to go back to the EGFR story, this is again a tsunami that has occurred where we now, and at least in the United States because of availability, the standard of care has largely become osimertinib, a third- generation EGFR TKI, which was developed specifically to block the T790M-resistance EGFR mutation that occurs after first or second generation TKIs. But it’s also a very good drug against the activating mutation such as exon 19 or L858R. We know from randomized trials, such as AURA3, that osimertinib is better than platinum chemotherapy, and that’s not surprising.
We now also know, based on the FLAURA randomized phase III trial, that osimertinib is superior to first- generation EGFR TKIs, either the investigator’s choice of gefitinib or erlotinib. We know that it’s superior for progression-free survival. We don’t yet know the overall survival data, although the trend is in the right direction.
Now that being said, in the United States this transition has already occurred. Worldwide, many countries do not have osimertinib available because I think the governments, the healthcare systems have said, it’s a great drug [for] second-line [therapy], let’s use it in that fashion.
At this ESMO meeting we heard for the first time a detailed analysis about mechanisms of acquired resistance to osimertinib, either when it’s used as a second-line therapy, or when it’s used first-line. And those came from analyses of the AURA3 study presented by Dr [Vassiliki A.] Papadimitrakopoulou [,MD], as well as the FLAURA trial presented by Suresh [S.] Ramalingam [,MD].
And I think we learned a lot from this analysis. Now that being said, it was blood, so it was circulating tumor DNA not based on tissue analysis. The availability of blood of course is universal. And they didn’t have follow-up tissue in these studies except on a small subset of patients. So, they decided to collect blood prospectively and it was analyzed by one of the commercially available platforms, the Guardant360 assay.
And in both of these analyses they were able to detect the synthesizing mutations still at the time of progression. And they were able to see what were, the mechanisms of acquired resistance. They also, in the FLAURA trial, had the comparator arm. In other words, that arm of patients that got gefitinib or erlotinib. And in that group of patients it was exactly what you would expect, about half the patients had T790M, and a smattering of patients had MET amplification, or multiple other mechanisms.
In the patients that received osimertinib in the AURA 3 trial, they still had multiple mechanisms, but, of course, they didn’t have emergence of T790M. It was still blocked, even at the time of progressive disease, by the osimertinib. But here the very interesting thing was that MET amplification really came up. And I think that’s particularly interesting because the presenter and the discussant pointed out that in blood, you may have less ability to see amplification, and yet it was quite prominent.
So to me that was a major message coming out of these analyses is that as we learn more about acquitted resistance, there’s going to be more emphasis on developing maybe upfront combinations. So if MET is a major factor, then there’s probably going to be rationale for using some of the several MET inhibitors that are in development in combination with osimertinib to head it off.
However, cancer is very clever, and I’m sure that then it will another way around that. I should have mentioned also that the C797 resistance mutation, which is fairly specific for third-generation inhibitors, was found in both subsets of these patients. But it wasn’t dominant. It wasn’t like T790M
Everett E. Vokes, MD: Don’t those sometimes respond back to first-generation agents?
David R. Gandara, MD: Yes, in theory they do, but if it is in conjunction with T790M where the best data are. In that situation it depends on how it is interacting with the T790M, whether it’s in cis or in trans. And what they pointed out in these analyses is that it was almost entirely in trans meaning that there would not be efficacy of the first- or second-generation agents. So I think depending on the clinical setting, there are studies trying to add gefitinib to osimertinib. But it may only work in certain situations.
Everett E. Vokes, MD: But I agree. The addition or the use of MET inhibitors is becoming very intriguing. And then I think it’ll be the same questions as before with osimertinib, do you add it at the time of progression if MET overamplification is the mechanism of resistance? Or do you try to pre-empt it from emerging by using it up-front? And toxicity profiles may guide us there a little bit, too, and interactions of these drugs. But I think that will be the next generation of trials to look at this.
David R. Gandara, MD: So it’s exciting times in immunotherapy. It’s exciting times in targeted therapy. Chemotherapy has made a comeback because we’re now giving it together with immunotherapy.
I think this closes our session. It’s been great to talk to you about some of these advances that are being made. And in many situations, I think for the practicing oncologist, there’s no replacement for clinical judgment. You can tell from Dr. Vokes and I discussing these things is we have data, and how you interpret it and how you apply that information can be quite varied, depending on where you practice around the world; depending on availability of tests like TMB [tumor mutational burden]; depending on availability of drugs. But as we move forward educational events, such as this one with OncLive®, I think will help all of us formulate our clinical judgments a little better.
Everett E. Vokes, MD: So thank you, David, I greatly enjoyed this discussion and hopefully it’ll be of use to our viewers.
David R. Gandara, MD: And thank you Ev as well, and thanks to OncLive® for supporting this educational event.
Transcript Edited for Clarity