Precision Medicine in Advanced Non-Small Cell Lung Cancer - Episode 4

Resistance Mechanisms in EGFR-Positive NSCLC


Benjamin P. Levy, MD: So, best drug first? Osimertinib, I think, in all of our minds, moves up front. I think that’s very exciting for us. It’s very exciting for patients, given all of the things that we’ve highlighted here. So, what do we do next? You get to the progression-free survival median at 19 months, and we have some patients who are, perhaps, on it longer. The question always comes up, and I used to know what to do. I had a patient on erlotinib. It was a cool story. I could do a plasma interrogation for T790M. If it was positive, I could give them osimertinib. We’ve now moved osimertinib up front. I think all of us agree with that. What are the next steps? What are the mechanisms of resistance that we know about with osimertinib? There is not a clear graph like we had with the first- or second-generation TKI mechanisms of resistance. Alex, do you have any thoughts on that, in terms of mechanisms of resistance?

Alexander Drilon, MD: I think Zofia should be talking about this because her data on this have recently been featured.

Benjamin P. Levy, MD: We’ll redirect to Zofia. You presented some nice work, in terms of C797S. Can you walk us through some of the mechanisms of resistance?

Zofia Piotrowska, MD: Yes. The first thing I have to say is that most of the work on osimertinib resistance that has been done to date has really been done in patients who were treated with osimertinib in the second-line or beyond settings. Patients had already developed T790M and had acquired resistance to first- and second-generation EGFR inhibitors.

What we don’t know yet is what resistance will look like to osimertinib in the frontline setting, although we extrapolate that there will be a lot of overlap with what we’ve seen in later lines of therapy. In those later lines of therapy, we’ve seen many of the same resistance mechanisms that we have seen in resistance to first- and second-generation EGFR inhibitors. But importantly, we’ve seen a new resistance mutation, the EGFR C797S mutation, which blocks the covalent bond formation between osimertinib and the targets. This has been a challenge. We don’t yet have the next drug to overcome that, although we hopefully will at some point. As you alluded to, we’ve looked at the context within which C797S occurs, whether it’s on the same allele or a differing allele than T790M. In a majority of patients, we’ve seen that it’s actually in the cis configuration on the same allele as T790M, and that’s really relevant. In preclinical models, we’ve seen that C797S and T790M, on the same allele, has been refractory to all currently available EGFR inhibitors.

We have also seen other bypass pathway activation—for example, MET amplification—which may actually be a little bit more prevalent after osimertinib than after the first- and second-generation drugs. In a small cohort of patients, we’ve seen that in up to 30% of patients. That’s promising because there are potential options to treat those patients with MET inhibitors on clinical trials, as well as with crizotinib in combination with osimertinib. There have been some published data there.

And then, as you alluded to, the rest of the pie chart becomes kind of scattered. We’ve seen BRAF mutations and other things. It’s also complicated by the fact that a lot of this data have been done in the plasma; less so in the tissue. The important questions are going to be, what does resistance look like after first-line osimertinib, and how can we overcome that?

Alexander Drilon, MD: I’m going to jump in and say that I think that beyond looking into drugging these other mechanisms, from a practical standpoint, if you have someone who receives first-line osimertinib and then progresses, the answer is chemotherapy.

Zofia Piotrowska, MD: I agree.

Alexander Drilon, MD: Something that has been a little bit more provocative have been the results from the recent platinum/pemetrexed and pembrolizumab trial. In a subset analysis, it seemed like the EGFR-mutant patients benefited. I’ll underscore the fact that those patients already had used a TKI. So, it may be something that we use, but we might also want to be a little bit more cognizant about potentially emerging toxicities if you give immunotherapy with chemotherapy after a prior TKI.

Benjamin P. Levy, MD: The IMpower trial—this is carboplatin, paclitaxel, bevacizumab, atezolizumab. This is one of the trials that showed the benefit in terms of EGFR and ALK. I think that regimen needs to be further explored for EGFR-mutant lung cancer patients.

Transcript Edited for Clarity