Case 4: EGFR Mutation Analysis Post-Osimertinib

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARDBenjamin P. Levy, MD:Let’s go back to the case. Greg, do you want to talk about the mutational analysis that we’re seeing post-TKI [tyrosine kinase inhibitor]—the resistance, and the T790M in presence. Should we be testing for this after osimertinib? Is this something that you’re doing at Rutgers?

Gregory Riedlinger, MD, PhD:We haven’t seen a lot of first-line use with osimertinib. Typically, we’ve only seen it when a secondary T790M mutation has been detected. Then, we see these tertiary mutations, such as a C797S mutation, and think about other cysteine mutations that we’re actually trying to further characterize a bit. Because we haven’t seen osimertinib in the first line, maybe these patients lose the T790M when they’re treated with osimertinib? I don’t know what the experience is at your institutions, but we haven’t seen a lot of first-line use with osimertinib. So, it may be a bit different of a mutation spectrum.

Benjamin P. Levy, MD:Clearly, osimertinib has redefined what we do frontline. We move this wonderful T790M-directed therapy in the resistant setting up front. We compare it to a first-generation TKI [tyrosine kinase inhibitor]. It outperforms. We’re starting to see an overall survival trend. Soon, we’ll know whether or not that’s real. Are we routinely testing for mechanisms of resistance post-osimertinib, or is this something that we should be recommending to community oncologists? Before we talk about mechanisms of resistance and the relevance of C797S, is that something that you’re doing, Anne, at [The University of Texas] MD Anderson Cancer Center?

Anne S. Tsao, MD:We certainly do. We have clinical trials that target some of these mechanisms for exon 20 insertion mutations. We have poziotinib. ForHER2mutants with exon 20 insertions, we can give poziotinib. There’s also an ARIAD Pharmaceuticals drug. So, we actually do that. I do recommend it out in the community, but it’s not necessarily going to determine what that patient’s going to receive in the second-line setting.

Benjamin P. Levy, MD:Yes. Paul?

Paul K. Paik, MD:That’s an important point. In the era of first-line, first-generation TKI therapy, it was easy to recommend a biopsy at progression because it mattered, in terms of finding T790M. We don’t have that right now. And so, while we encourage it, it doesn’t really make too much of a practical difference outside of some small select cases. But, the onus is on us, in the academic community, to do the testing to find those things to be able to have the clinical ramifications to provide for the community.

Benjamin P. Levy, MD:Is there an opportunity for plasma here?

Anne S. Tsao, MD:I always do plasma.

Benjamin P. Levy, MD:If you’re going to do some sort of interrogation, it always starts with plasma.

Anne S. Tsao, MD:I always do. With first-generation EGFR TKIs, we got in the habit because they would often fail in the brain and we weren’t able to access tissue. With osimertinib, we’re seeing less CNS [central nervous system] failure. And so, we’ve been in the habit of doing that.

Benjamin P. Levy, MD:Are we using what we routinely find in these studies, these interrogations, be it plasma or tissue? Does C797S make a difference regarding what we do? We’ve had some data suggest that they may respond to a first-generation TKI. It may have to do with location or relevance to T790M. Is this something that’s truly, routinely actionable in clinical practice? Is there a message to the community of, “If you see this, go ahead and continue the osimertinib. Add back a first-generation TKI, or switch to a first-generation TKI.”?

Paul K. Paik, MD:I think it’s hard to make recommendations outside of some consolidated set of data. We don’t have the consolidated set of data. Again, the onus is on us to try to generate that. At our center, and even amongst oncologists, there’s a different threshold for utilizing those results versus moving forward with whatever the standard therapy might be.

Anne S. Tsao, MD:I confess that I’ve done it.

Benjamin P. Levy, MD:OK. You’ve used it to make a decision? You’ve put them on erlotinib or…

Anne S. Tsao, MD:I have continued osimertinib with erlotinib in 2 patients. One of the patients had a reestablishment of sensitivity and control of disease. The other one progressed.

Paul K. Paik, MD:I have very few qualms about doing that. I had a case whereMETamplification was the resistance mechanism. So, I added crizotinib to osimertinib.

Benjamin P. Levy, MD:We’ve done that. We’ve done that a few times.

Paul K. Paik, MD:And it’s worked. So, again, within reason, it’s reasonable to try. The question is, when? Looking at IMpower 150, how do we sort that temporally for the patient?

Transcript edited for clarity.