Resistance Mechanisms in EGFR+ NSCLC

Transcript:

John V. Heymach, MD, PhD: What are you going to do with these cells that can’t be killed by osimertinib, these residual tumors? We have one testing consolidative therapy with radiation and surgery to try to eradicate it. I think those were all great questions, but at least to me we’ve got at least a backbone that we can ask those questions on top of, from my perspective. And I think we’re about to enter a more complicated era of a resistance.

Mark A. Socinski, MD: Yeah, I was going to ask you, what do we know about resistance to osimertinib?

John V. Heymach, MD, PhD: Yeah. Well you know, life was a little simpler when we had erlotinib and gefitinib in and a single mutation, T790M, was at least half, 50% to 60% of resistance. You know we just had 3 studies come out in the last couple of months. One from the MGH group, the trial, the one from Dana-Farber Cancer Institute, Geoffrey R. Oxnard, MD, and one from the Shingly and our group and Moffitt Cancer Center. And all of them say, have the same basic point, which is, if you look at osimertinib resistance, you get diverse and largely EGFR-independent mechanisms. So in all the studies, sometimes you see fusions, RET fusions, ALK fusions, ROS1 fusions. Sometimes you see the KRAS pathway get turned on or PIK3ca. In all the studies, MET amplification is about a quarter of the patients, and that’s an important mechanism. And in about a quarter of the patients you get additional EGFR mutations. They’re mainly C797S, and the L792H mutations.

So where we had a pretty simple space before and then a drug to target it, now we’ve got a quarter with diverse EGFR mutations, a quarter with MET amplifications, and then half of them, they have just a wild mix. I think a lot of those are mesenchymal tumors. So it means we’re going to need to be more imaginative in our next generation of how we tackle resistance.

Mark A. Socinski, MD: Yeah. And before we leave that point, I want to get your perspective on, you know we know that all EGFR mutations are not created equal. Some are more sensitive than others, some are resistant. You’ve done some work in the exon 20 insertions, and now we have a couple of drugs targeting that. Could you review that for us?

John V. Heymach, MD, PhD: Yeah. And just to remind people. You know we think about 80% of EGFR mutations are classical mutations. So the exon 19 deletion, or the LA58R. But about 20% are atypical. And out of atypicals, or nonclassical, about half of them are in exon 20, and then half of them are outside of exon 20. The ones, the atypicals outside of exon 20 include the G719, the L861, and the, there’s another one called S768i. Now that one’s actually in exon 20, it’s a point mutation.

Afatinib was just FDA approved for those 3 atypicals. Those are 3 of the more common atypicals. But we’ve never had any drugs before that had substantial activity within exon 20. And now exon 20, there’s diverse mutations there. Most are insertions. And all these insertions impact the binding pocket for drugs to make the binding pocket smaller and sort of, it’s got a big lump in the middle where you need a molecule that can sort of squeeze around and twist.

So we spent a lot of time modeling this and testing drugs, and it turned out there was a drug that was developed for a T7090M EGFR, poziotinib. It turned out to not be as good as other drugs like osimertinib so it was discontinued for lung cancer. But it turned out it had those properties that while it wasn’t a good T790M inhibitor, it was a very good exon 20inhibitor. So we tested this and then we just reported on the first 50 patients with EGFR mutations. The best objective response in that study was 55%. Confirmed objective responses, and they didn’t get confirmed until 4 months, it was 43%. And PFS [progression-free survival] is about 6 months. So it tells us the drugs are clearly active in that space. They don’t have the duration of response that we see with drugs like osimertinib for classical mutations. That’s likely because the pocket is a much tougher one to inhibit. It’s much together to differentiate it from the wild-type receptor, but the good news is this population now has drugs that are at least active to test.

There’s data presented for TAK-788, that’s another drug in the space. That also has activity. Their studies are, there’s a few of the patients have been tested, but there’s activity there. There’s a new compound from Daiichi Sankyo that’s also going along. And for HER2 exon 20, a similar issue. The poziotinib is, has demonstrated activity there as well, but there we also have HER2 antibody—drug conjugates. There’s one, there’s T-DM1, a study that shows activity there. And an antibody–drug conjugate from Daiichi Sankyo that shows activity there.

So I think the big take home, you know we’ll need a little more data before any of these drugs can go through and be available for patients. But the good news is we at least now have drugs that are active in that space and something to build on.

Mark A. Socinski, MD: And the clinical trials are accruing, actually quite well.

John V. Heymach, MD, PhD: Clinical trials, you know, in addition to our The University of Texas MD Anderson [Cancer Center] study, there’s been a large international study for poziotinib, and we’ll be hearing results about that in the near future, so I’m looking forward that.

Mohammad Jahanzeb, MD: And double dose osimertinib is also being looked at in that population.

Transcript Edited for Clarity